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Constitutional risk factors in prostate cancer
Actas Urol Esp. 2011;35(5):282---288
Actas Urológicas Españolas www.elsevier.es/actasuro
REVIEW ARTICLE
Constitutional risk factors in prostate cancer夽 J. Ferrís-i-Tortajada a,∗ , J. García-i-Castell b , O. Berbel-Tornero c , J.A. Ortega-García d a
Unidad de Salud Medioambiental Pediátrica, Unidad de Oncología Pediátrica, Hospital Infantil Universitario La Fe, Valencia, Spain b Sección de Anatomía Patológica, Hospital de Sagunto, Valencia, Spain c Centro de Salud de Chella, Chella, Valencia, Spain d Unidad de Salud Medioambiental Pediátrica, Hospital Materno-Infantil Universitario Virgen de la Arrixaca, Murcia, Spain Received 21 December 2010; accepted 21 December 2010 Available online 9 August 2011
KEYWORDS Prostate cancer; Constitutional risk factors; Carcinogenesis; Epidemiology
Abstract Introduction: The aim of this review is to update and divulge the main constitutional risk factors involved in the etiopathology of prostate cancer. Materials and methods: Bibliographic review of the scientific literature on the constitutional risk factors associated with prostate cancer between 1985 and 2010, obtained from MedLine, CancerLit, Science Citation Index and Embase. The search profiles were Risk Factors, Genetic Factors, Genetic Polymorphisms, Genomics, Etiology, Epidemiology, Hormonal Factors, Endocrinology, Primary Prevention and Prostate Cancer. Results: The principal constitutional risk factors are: age (before the age of 50 years at least 0.7% of these neoplasms are diagnosed and between 75 and 85% are diagnosed after the age of 65 years), ethnic---racial and geographic (African Americans present the highest incidence rates, and the lowest are found in South East Asia), genetic, family and hereditary (family syndromes cover 13---26% of all prostate cancers, of which 5% are of autosomal dominant inheritance), hormonal (it is a hormone-dependent tumor), anthropometric (obesity increases the risk), perinatal, arterial hypertension and type 2 diabetes. Conclusions: Constitutional risk factors play a very important role in the etiopathology of prostate cancer, especially age, ethnic---racial---geographic factors and genetic---family factors. We cannot know what percentage of these neoplasms are a result of constitutional factors because our knowledge of these factors is currently lacking. © 2010 AEU. Published by Elsevier España, S.L. All rights reserved.
夽 Please cite this article as: Ferrís-i-Tortajada J, et al. Factores de riesgo constitucionales en el cáncer de próstata. Actas Urol Esp. 2011;35:282---8. ∗ Corresponding author. E-mail address: ferris [email protected] (J. Ferrís-i-Tortajada).
2173-5786/$ – see front matter © 2010 AEU. Published by Elsevier España, S.L. All rights reserved.
Constitutional risk factors in prostate cancer
PALABRAS CLAVE Cáncer de próstata; Factores de riesgo constitucionales; Carcinogénesis; Epidemiología
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Factores de riesgo constitucionales en el cáncer de próstata Resumen Introducción: en esta revisión se pretende actualizar y divulgar los principales factores de riesgo constitucionales implicados en la etiopatogenia del cáncer de próstata. Material y métodos: revisión bibliográfica de la literatura científica acerca de los factores de riesgo constitucionales asociados a cáncer de próstata entre 1985 y 2010, obtenida de MedLine, CancerLit, Science Citation Index y Embase. Los perfiles de búsqueda han sido Risk Factors, Genetic Factors, Genetic Polymorphisms, Genomics, Etiology, Epidemiology, Hormonal Factors, Endocrinology, Primary Prevention y Prostate Cancer. Resultados: los principales factores de riesgo constitucionales son: edad (antes de los 50 a˜ nos se diagnostican menos del 0,7% de estas neoplasias y en mayores de 65 a˜ nos, entre el 75-85%), étnico-raciales y geográficos (los afroamericanos presentan las mayores tasas de incidencia y las más bajas en el sudeste asiático), genéticos, familiares y hereditarios (los síndromes familiares engloban el 13-26% de todos los cánceres de próstata, de los cuales el 5% se heredan de forma autosómica dominante), hormonales (es un tumor hormonodependiente), antropométricos (la obesidad incrementa el riesgo), perinatales, hipertensión arterial y diabetes tipo 2. Conclusiones: los factores de riesgo constitucionales desarrollan un papel muy importante en la etiopatogenia del cáncer prostático, especialmente la edad, los factores étnico-racialesgeográficos y los factores genético-familiares. No podemos saber qué porcentaje de estas neoplasias se atribuye a factores constitucionales, porque el conocimiento de dichos factores es actualmente incompleto. © 2010 AEU. Publicado por Elsevier España, S.L. Todos los derechos reservados.
Introduction Globally one-third of all cancers in men are urological neoplasias and prostate cancer is the most common of them.1 It is also the most common non-cutaneous cancer in men in most industrialized countries. Likewise, and despite the advances made in its early diagnosis, treatment and increased survival, it is the second leading cause of cancer death after bronchopulmonary cancer in these countries.1 In Europe, in 2008, 382,300 new cases were diagnosed and 89,300 patients died.2 In the U.S., 192,280 new cases were diagnosed in 2009 and 27,360 died.3 Given the high incidence and significant mortality, primary prevention is one of the major health challenges to reduce the personal, social and economic impact it entails.4 Our intention here is to review and update the major constitutional risk factors, with more or less scientific evidence, associated with the development of this disease, based on concise bibliographic research.
Constitutional factors Age It is one of the most important risk factors.5---7 There is a directly proportional relationship between increasing age and greater risk of developing prostate cancer. Less than 0.6% of all cases are diagnosed before the age of 45, and between 62% and 85% after the age of 65 years.5,6 In the U.S., the risk of developing prostate cancer between birth and 39 years of age is 0.01 (one case out of 10,002 men). Between the ages of 40 and 59 years, it is 2.43 (one case out of 41 men). For men between 60 and 69 years, it is 6.42
(one case out of every 16 men). Finally, at age 70, the risk is 12.49 (one case out of 8 men).3 In the white population of the U.S. aged between 75 and 79 years, the risk is 130 times higher than in the 45---49 years age bracket.5 In addition to the age factor, this significant difference also reflects the increase associated with systematic PSA screening and rectal examination as of 50 years of age.5 The introduction of this screening has generated an age migration, with a 50% increase of cases in men aged 50---59 years. With age, atypical small acinar proliferation and prostatic intraepithelial neoplasia (PIN) appear. The development of low-grade PIN requires a minimum latency period of 20 years. Its transformation to high-grade PIN requires more than 10 additional years and, to become clinically detectable carcinoma, it further requires an evolutionary period of 3---15 years.5
Racial/ethnic and geographical factors There are significant variations in the annual incidence of age-adjusted prostate cancer among countries and ethnic and racial groups.1,2,5,8 We found the world’s highest rates in America, exceeding 270 new cases per 100,000 males per year among African Americans in the U.S. and Caribbean islands of Trinidad, Tobago, Martinique and Jamaica. The reasons for this 60% higher risk in African Americans and 38% lower risk in Asian Americans in comparison to white Caucasians, are still elusive. Asia is the continent with the lowest incidence worldwide; however, there are differences among its countries. The more westernized countries such as Japan and Israel have rates of 20---50 new cases per 100,000 males per year, while India, Thailand, Pakistan and China have the lowest
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Table 1 Variability in the incidence of prostate cancer in Europe in 2008. Europe and regions
Incidencea
Europe.. .. .. .. .. .. .. .. .. .. .. .. ... . Western Europe. .. .. .. .. .. .. .. ... Northern Europe. .. .. .. .. .. .. .. .. .. ... Southern Europe.. .. .. .. .. .. .. .. .. .. .. ... Central/Eastern Europe. .. .. .. .. ... .
93.4 142.3 131.3 78.7 42.0
Countries with highest incidence Ireland.. .. .. .. .. .. .. .. .. .. .. .. .. ... France.. .. .. .. .. .. .. .. .. .. .. .. .. ... Norway.. .. .. .. .. .. .. .. .. .. .. .. ... . Sweden.. .. .. .. .. .. .. .. .. .. .. .. .. ... . Iceland.. .. .. .. .. .. .. .. .. .. .. .. ... . Belgium. .. .. .. .. .. .. .. .. .. .. .. .. ... Finland. .. .. .. .. .. .. .. .. .. .. .. ... Switzerland.. .. .. .. .. .. .. .. .. .. .. .. .. ... . Germany. .. .. .. .. .. .. .. .. .. .. .. ... Austria.. .. .. .. .. .. .. .. .. .. .. .. ... .
183.1 178.7 172.7 168.6 153.3 152.9 145.3 137.1 125.6 122.6
Countries with lowest incidence Moldova.. .. .. .. .. .. .. .. .. .. .. .. ... Ukraine.. .. .. .. .. .. .. .. .. .. .. .. ... . Albania.. .. .. .. .. .. .. .. .. .. .. .. ... . Greece.. .. .. .. .. .. .. .. .. .. .. .. .. ... Romania. .. .. .. .. .. .. .. .. .. .. .. ... . Montenegro.. .. .. .. .. .. .. .. .. .. .. ... Serbia.. .. .. .. .. .. .. .. .. .. .. .. .. ... . Macedonia.. .. .. .. .. .. .. .. .. .. .. ... . Russian Federation.. .. .. .. .. .. .. .. .. ... Bulgaria.. .. .. .. .. .. .. .. .. .. .. .. ...
23.3 27.7 30.7 31.1 32.0 31.9 32.9 33.9 34.3 35.6
Adapted from Ferlay et al.2 a Rate of incidence per 100,000 males.
rates, which range from 1.4 to 8.4 new cases per 100,000 males per year. In 2008, 382,300 patients were diagnosed in Europe, which corresponds to an estimated incidence of 93.4 new cases per 100,000 males; 89,300 patients died.2 Comparing the data obtained in 1995, we noted a dramatic increase in incidence, which almost doubled the rate of 47.4 for that year.8 In our continent, the incidence also varies greatly between regions and countries (Table 1); in the region with the highest incidence, it is 3.4 times higher than that of the region with the lowest incidence, and in the country with the highest incidence, it is 7.8 times higher in the country with the lowest incidence. With respect to countries, the huge difference between Ireland, with 32.3, and Moldova with 183.1 new cases per 100,000 males, is worth mentioning. Spain occupies an intermediate position with 88.9, behind Italy with 91.2 and preceding Portugal and Malta with 76.6 cases per 100,000 males.
Genetic, familial and hereditary factors Like all cancers, prostate cancer is a genetic disease caused by the accumulation of chromosomal mutations generated by the clonal selection of aggressive cells. In the vast majority of cases, the mutations are somatic and only occur in
the tumoral cells of the prostate epithelium. When some mutations are present in germ cells, they are passed from generation to generation and are present in all body cells, including the prostate, logically. This gives rise to familial syndromes of prostate cancer, which are between 13% and 26% of the total of these tumors.9---13 In the majority of these syndromes, the mutations are allelic and low-penetrance; however, in 5%, the mutations are high-penetrance and transmitted as autosomal dominant, following the classic patterns of Mendelian inheritance (Table 2). These highpenetrance mutations give rise to strictly hereditary forms of prostate cancer. Clinically, familial syndromes of prostate cancer occur at younger ages than sporadic syndromes, representing 43% of those under 70 years of age and only 9% of those diagnosed at 85 years of age. The familial hereditary variety is diagnosed before 55 years of age, and although some subvarieties are associated with increased biological aggressiveness, overall, it has not been sufficiently proven that they entail a worse prognosis than sporadic forms.9 Another clinical characteristic of familial prostate cancers is the coexistence of two or more cases in first and second-degree relatives. Numerous epidemiological studies have documented that the siblings and children of a patient with prostate cancer have a 2---3 times greater risk of developing the disease than expected for their age, ethnicity and geographic location. The risk increases in accordance with the number of sick family members. Thus, for one family member affected, the relative risk is 2; if two family members are sick, the relative risk is 5, and in the case of three affected family members, the relative risk is 11. To suspect the hereditary variety, clinical criteria are stricter and are: (a) three or more first-degree relatives affected, (b) at least three cases in first and second-degree relatives, taking into account X-linked transmission, and (c) two firstdegree relatives diagnosed before age 55. In the inherited form with autosomal dominant inheritance, there is a sexlinked mode, in which females are carriers and transmit it to their children. This method probably underestimates the actual number of cases, since the disease skips one or more generations. Some families with prostate cancer also have an increased risk of suffering other malignancies (breast, ovary, brain, etc.), due to the coexistence of mutations in the germ cells that give rise to different neoplasias. The necessary interaction between genetic and environmental factors is demonstrated by studies of prostate cancer in twins. In homozygotes, the healthy brother has an 18% higher absolute risk than expected to develop the process, while in dizygotic twins, it is only 3%.9 Advances in biogenetics have allowed identifying the numerous allelic low-penetrance mutations denominated genetic polymorphisms, which are involved in the rest of familial forms of prostate cancer and which, as they are relatively more frequent, are found in far more cases than in strictly familial cancers. Thus, some authors attribute up to 40% of all prostate cancers to genetic factors. The greatest risk is caused by the involvement of the metabolic pathways mentioned in Table 3, which increase the neoplastic transformation of prostate epithelial cells.10---13
Constitutional risk factors in prostate cancer Table 2
285
Main genes involved in the hereditary formation of familial prostate cancer.
Chromosomal location
Gene
Characteristics
1q24---25 1q42---43 Xp11 Xp27---28 17p11 20q13 5q31---33 7q32 19q12---13 1p36 10q25 8p22---23 17q24 16q23 8q24 (region 1)
HPC1 PCaP --HPCX HPC2 HPC20
Autosomal dominant inheritance. Associated with brain tumors Autosomal dominant inheritance Sex-related inheritance Sex-related inheritance
8q24 (region 2) 8q24 (region 3) 2p15; 3p12; 6q25 7p21; 10q11; 10q26 11q13; 17q12 17q21; 13q12---13
Very aggressive clinical evolutionary forms
CAPB PRCA1 PG1/MSR1 ELAC2
Associated with brain tumors
Very aggressive clinical evolutionary forms association with colorectal, breast, ovary and urinary bladder cancers
BRCA1; BRCA2
Hereditary breast and ovarian cancer
Adapted from Platz and Giovannucci5 and Cussenot and Cancel-Tassin.9
Hormonal factors Androgens influence the development, maturation and growth of the prostate and affect both the proliferation and the differentiation of its epithelium.7,14---18 Testosterone, the main circulating androgen, and dihydrotestosterone, the main tissue androgen, are the two most important androgens. The second is synthesized from the first by 5 ␣ reductase, isoenzyme type 1 (skin and hair) and type 2 Table 3
(prostate, skin and genitals). The action of androgens in prostate cells is mediated by the androgen receptor, which leads to the activation of transcription of genes involved in DNA synthesis and cell proliferation. Numerous prospective studies have investigated the role of plasmatic androgens on prostate cancer, but few have demonstrated that men with elevated serum androgen levels have an increased risk of developing the disease. In the Physician’s Health Study Cohort16 increased risk
Main low-penetrance genetic polymorphisms and prostate cancer.
Gene (marker) Biosynthesis and androgenic metabolism CYP17 (MspA1); CYP19 (TTTA repeats, N264C); SRD5A2 (V89L, A49T, R227Q, TA repeats); AR (CAG repeats, GGN repeats, E211 G > A); HSD3B1 (N367T, c7062t); HSD3B2 (c7159g, c7474t); HSD17B3 (G289S); ER-alpha (XbaI, PvuII); ER-beta (RsaI) Growth factors and non-androgenic hormonal pathway VDR (BsmI, TaqI, polyA, ApaI, FOPI); INS (+1127PstI); TH (-4217PstI); IRS1 (G972R); IRS2 (G1079D); IGF-I (CA repeats); IGF-II (MspI); IGFBP-3 (-a202c, A32G) Carcinogen metabolism pathway GSTT1 (Deletion); GSTM1 (Deletion); GSTM3; GSTP1 (I105V); NAT1; NAT2; PON1 (I102V, Q192R, L55M); CYP1A1 (2455A > G, 3801T > C, 2453C > A); CYP3A4 (5 promoter variant *1B); CYP3A5 (intron 3 missense variant *1); CYP3A43 (exon 10 A > P variant*3); CYP1B1 (L432V); CYP2D6(* 4); MnSOD(V → A) DNA repair pathway XRCC1 (R399Q, R194W, R280H); XRCC3(T241M); XPD (D312N, K751Q); hOGG1(S326C, +11657A/G); MGMT (L84F, I143V); ATM(D1853N, D1853V,ivs38-8t > c, ivs38-15g > c, P1054R) Inflammation/angiogenesis/cytokines TGF-beta (L10P, c509t); COX-2 (−1285A/G, −1265G/A, −899G/C, −297C/G); TNFalpha (TNF-alpha-308); IL-1-beta (IL-1-beta-511); PPAR-gamma (P12A); VEGF (VEGF-1154, VEGF- 460); IL-8 (IL-8-251); IL-10 (IL-10-1082) Adapted from Gsur et al.10 , Dianat et al.11 , Hsing et al.12 and Park et al.13
286 with elevated levels of testosterone and low levels of sex hormone-binding globulin (SHBG) was observed, although a subsequent meta-analysis of 8 cohort studies and other studies14,18 showed that there was no relationship between the development of prostate cancer and plasma testosterone levels, dihydrotestosterone, androstenedione or dehydroepiandrosterone sulfate. One of the most important studies on the influence of androgens in prostate cancer development is provided by the Prostate Cancer Preventive Trial,17 which randomized 18,000 males to receive placebo or finasteride (inhibitor of 5 ␣ reductase isoenzyme type 2) for 7 years. Patients were monitored by means of serum PSA determination, digital rectal examination and biopsy when PSA levels exceeded 4 ng/ml and at the end of the study. The trial demonstrated a 25% reduction in the risk of developing cancer with finasteride. The effect of finasteride in patients with SRD5A2 polymorphisms is currently being studied, which will help clarify whether genotyping may help to identify patients who would benefit the most from the administration of finasteride for preventive purposes. Estrogens also have been the focus of several epidemiological studies with the aim of investigating their association with prostate cancer.5,16---18 Although an inverse association between prostate cancer and levels of 17--estradiol (E2) was observed in the Physician’s Health Study Cohort,16 other studies that include a meta-analysis found no such relationship. In experimental animals it was found that prenatal exposure to estrogens ‘‘marks’’ the prostate to increase proliferation, inflammation and dysplastic epithelial changes in later life. Estrogens are metabolized to catechol-estrogens by the enzyme cytochrome P450, encoded by the genes CYP1A1 and CYP1B1. The catechol-estrogens generate reactive oxygen compounds and free radicals, which damage DNA. The two main types of estrogen receptors, ER-␣ and ER-, are expressed in both normal and tumor prostate, albeit with different cellular locations. Since these two receptors are different, it is likely that an imbalance of expression may be critical in determining the estrogenic effects on prostate tumor cells. The activation of ER- appears to limit the proliferation of cells directly or through inhibition of ER␣ and therefore the loss of ER- is always associated with tumor progression. Similarly, the hypothesis of a mechanism that affects ER-␣, resulting in an altered expression of the receptor and disruption of critical developmental genes and interference with the growth and differentiation of the prostate gland, is raised. In summary, the epidemiological data available does not support the association between baseline plasma levels of estrogen and the development of prostate cancer. Although some authors have found an inverse relationship between levels of sex hormone-binding globulin and the risk of developing the disease, most studies did not find this association.5,14 It also appears that insulin acts as a hormonal growth factor, regulating cell proliferation, differentiation and apoptosis. Thus, hyperinsulinemia associated with insulin resistance is considered as a risk factor for the development of various cancers (breast, pancreas, liver, colon, bladder and oral cavity) and benign tumors (BPH). In relation to prostate cancer, studies are contradictory, but seem to demonstrate that hyperinsulinemia is a risk factor for prostate carcinogenesis.14,19,20
J. Ferrís-i-Tortajada et al.
Anthropometric factors Due to the close correlation between body mass index (BMI) and sex hormones, this parameter has been explored in numerous epidemiological studies on prostate cancer. Studies based on case---control are not directly related, but prospective studies have documented positive associations between BMI and the incidence and mortality of this disease.5,6,21---30 In the event that there is really a direct relationship between the two parameters measured, it is not clear which of the two factors that influence BMI, body fat or muscle volume, is the most important. BMI does not distinguish between the two and, sometimes, muscle tissue is a better reflection as it has greater density than adipose tissue. Regardless of height, relatively greater muscle mass will result in a higher BMI. A prospective study of Japanese Americans found that the risk of prostate cancer is associated with muscle mass and not fat accumulation in the upper extremities.25 Arm muscle volume is correlated with plasma testosterone levels/dihydrotestosterone, and numerous epidemiological studies associate these levels with a higher risk of the disease, as we mentioned previously.5,26 Some studies have tried to characterize the relationship between the BMI, different ages and the subsequent development of prostate cancer, but at present, we do not know in what age bracket of exposure it is determinant. In two studies carried out in the U.S., one of them a case---control study27 and the other a cohort study,28 no association was found between BMI at 25 years of age and subsequent risk. On the contrary, another cohort study conducted in the Netherlands29 found a significant direct relationship between BMI from age 20 and increased risk of prostate cancer. Obesity (BMI > 30), particularly abdominal or central, and the relationship between maximum abdominal and pelvic diameters are associated with increased risk of localized and metastatic prostate cancer, as well as with increased mortality.5,14 This direct association is based on metabolic and hormonal mechanisms inherent to obesity, which are contributing factors of increased neoplastic risk in general and prostatic risk in particular. A meta-analysis has demonstrated that for every increase of 5 in the BMI of obese men, the risk of developing prostate cancer increases by 5% and by 12% in the subgroup with advanced disease.30 The scientific community unanimously accepts the association between obesity and poorer prognosis for prostate cancer, due to delayed diagnosis and lower therapeutic response. Moreover, childhood obesity has been inversely associated with subsequent risk of developing the disease.22 Obesity in men increases the plasma levels of estrogens and decreases those of androgens. This hormonal balance in obese children may be modular and protect prepubertal prostate tissue from developing cancer in adulthood. A study on the U.S. population between 1980 and 2002 regarding the impact of obesity on prostate cancer incidence and mortality showed that obesity increased the incidence of high-grade lesions by 15% and mortality by between 7% and 23%.21 In an epidemiological cohort study,28 the authors suggest that weight reductions in adulthood may be important for reducing the risk of prostate cancer. Articles studying the relationship between height and the risk of prostate cancer have contradictory results.5,22,24
Constitutional risk factors in prostate cancer
Hypertension It has been the subject of several epidemiological studies, both of case---control and cohort studies, to assess the impact of hypertension (HT) in prostate cancer. Although most authors claim that it increases the risk of developing the disease, others have not documented such an association.31---33 Recently, a cohort study in the Norwegian population found that hypertension was associated with an increased risk of prostate cancer, especially in those of high histological grade.31 The authors suggest that if the association were causal, hypertension could be responsible for 3% of all prostate cancers.
Perinatal factors Birth weight is the result of transplacental exposure to maternal nutrients, especially glucose, fetal growth factors and steroid hormones, and has been associated with increased risk of prostate cancer.5,34---36 A prospective study34 found the risk 4 times higher, comparing the higher percentiles with the lower percentiles of birth weight, although subsequently, this finding has not been confirmed by other authors.35 A case-cohort study36 also found that eclampsia and prematurity, factors probably related to transplacental maternal hormones and other fetal growth factors, were inversely associated with subsequent prostate cancer incidence and mortality, as with the degree of maternal parity.
287 ulation screening with PSA and DRE from the age of 50 years, (b) differences in life expectancy between industrialized and underdeveloped countries, (c) common genetic polymorphisms in ethnic groups that predominate in geographic regions, and (d) the influence of socioeconomic and cultural factors, including nutritional habits, due to the close correlation between dietary factors and carcinogenesis. With respect to genetic factors, we see that despite increasing the individual vulnerability of carriers, they need to interact with environmental factors for more than four decades to complete carcinogenesis in the prostate. Transplacental exposure to diethylstilbestrol, a hormonal compound classified as a safe human carcinogen by the International Agency for Research on Cancer, is associated with the development of vaginal clear cell adenocarcinoma after long latency periods that even exceed 4 decades.39 Prostate cancer also requires long periods of latency until clinical expression, therefore, to associate its degree of risk with specific hormonal determinations at the time of detection or diagnosis, allows for conflicting results between different groups of researchers. Most certainly, in order to know the true interrelation of hormonal factors with prostate cancer, we should monitor vital exposure of prostatic tissue with the plasma and intracellular levels of androgens and estrogens, from conception to senescence or at the time of diagnosis. Furthermore, during monitoring, special attention must be paid to the critical periods of exposure of the prostate gland, fundamentally during its formation in the fetal period (embryogenesis and histogenesis) and during peri-pubertal maturation.
Type 2 diabetes References An inverse association between type 2 diabetes and the risk of prostate cancer has been described.37,38 The results of a meta-analysis based on 12 cohort studies and 7 case---control studies suggest that diabetic patients have a 16% lower risk than expected of developing the disease.37 It is curious to note that one of the allelic polymorphisms involved in the increased susceptibility to prostate cancer, the TCF gene 2 (chromosome 17q12), is associated with a lower risk of diabetes.38 Other hypotheses that can sustain the inverse association include hormonal factors, such as insulin levels and the insulin-like growth factor, as well as differences in population screening practices and a greater risk of mortality that reduces the average life expectancy in diabetic patients. We must therefore emphasize that type 2 diabetes mellitus is the only constitutional risk factor that acts preventively, reducing the risk of developing prostate cancer.
Conclusion Of all the factors analyzed, the three that carry the greatest specific weight and unanimity in the results published are age, ethnic---geographical and genetic factors. The increased risk associated with age expresses the innate resistance of prostate cells to carcinogenic risk factors and the slow process of prostate carcinogenesis. With respect to the significant risk differences associated with ethnic and geographical factors, they can be explained by these underlying mechanisms: (a) the presence or absence of systematic pop-
1. World Cancer Report 2008. World Health Organization. In: Boyle P, Levin B, editors. Lyon: WHO-IARC Publ; 2008. 2. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46:765---81. 3. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009 CA. Cancer J Clin. 2009;59:225---49. 4. Crawford ED, Black L, Eaddy M, Kruep EJ. A retrospective analysis illustrating the substantial clinical and economic burden of prostate cancer. Prostate Cancer Prostatic Dis. 2010;13:162---7. 5. Platz EA, Giovannucci E. Prostate cancer. In: Schottenfeld D, Fraumeni Jr JF, editors. Cancer epidemiology and prevention. 3rd edition Oxford: Oxford University Press; 2006. p. 1128---50. 6. Fournier G, Valei A, Mangin P, Cussenot O. Prostate cancer. Epidemiology. Risk factors. Pathology. Ann Urol (Paris). 2004;38:187---206. 7. Patel AR, Klein EA. Risk factors for prostate cancer. Nat Clin Pract Urol. 2009;6:87---95. 8. Karim-Koss HE, de Vries E, Soerjomataram I, Lemmens V, Siesling S, Coebergh JW. Recent trends of cancer in Europe: a combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. Eur J Cancer. 2008;44:1345---89. 9. Cussenot O, Cancel-Tassin G. Facteurs de risque génétiques pour le cancer de la prostate. Med Sci (Paris). 2004;20:562---8. 10. Gsur A, Feik E, Madersbacher S. Genetic polymorphisms and prostate cancer risk. World J Urol. 2004;21:414---23. 11. Dianat SS, Margreiter M, Eckersberger E, Finkelstein J, Kuehas F, Herwig R, et al. Gene polymorphisms and prostate cancer: the evidence. BJU Int. 2009;104:1560---72. 12. Hsing AW, Chokkalingam AP. Prostate cancer epidemiology. Front Biosci. 2006;11:1388---413.
288 13. Park JY, Huang Y, Sellers TA. Single nucleotide polymorphisms in DNA repair genes and prostate cancer risk. Methods Mol Biol. 2009;471:361---85. 14. Wigle DT, Turner MC, Gomes J, Parent ME. Role of hormonal and other factors in human prostate cancer. J Toxicol Environ Health B Crit Rev. 2008;11:242---59. 15. Ip C, Hall SJ. Hormonal implications in the development and treatment of prostate cancer. Endocrinol Metab Clin N Am. 2007;36:421---34. 16. Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst. 1996;88:1118---26. 17. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349: 215---24. 18. Eaton NE, Reeves GK, Appleby PN, Key TJ. Endogenous sex hormones and prostate cancer: a quantitative review of prospective studies. Br J Cancer. 1999;80:930---4. 19. Kojima S, Inahara M, Suzuki H, Ichikawa T, Furuya Y. Implications of insulin-like growth factor-I for prostate cancer therapies. Int J Urol. 2009;16:161---7. 20. Nandeesha H. Insulin: a novel agent in the pathogenesis of prostate cancer. Int Urol Nephrol. 2009;41:267---72. 21. Fesinmeyer MD, Gulati D, Zeliadt S, Weiss N, Kristal AR, Etzioni R. Effect of population trends in body mass index on prostate cancer incidence and mortality in the United States. Cancer Epidemiol Biomarkers Prev. 2009;18:808---15. 22. Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Willet WC. Height, body weight, and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 1997;6:557---63. 23. Kaaks R, Stattin P. Obesity, endogenous hormone metabolism, and prostate cancer risk: a conundrum of ‘‘highs’’ and ‘‘lows’’. Cancer Prev Res (Phila Pa). 2010;3:259---62. 24. Hernández BY, Park SY, Wilkens LR, Henderson BE, Kolonel LN. Relationship of body mass, height, and weight gain to prostate cancer risk in the multiethnic cohort. Cancer Epidemiol Biomarkers Prev. 2009;18:2413---21. 25. Severson RK, Grove JS, Nomura AM, Stemmermann GN. Body mass and prostatic cancer: a prospective study. Br Med J. 1988;297:713---5. 26. Henderson BE. Summary report of the sixth symposium on cancer registries and epidemiology in the Pacific Basin. J Natl Cancer Inst. 1990;82:1186---90.
J. Ferrís-i-Tortajada et al. 27. Hayes RB, Ziegler RG, Gridley G, Swanson C, Greenberg RS, Swanson GM, et al. Dietary factors and risks for prostate cancer among blacks and whites in the United States. Cancer Epidemiol Biomarkers Prev. 1999;8:25---34. 28. Cerhan JR, Torner JC, Lynch CF, Rubenstein LM, Lemke JH, Cohen MB, et al. Association of smoking, body mass, and physical activity with risk of prostate cancer in the Iowa 65+ Rural Health Study (United States). Cancer Causes Control. 1997;8:229---38. 29. Schuurman AG, Goldbohm RA, Dorant E, van den Brandt PA. Anthropometry in relation to prostate cancer risk in the Netherlands cohort study. Am J Epidemiol. 2000;151:541---9. 30. MacInnis RJ, MacInnis RJ, English DR, Gertig DM, Hopper JL, Giles GG. Body size and composition and prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2003;12:1417---21. 31. Martin RM, Vatten L, Gunnell D, Romundstad P. Blood pressure and risk of prostate cancer: cohort Norway (CONOR). Cancer Causes Control. 2010;21:463---72. 32. Hammarsten J, Högstedt B. Clinical, haemodynamic, anthropometric, metabolic and insulin profile of men with highstage and high-grade clinical prostate cancer. Blood Press. 2004;13:47---55. 33. Friedman GD. Blood pressure and heart rate: no evidence for a positive association with prostate cancer. Ann Epidemiol. 1997;7:486---9. 34. Tibblin G, Eriksson M, Cnattingius S, Ekbom A. High birthweight as a predictor of prostate cancer risk. Epidemiology. 1995;6:423---4. 35. Platz EA, Giovannucci E, Rimm EB, Curhan GC, Spiegelman D, Colditz GA, et al. Retrospective analysis of birth weight and prostate cancer in the health professionals follow-up study. Am J Epidemiol. 1998;147:1140---4. 36. Ekbon A, Ekbom A, Hsieh CC, Lipworth L, Wolk A, Pontén J, et al. Perinatal characteristics in relation to incidence of and mortality from prostate cancer. Br Med J. 1996;313:337---41. 37. Kasper JS, Giovannucci E. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:2056---62. 38. Gudmundsson J, Sulem P, Steinthorsdottir V, Bergthorsson JT, Thorleifsson G, Manolescu A, et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet. 2007;39:977---83. 39. Veurink M, Koster M, Berg LT. The history of DES, lessons to be learned. Pharm World Sci. 2005;27:139---43.
Actas Urológicas Españolas www.elsevier.es/actasuro
REVIEW ARTICLE
Constitutional risk factors in prostate cancer夽 J. Ferrís-i-Tortajada a,∗ , J. García-i-Castell b , O. Berbel-Tornero c , J.A. Ortega-García d a
Unidad de Salud Medioambiental Pediátrica, Unidad de Oncología Pediátrica, Hospital Infantil Universitario La Fe, Valencia, Spain b Sección de Anatomía Patológica, Hospital de Sagunto, Valencia, Spain c Centro de Salud de Chella, Chella, Valencia, Spain d Unidad de Salud Medioambiental Pediátrica, Hospital Materno-Infantil Universitario Virgen de la Arrixaca, Murcia, Spain Received 21 December 2010; accepted 21 December 2010 Available online 9 August 2011
KEYWORDS Prostate cancer; Constitutional risk factors; Carcinogenesis; Epidemiology
Abstract Introduction: The aim of this review is to update and divulge the main constitutional risk factors involved in the etiopathology of prostate cancer. Materials and methods: Bibliographic review of the scientific literature on the constitutional risk factors associated with prostate cancer between 1985 and 2010, obtained from MedLine, CancerLit, Science Citation Index and Embase. The search profiles were Risk Factors, Genetic Factors, Genetic Polymorphisms, Genomics, Etiology, Epidemiology, Hormonal Factors, Endocrinology, Primary Prevention and Prostate Cancer. Results: The principal constitutional risk factors are: age (before the age of 50 years at least 0.7% of these neoplasms are diagnosed and between 75 and 85% are diagnosed after the age of 65 years), ethnic---racial and geographic (African Americans present the highest incidence rates, and the lowest are found in South East Asia), genetic, family and hereditary (family syndromes cover 13---26% of all prostate cancers, of which 5% are of autosomal dominant inheritance), hormonal (it is a hormone-dependent tumor), anthropometric (obesity increases the risk), perinatal, arterial hypertension and type 2 diabetes. Conclusions: Constitutional risk factors play a very important role in the etiopathology of prostate cancer, especially age, ethnic---racial---geographic factors and genetic---family factors. We cannot know what percentage of these neoplasms are a result of constitutional factors because our knowledge of these factors is currently lacking. © 2010 AEU. Published by Elsevier España, S.L. All rights reserved.
夽 Please cite this article as: Ferrís-i-Tortajada J, et al. Factores de riesgo constitucionales en el cáncer de próstata. Actas Urol Esp. 2011;35:282---8. ∗ Corresponding author. E-mail address: ferris [email protected] (J. Ferrís-i-Tortajada).
2173-5786/$ – see front matter © 2010 AEU. Published by Elsevier España, S.L. All rights reserved.
Constitutional risk factors in prostate cancer
PALABRAS CLAVE Cáncer de próstata; Factores de riesgo constitucionales; Carcinogénesis; Epidemiología
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Factores de riesgo constitucionales en el cáncer de próstata Resumen Introducción: en esta revisión se pretende actualizar y divulgar los principales factores de riesgo constitucionales implicados en la etiopatogenia del cáncer de próstata. Material y métodos: revisión bibliográfica de la literatura científica acerca de los factores de riesgo constitucionales asociados a cáncer de próstata entre 1985 y 2010, obtenida de MedLine, CancerLit, Science Citation Index y Embase. Los perfiles de búsqueda han sido Risk Factors, Genetic Factors, Genetic Polymorphisms, Genomics, Etiology, Epidemiology, Hormonal Factors, Endocrinology, Primary Prevention y Prostate Cancer. Resultados: los principales factores de riesgo constitucionales son: edad (antes de los 50 a˜ nos se diagnostican menos del 0,7% de estas neoplasias y en mayores de 65 a˜ nos, entre el 75-85%), étnico-raciales y geográficos (los afroamericanos presentan las mayores tasas de incidencia y las más bajas en el sudeste asiático), genéticos, familiares y hereditarios (los síndromes familiares engloban el 13-26% de todos los cánceres de próstata, de los cuales el 5% se heredan de forma autosómica dominante), hormonales (es un tumor hormonodependiente), antropométricos (la obesidad incrementa el riesgo), perinatales, hipertensión arterial y diabetes tipo 2. Conclusiones: los factores de riesgo constitucionales desarrollan un papel muy importante en la etiopatogenia del cáncer prostático, especialmente la edad, los factores étnico-racialesgeográficos y los factores genético-familiares. No podemos saber qué porcentaje de estas neoplasias se atribuye a factores constitucionales, porque el conocimiento de dichos factores es actualmente incompleto. © 2010 AEU. Publicado por Elsevier España, S.L. Todos los derechos reservados.
Introduction Globally one-third of all cancers in men are urological neoplasias and prostate cancer is the most common of them.1 It is also the most common non-cutaneous cancer in men in most industrialized countries. Likewise, and despite the advances made in its early diagnosis, treatment and increased survival, it is the second leading cause of cancer death after bronchopulmonary cancer in these countries.1 In Europe, in 2008, 382,300 new cases were diagnosed and 89,300 patients died.2 In the U.S., 192,280 new cases were diagnosed in 2009 and 27,360 died.3 Given the high incidence and significant mortality, primary prevention is one of the major health challenges to reduce the personal, social and economic impact it entails.4 Our intention here is to review and update the major constitutional risk factors, with more or less scientific evidence, associated with the development of this disease, based on concise bibliographic research.
Constitutional factors Age It is one of the most important risk factors.5---7 There is a directly proportional relationship between increasing age and greater risk of developing prostate cancer. Less than 0.6% of all cases are diagnosed before the age of 45, and between 62% and 85% after the age of 65 years.5,6 In the U.S., the risk of developing prostate cancer between birth and 39 years of age is 0.01 (one case out of 10,002 men). Between the ages of 40 and 59 years, it is 2.43 (one case out of 41 men). For men between 60 and 69 years, it is 6.42
(one case out of every 16 men). Finally, at age 70, the risk is 12.49 (one case out of 8 men).3 In the white population of the U.S. aged between 75 and 79 years, the risk is 130 times higher than in the 45---49 years age bracket.5 In addition to the age factor, this significant difference also reflects the increase associated with systematic PSA screening and rectal examination as of 50 years of age.5 The introduction of this screening has generated an age migration, with a 50% increase of cases in men aged 50---59 years. With age, atypical small acinar proliferation and prostatic intraepithelial neoplasia (PIN) appear. The development of low-grade PIN requires a minimum latency period of 20 years. Its transformation to high-grade PIN requires more than 10 additional years and, to become clinically detectable carcinoma, it further requires an evolutionary period of 3---15 years.5
Racial/ethnic and geographical factors There are significant variations in the annual incidence of age-adjusted prostate cancer among countries and ethnic and racial groups.1,2,5,8 We found the world’s highest rates in America, exceeding 270 new cases per 100,000 males per year among African Americans in the U.S. and Caribbean islands of Trinidad, Tobago, Martinique and Jamaica. The reasons for this 60% higher risk in African Americans and 38% lower risk in Asian Americans in comparison to white Caucasians, are still elusive. Asia is the continent with the lowest incidence worldwide; however, there are differences among its countries. The more westernized countries such as Japan and Israel have rates of 20---50 new cases per 100,000 males per year, while India, Thailand, Pakistan and China have the lowest
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Table 1 Variability in the incidence of prostate cancer in Europe in 2008. Europe and regions
Incidencea
Europe.. .. .. .. .. .. .. .. .. .. .. .. ... . Western Europe. .. .. .. .. .. .. .. ... Northern Europe. .. .. .. .. .. .. .. .. .. ... Southern Europe.. .. .. .. .. .. .. .. .. .. .. ... Central/Eastern Europe. .. .. .. .. ... .
93.4 142.3 131.3 78.7 42.0
Countries with highest incidence Ireland.. .. .. .. .. .. .. .. .. .. .. .. .. ... France.. .. .. .. .. .. .. .. .. .. .. .. .. ... Norway.. .. .. .. .. .. .. .. .. .. .. .. ... . Sweden.. .. .. .. .. .. .. .. .. .. .. .. .. ... . Iceland.. .. .. .. .. .. .. .. .. .. .. .. ... . Belgium. .. .. .. .. .. .. .. .. .. .. .. .. ... Finland. .. .. .. .. .. .. .. .. .. .. .. ... Switzerland.. .. .. .. .. .. .. .. .. .. .. .. .. ... . Germany. .. .. .. .. .. .. .. .. .. .. .. ... Austria.. .. .. .. .. .. .. .. .. .. .. .. ... .
183.1 178.7 172.7 168.6 153.3 152.9 145.3 137.1 125.6 122.6
Countries with lowest incidence Moldova.. .. .. .. .. .. .. .. .. .. .. .. ... Ukraine.. .. .. .. .. .. .. .. .. .. .. .. ... . Albania.. .. .. .. .. .. .. .. .. .. .. .. ... . Greece.. .. .. .. .. .. .. .. .. .. .. .. .. ... Romania. .. .. .. .. .. .. .. .. .. .. .. ... . Montenegro.. .. .. .. .. .. .. .. .. .. .. ... Serbia.. .. .. .. .. .. .. .. .. .. .. .. .. ... . Macedonia.. .. .. .. .. .. .. .. .. .. .. ... . Russian Federation.. .. .. .. .. .. .. .. .. ... Bulgaria.. .. .. .. .. .. .. .. .. .. .. .. ...
23.3 27.7 30.7 31.1 32.0 31.9 32.9 33.9 34.3 35.6
Adapted from Ferlay et al.2 a Rate of incidence per 100,000 males.
rates, which range from 1.4 to 8.4 new cases per 100,000 males per year. In 2008, 382,300 patients were diagnosed in Europe, which corresponds to an estimated incidence of 93.4 new cases per 100,000 males; 89,300 patients died.2 Comparing the data obtained in 1995, we noted a dramatic increase in incidence, which almost doubled the rate of 47.4 for that year.8 In our continent, the incidence also varies greatly between regions and countries (Table 1); in the region with the highest incidence, it is 3.4 times higher than that of the region with the lowest incidence, and in the country with the highest incidence, it is 7.8 times higher in the country with the lowest incidence. With respect to countries, the huge difference between Ireland, with 32.3, and Moldova with 183.1 new cases per 100,000 males, is worth mentioning. Spain occupies an intermediate position with 88.9, behind Italy with 91.2 and preceding Portugal and Malta with 76.6 cases per 100,000 males.
Genetic, familial and hereditary factors Like all cancers, prostate cancer is a genetic disease caused by the accumulation of chromosomal mutations generated by the clonal selection of aggressive cells. In the vast majority of cases, the mutations are somatic and only occur in
the tumoral cells of the prostate epithelium. When some mutations are present in germ cells, they are passed from generation to generation and are present in all body cells, including the prostate, logically. This gives rise to familial syndromes of prostate cancer, which are between 13% and 26% of the total of these tumors.9---13 In the majority of these syndromes, the mutations are allelic and low-penetrance; however, in 5%, the mutations are high-penetrance and transmitted as autosomal dominant, following the classic patterns of Mendelian inheritance (Table 2). These highpenetrance mutations give rise to strictly hereditary forms of prostate cancer. Clinically, familial syndromes of prostate cancer occur at younger ages than sporadic syndromes, representing 43% of those under 70 years of age and only 9% of those diagnosed at 85 years of age. The familial hereditary variety is diagnosed before 55 years of age, and although some subvarieties are associated with increased biological aggressiveness, overall, it has not been sufficiently proven that they entail a worse prognosis than sporadic forms.9 Another clinical characteristic of familial prostate cancers is the coexistence of two or more cases in first and second-degree relatives. Numerous epidemiological studies have documented that the siblings and children of a patient with prostate cancer have a 2---3 times greater risk of developing the disease than expected for their age, ethnicity and geographic location. The risk increases in accordance with the number of sick family members. Thus, for one family member affected, the relative risk is 2; if two family members are sick, the relative risk is 5, and in the case of three affected family members, the relative risk is 11. To suspect the hereditary variety, clinical criteria are stricter and are: (a) three or more first-degree relatives affected, (b) at least three cases in first and second-degree relatives, taking into account X-linked transmission, and (c) two firstdegree relatives diagnosed before age 55. In the inherited form with autosomal dominant inheritance, there is a sexlinked mode, in which females are carriers and transmit it to their children. This method probably underestimates the actual number of cases, since the disease skips one or more generations. Some families with prostate cancer also have an increased risk of suffering other malignancies (breast, ovary, brain, etc.), due to the coexistence of mutations in the germ cells that give rise to different neoplasias. The necessary interaction between genetic and environmental factors is demonstrated by studies of prostate cancer in twins. In homozygotes, the healthy brother has an 18% higher absolute risk than expected to develop the process, while in dizygotic twins, it is only 3%.9 Advances in biogenetics have allowed identifying the numerous allelic low-penetrance mutations denominated genetic polymorphisms, which are involved in the rest of familial forms of prostate cancer and which, as they are relatively more frequent, are found in far more cases than in strictly familial cancers. Thus, some authors attribute up to 40% of all prostate cancers to genetic factors. The greatest risk is caused by the involvement of the metabolic pathways mentioned in Table 3, which increase the neoplastic transformation of prostate epithelial cells.10---13
Constitutional risk factors in prostate cancer Table 2
285
Main genes involved in the hereditary formation of familial prostate cancer.
Chromosomal location
Gene
Characteristics
1q24---25 1q42---43 Xp11 Xp27---28 17p11 20q13 5q31---33 7q32 19q12---13 1p36 10q25 8p22---23 17q24 16q23 8q24 (region 1)
HPC1 PCaP --HPCX HPC2 HPC20
Autosomal dominant inheritance. Associated with brain tumors Autosomal dominant inheritance Sex-related inheritance Sex-related inheritance
8q24 (region 2) 8q24 (region 3) 2p15; 3p12; 6q25 7p21; 10q11; 10q26 11q13; 17q12 17q21; 13q12---13
Very aggressive clinical evolutionary forms
CAPB PRCA1 PG1/MSR1 ELAC2
Associated with brain tumors
Very aggressive clinical evolutionary forms association with colorectal, breast, ovary and urinary bladder cancers
BRCA1; BRCA2
Hereditary breast and ovarian cancer
Adapted from Platz and Giovannucci5 and Cussenot and Cancel-Tassin.9
Hormonal factors Androgens influence the development, maturation and growth of the prostate and affect both the proliferation and the differentiation of its epithelium.7,14---18 Testosterone, the main circulating androgen, and dihydrotestosterone, the main tissue androgen, are the two most important androgens. The second is synthesized from the first by 5 ␣ reductase, isoenzyme type 1 (skin and hair) and type 2 Table 3
(prostate, skin and genitals). The action of androgens in prostate cells is mediated by the androgen receptor, which leads to the activation of transcription of genes involved in DNA synthesis and cell proliferation. Numerous prospective studies have investigated the role of plasmatic androgens on prostate cancer, but few have demonstrated that men with elevated serum androgen levels have an increased risk of developing the disease. In the Physician’s Health Study Cohort16 increased risk
Main low-penetrance genetic polymorphisms and prostate cancer.
Gene (marker) Biosynthesis and androgenic metabolism CYP17 (MspA1); CYP19 (TTTA repeats, N264C); SRD5A2 (V89L, A49T, R227Q, TA repeats); AR (CAG repeats, GGN repeats, E211 G > A); HSD3B1 (N367T, c7062t); HSD3B2 (c7159g, c7474t); HSD17B3 (G289S); ER-alpha (XbaI, PvuII); ER-beta (RsaI) Growth factors and non-androgenic hormonal pathway VDR (BsmI, TaqI, polyA, ApaI, FOPI); INS (+1127PstI); TH (-4217PstI); IRS1 (G972R); IRS2 (G1079D); IGF-I (CA repeats); IGF-II (MspI); IGFBP-3 (-a202c, A32G) Carcinogen metabolism pathway GSTT1 (Deletion); GSTM1 (Deletion); GSTM3; GSTP1 (I105V); NAT1; NAT2; PON1 (I102V, Q192R, L55M); CYP1A1 (2455A > G, 3801T > C, 2453C > A); CYP3A4 (5 promoter variant *1B); CYP3A5 (intron 3 missense variant *1); CYP3A43 (exon 10 A > P variant*3); CYP1B1 (L432V); CYP2D6(* 4); MnSOD(V → A) DNA repair pathway XRCC1 (R399Q, R194W, R280H); XRCC3(T241M); XPD (D312N, K751Q); hOGG1(S326C, +11657A/G); MGMT (L84F, I143V); ATM(D1853N, D1853V,ivs38-8t > c, ivs38-15g > c, P1054R) Inflammation/angiogenesis/cytokines TGF-beta (L10P, c509t); COX-2 (−1285A/G, −1265G/A, −899G/C, −297C/G); TNFalpha (TNF-alpha-308); IL-1-beta (IL-1-beta-511); PPAR-gamma (P12A); VEGF (VEGF-1154, VEGF- 460); IL-8 (IL-8-251); IL-10 (IL-10-1082) Adapted from Gsur et al.10 , Dianat et al.11 , Hsing et al.12 and Park et al.13
286 with elevated levels of testosterone and low levels of sex hormone-binding globulin (SHBG) was observed, although a subsequent meta-analysis of 8 cohort studies and other studies14,18 showed that there was no relationship between the development of prostate cancer and plasma testosterone levels, dihydrotestosterone, androstenedione or dehydroepiandrosterone sulfate. One of the most important studies on the influence of androgens in prostate cancer development is provided by the Prostate Cancer Preventive Trial,17 which randomized 18,000 males to receive placebo or finasteride (inhibitor of 5 ␣ reductase isoenzyme type 2) for 7 years. Patients were monitored by means of serum PSA determination, digital rectal examination and biopsy when PSA levels exceeded 4 ng/ml and at the end of the study. The trial demonstrated a 25% reduction in the risk of developing cancer with finasteride. The effect of finasteride in patients with SRD5A2 polymorphisms is currently being studied, which will help clarify whether genotyping may help to identify patients who would benefit the most from the administration of finasteride for preventive purposes. Estrogens also have been the focus of several epidemiological studies with the aim of investigating their association with prostate cancer.5,16---18 Although an inverse association between prostate cancer and levels of 17--estradiol (E2) was observed in the Physician’s Health Study Cohort,16 other studies that include a meta-analysis found no such relationship. In experimental animals it was found that prenatal exposure to estrogens ‘‘marks’’ the prostate to increase proliferation, inflammation and dysplastic epithelial changes in later life. Estrogens are metabolized to catechol-estrogens by the enzyme cytochrome P450, encoded by the genes CYP1A1 and CYP1B1. The catechol-estrogens generate reactive oxygen compounds and free radicals, which damage DNA. The two main types of estrogen receptors, ER-␣ and ER-, are expressed in both normal and tumor prostate, albeit with different cellular locations. Since these two receptors are different, it is likely that an imbalance of expression may be critical in determining the estrogenic effects on prostate tumor cells. The activation of ER- appears to limit the proliferation of cells directly or through inhibition of ER␣ and therefore the loss of ER- is always associated with tumor progression. Similarly, the hypothesis of a mechanism that affects ER-␣, resulting in an altered expression of the receptor and disruption of critical developmental genes and interference with the growth and differentiation of the prostate gland, is raised. In summary, the epidemiological data available does not support the association between baseline plasma levels of estrogen and the development of prostate cancer. Although some authors have found an inverse relationship between levels of sex hormone-binding globulin and the risk of developing the disease, most studies did not find this association.5,14 It also appears that insulin acts as a hormonal growth factor, regulating cell proliferation, differentiation and apoptosis. Thus, hyperinsulinemia associated with insulin resistance is considered as a risk factor for the development of various cancers (breast, pancreas, liver, colon, bladder and oral cavity) and benign tumors (BPH). In relation to prostate cancer, studies are contradictory, but seem to demonstrate that hyperinsulinemia is a risk factor for prostate carcinogenesis.14,19,20
J. Ferrís-i-Tortajada et al.
Anthropometric factors Due to the close correlation between body mass index (BMI) and sex hormones, this parameter has been explored in numerous epidemiological studies on prostate cancer. Studies based on case---control are not directly related, but prospective studies have documented positive associations between BMI and the incidence and mortality of this disease.5,6,21---30 In the event that there is really a direct relationship between the two parameters measured, it is not clear which of the two factors that influence BMI, body fat or muscle volume, is the most important. BMI does not distinguish between the two and, sometimes, muscle tissue is a better reflection as it has greater density than adipose tissue. Regardless of height, relatively greater muscle mass will result in a higher BMI. A prospective study of Japanese Americans found that the risk of prostate cancer is associated with muscle mass and not fat accumulation in the upper extremities.25 Arm muscle volume is correlated with plasma testosterone levels/dihydrotestosterone, and numerous epidemiological studies associate these levels with a higher risk of the disease, as we mentioned previously.5,26 Some studies have tried to characterize the relationship between the BMI, different ages and the subsequent development of prostate cancer, but at present, we do not know in what age bracket of exposure it is determinant. In two studies carried out in the U.S., one of them a case---control study27 and the other a cohort study,28 no association was found between BMI at 25 years of age and subsequent risk. On the contrary, another cohort study conducted in the Netherlands29 found a significant direct relationship between BMI from age 20 and increased risk of prostate cancer. Obesity (BMI > 30), particularly abdominal or central, and the relationship between maximum abdominal and pelvic diameters are associated with increased risk of localized and metastatic prostate cancer, as well as with increased mortality.5,14 This direct association is based on metabolic and hormonal mechanisms inherent to obesity, which are contributing factors of increased neoplastic risk in general and prostatic risk in particular. A meta-analysis has demonstrated that for every increase of 5 in the BMI of obese men, the risk of developing prostate cancer increases by 5% and by 12% in the subgroup with advanced disease.30 The scientific community unanimously accepts the association between obesity and poorer prognosis for prostate cancer, due to delayed diagnosis and lower therapeutic response. Moreover, childhood obesity has been inversely associated with subsequent risk of developing the disease.22 Obesity in men increases the plasma levels of estrogens and decreases those of androgens. This hormonal balance in obese children may be modular and protect prepubertal prostate tissue from developing cancer in adulthood. A study on the U.S. population between 1980 and 2002 regarding the impact of obesity on prostate cancer incidence and mortality showed that obesity increased the incidence of high-grade lesions by 15% and mortality by between 7% and 23%.21 In an epidemiological cohort study,28 the authors suggest that weight reductions in adulthood may be important for reducing the risk of prostate cancer. Articles studying the relationship between height and the risk of prostate cancer have contradictory results.5,22,24
Constitutional risk factors in prostate cancer
Hypertension It has been the subject of several epidemiological studies, both of case---control and cohort studies, to assess the impact of hypertension (HT) in prostate cancer. Although most authors claim that it increases the risk of developing the disease, others have not documented such an association.31---33 Recently, a cohort study in the Norwegian population found that hypertension was associated with an increased risk of prostate cancer, especially in those of high histological grade.31 The authors suggest that if the association were causal, hypertension could be responsible for 3% of all prostate cancers.
Perinatal factors Birth weight is the result of transplacental exposure to maternal nutrients, especially glucose, fetal growth factors and steroid hormones, and has been associated with increased risk of prostate cancer.5,34---36 A prospective study34 found the risk 4 times higher, comparing the higher percentiles with the lower percentiles of birth weight, although subsequently, this finding has not been confirmed by other authors.35 A case-cohort study36 also found that eclampsia and prematurity, factors probably related to transplacental maternal hormones and other fetal growth factors, were inversely associated with subsequent prostate cancer incidence and mortality, as with the degree of maternal parity.
287 ulation screening with PSA and DRE from the age of 50 years, (b) differences in life expectancy between industrialized and underdeveloped countries, (c) common genetic polymorphisms in ethnic groups that predominate in geographic regions, and (d) the influence of socioeconomic and cultural factors, including nutritional habits, due to the close correlation between dietary factors and carcinogenesis. With respect to genetic factors, we see that despite increasing the individual vulnerability of carriers, they need to interact with environmental factors for more than four decades to complete carcinogenesis in the prostate. Transplacental exposure to diethylstilbestrol, a hormonal compound classified as a safe human carcinogen by the International Agency for Research on Cancer, is associated with the development of vaginal clear cell adenocarcinoma after long latency periods that even exceed 4 decades.39 Prostate cancer also requires long periods of latency until clinical expression, therefore, to associate its degree of risk with specific hormonal determinations at the time of detection or diagnosis, allows for conflicting results between different groups of researchers. Most certainly, in order to know the true interrelation of hormonal factors with prostate cancer, we should monitor vital exposure of prostatic tissue with the plasma and intracellular levels of androgens and estrogens, from conception to senescence or at the time of diagnosis. Furthermore, during monitoring, special attention must be paid to the critical periods of exposure of the prostate gland, fundamentally during its formation in the fetal period (embryogenesis and histogenesis) and during peri-pubertal maturation.
Type 2 diabetes References An inverse association between type 2 diabetes and the risk of prostate cancer has been described.37,38 The results of a meta-analysis based on 12 cohort studies and 7 case---control studies suggest that diabetic patients have a 16% lower risk than expected of developing the disease.37 It is curious to note that one of the allelic polymorphisms involved in the increased susceptibility to prostate cancer, the TCF gene 2 (chromosome 17q12), is associated with a lower risk of diabetes.38 Other hypotheses that can sustain the inverse association include hormonal factors, such as insulin levels and the insulin-like growth factor, as well as differences in population screening practices and a greater risk of mortality that reduces the average life expectancy in diabetic patients. We must therefore emphasize that type 2 diabetes mellitus is the only constitutional risk factor that acts preventively, reducing the risk of developing prostate cancer.
Conclusion Of all the factors analyzed, the three that carry the greatest specific weight and unanimity in the results published are age, ethnic---geographical and genetic factors. The increased risk associated with age expresses the innate resistance of prostate cells to carcinogenic risk factors and the slow process of prostate carcinogenesis. With respect to the significant risk differences associated with ethnic and geographical factors, they can be explained by these underlying mechanisms: (a) the presence or absence of systematic pop-
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