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Human leukocyte antigen patterns in a family with cervical cancer
GYNECOLOGIC
ONCOLOGY
12, 249-252 (1981)
CASE REPORT Human Leukocyte Antigen Patterns in a Family with Cervical Cancer HEIN W. BRUINSE,
M.D. ,* EGBERT R. TE VELDE, BERT C. DE GAST, PH.D.-F
M.D. ,* AND
*Department of Obstetrics and Gynecology and the tBIoodbank of the Academisch Ziekenhuis, University of Utrecht, Catharijnesingel 101, Vtrecht, The Netherlands Received December 11, 1980 In a family consisting of a mother, two sons, and seven daughters HLA typing was performed. Three of the daughters have been suffering from cancer of the uterine cervix stage 0. No association between the HLA-haplotype pattern and carcinoma in situ appeared to be present. This does not exclude some unexplained genetic susceptibility for cervical cancer in this family.
INTRODUCTION Initially human leukocyte antigens (HLA) or histocompatibility antigens were thought to be exclusively situated on the surface of leukocytes. Dausset [l] first described HLA antigens using sera from polytransfused patients which could agglutinate leukocytes. Using agglutinines formed after pregnancy, van Rood [2] described a great number of HLA antigens and by computer analysis a polymorphic pattern of inheritance emerged. An important discovery came with the appreciation that genes of the sixth chromosome determine the type of HLA antigens expressed on the surface of all nucleated cells [3]. This region is called the major histocompatibility complex (MHC), and consists of four major loci (A, B, C, and D) on which the genes coding for HLA are located. Most genes exist in a considerable number of alternative variants (alleles) which contribute to the enormous heterogenicity of the population. Mammals being diploid have paired chromosomes and the alleles on one chromosome are called a haplotype. One haplotype is inherited from each parent. These haplotypes are codominant which means that an individual will express all the antigens he has inherited. It is obvious that this system is very complex and results in extreme polymorphism. The real number of HLA combinations in the population is, however, less than theoretically expected as certain HLA are frequently linked. This phenomenon is called linkage disequilibrium and is probably explained by some evolutionary selection advantage 141. Under the pressure of clinical necessity most of the knowledge of HLA and their genetic control has been focused on allograft rejection. However, it is appreciated that the biological importance of the MHC region goes far beyond 249 0090-8258/81/050249-04$01.00/O Copyright 0 1981 by Academic Press, Inc. All rights of reproduction in any form reserved.
250
BRUINSE, TE VELDE, AND DE GAS-I
its role in transplantation [4]. Some fundamental biologic phenomena, such as immunoresponsiveness, development, and susceptibility to disease are thought to be at least partially associated with, or controlled by, this genetic region. Innumerable studies have been undertaken to associate HLA with disease [5]. The strongest associations have been found in some rheumatic and autoimmune diseases. The majority of these investigations were designed as population studies in which the frequency of HLA in a certain disease was compared to that in a normal population. Such studies appear to be of relatively limited value and probably reflect linkage disequilibrium in a certain population. Koenig and Miier [6,7] showed in similar studies that in patients with the localized form of cervical carcinoma a decrease of HLA-Al and an increase in HLA-A3 and HLA-A28 could be found. A different, and probably more valuable design is the study of a family by which a possible linkage between a certain haplotype and disease can be determined. We used this approach when we came across a family in which three sisters were suffering from the localized form of cervical carcinoma. MATERIALS
AND METHODS
The family we studied consisted of a mother, seven daughters, and two sons (Table 1). Three of the daughters were found to have cervical carcinoma stage 0. In the first patient (49 years of age) a carcinoma in situ was diagnosed cytologically and confirmed histologically in 1974. She was treated by conization but the surgical margins contained tumor tissue; consequently a hysterectomy was performed, in which no tumor was found.
RESULTS OF
A2--SW51 A3--37
daughter son 1
(a) Cc) 1*(49)
TABLE 1 HLA TYPING IN A FAMILY
n2--a~51 A3--BW51
daughter son 2
(a) Cd)
A28--B40 A3--B7
2 (45)
daughter daughter
WITH CERVICAL
(b) (c)
4*(42) 6 (31)
CANCER
A28--B40 A3--BW51
daughter daughter daughter
(b) Cd)
3*(43) 5 (34) 7 (25)
Note. Daughters with cervical cancer are marked by asterisks. The present age is indicated in oarentheses.
HLA
PATTERNS
IN
CERVICAL
CANCER
251
In the second patient (43 years of age) cytological and histological evidence of a carcinoma in situ was present in the same year. She was treated in a similar way by conization and hysterectomy for surgical margins of the cone contained tumor tissue. Also in 1974 a carcinoma in situ was diagnosed by biopsy in the third sister (40 years of age). Four years later a hysterectomy was performed because of irregular bleeding. No evidence of disease was found in the uterus. For the purpose of this study the operation specimens were recently reviewed and the diagnosis of cervical carcinoma stage 0 could be confirmed. At the same time the mother and all of her daughters were examined cytologically and colposcopically. No evidence of disease has been discovered so far. This study concerns a respectable family of conservative catholic traditions with stable marriages in which promiscuity is out of the question to the best of our knowledge. HLA typing was carried out by standard lymphocytotoxicity methods [8]. HLA-D typing was not performed. Since the father was not alive his HLA pattern had to be composed in retrospect. We demonstrated that all three cervical cancer patients had different HLA patterns. DISCUSSION It has been well established that the epidemiological pattern of cervical carcinoma is directly related to factors of young age of sexual activity, first pregnancy, promiscuity and multiparity [93. However, these factors were absent in the members of this family which place them in the low risk group from an epidemiological point of view. It was argued therefore, that some genetic variation may contribute to the susceptibility of the disease in this family. Several hypothetic models have been designed to explain associations between HLA patterns and disease. In one of them it is proposed that certain HLA antigens may serve as receptors for (oncogenic) viruses and other microorganisms [ 10, Ill. Circumstantial evidence has been accumulated which implicates herpes simplex virus type 2 with carcinoma of the uterine cervix [12]. Moreover the oncogenic potential of herpes virus in other animal hosts suggests the possibility of a similar role in human beings [13]. Since the minority of patients suffering from genital herpes eventually develop cervical cancer an individual susceptibility appears to be important [14]. In this respect it would be conceivable that certain HLA combine with the herpes virus, consequently transforming the cell. In this family study no association between cervical cancer and HLA-haplotype pattern was found, casting some doubt on this theory. It does not exclude, however, some unexplained genetic susceptibility in this family. Therefore we will follow the younger sisters of the patients with interest and care. ACKNOWLEDGMENTS The authors wish to thank Miss D. Go, cytopathologist at the Institute of Pathology of the Academisch Ziekenhuis in Utrecht, for revising all the specimens.
252
BRUINSE,
TE VELDE,
AND
DE GAST
REFERENCES 1. Dausset, J. Leuco-agglutinius IV. Leuco-agglutinius and blood transfusion, VOX Sanguinis 6, 190 (1954). 2. van Rood, J. J. Leucocyte grouping: A method and its application, Thesis, University of Leiden (1962). 3. Batchelor, J. R., and Chapman, B. A. Genetic background and transplantation antigens, J. Clin. Z’athol. 20, 415 (1967). 4. Bach, F. H., van Rood, J. J. The major histocompatibility complex. Genetics and biology, N. Engl. Journal of Medicine, 295, 806, 872, (1976). 5. MC Intyre, J. A., Turner, R. E., and Carwile, E. Human leucocyte antigens (HLA), South. Med. J. 71, 10, 1269 (1978). 6. Koenig, V. D., and Mtiller, N. Untersuchungen zur Bedeutung der Histocomptabilitats antigene bei Zervix Karzinom patientinnen, Geburtshilfe Frauenheilkunde 36, 416 (1976). 7. Koenig, V. D., and Mtiller, N. Der HLA-Polymor fismus und seine Beziehung zur ZervixNeoplasie, Fortschritten Medizin 95, 9, 565 (1977). 8. Teresaki, P. I., MC Clelland, J. D. Microdroplets assay of human serum cytotoxins, Nature (London) 204, 998 (1964). 9. Beral, Y. Cancer of the cervix: A sexually transmitted infection? Lancet I, 1037 (1974). 10. McDavitt, H. O., and Benacerraf, B. Genetic control of specific immuneresponses, Advan. Zmmunol. 11, 31 (1969). 11. Lawler Sylvia, D. HLA-antigens and malignant disease, Brit. J. Cancer 28 (Suppl.) 243 (1973). 12. Aurelian, L. The “viruses of love” and cancer, Amer. .Z. Med. Technol. 40, 11, 496 (1974). 13. Rapp, F., Reed, C. Experimental evidence for the oncogenic potential of herpes simplex virus, Cancer Res. 36, 800 (1976). 14. Naib, Z. M., Nahmias, A. J., Josey, W. E., et al. Relation of cyto-histopathology of genital herpes virus infection to anaplasia, Cancer Res. 33, 1452 (1973).
ONCOLOGY
12, 249-252 (1981)
CASE REPORT Human Leukocyte Antigen Patterns in a Family with Cervical Cancer HEIN W. BRUINSE,
M.D. ,* EGBERT R. TE VELDE, BERT C. DE GAST, PH.D.-F
M.D. ,* AND
*Department of Obstetrics and Gynecology and the tBIoodbank of the Academisch Ziekenhuis, University of Utrecht, Catharijnesingel 101, Vtrecht, The Netherlands Received December 11, 1980 In a family consisting of a mother, two sons, and seven daughters HLA typing was performed. Three of the daughters have been suffering from cancer of the uterine cervix stage 0. No association between the HLA-haplotype pattern and carcinoma in situ appeared to be present. This does not exclude some unexplained genetic susceptibility for cervical cancer in this family.
INTRODUCTION Initially human leukocyte antigens (HLA) or histocompatibility antigens were thought to be exclusively situated on the surface of leukocytes. Dausset [l] first described HLA antigens using sera from polytransfused patients which could agglutinate leukocytes. Using agglutinines formed after pregnancy, van Rood [2] described a great number of HLA antigens and by computer analysis a polymorphic pattern of inheritance emerged. An important discovery came with the appreciation that genes of the sixth chromosome determine the type of HLA antigens expressed on the surface of all nucleated cells [3]. This region is called the major histocompatibility complex (MHC), and consists of four major loci (A, B, C, and D) on which the genes coding for HLA are located. Most genes exist in a considerable number of alternative variants (alleles) which contribute to the enormous heterogenicity of the population. Mammals being diploid have paired chromosomes and the alleles on one chromosome are called a haplotype. One haplotype is inherited from each parent. These haplotypes are codominant which means that an individual will express all the antigens he has inherited. It is obvious that this system is very complex and results in extreme polymorphism. The real number of HLA combinations in the population is, however, less than theoretically expected as certain HLA are frequently linked. This phenomenon is called linkage disequilibrium and is probably explained by some evolutionary selection advantage 141. Under the pressure of clinical necessity most of the knowledge of HLA and their genetic control has been focused on allograft rejection. However, it is appreciated that the biological importance of the MHC region goes far beyond 249 0090-8258/81/050249-04$01.00/O Copyright 0 1981 by Academic Press, Inc. All rights of reproduction in any form reserved.
250
BRUINSE, TE VELDE, AND DE GAS-I
its role in transplantation [4]. Some fundamental biologic phenomena, such as immunoresponsiveness, development, and susceptibility to disease are thought to be at least partially associated with, or controlled by, this genetic region. Innumerable studies have been undertaken to associate HLA with disease [5]. The strongest associations have been found in some rheumatic and autoimmune diseases. The majority of these investigations were designed as population studies in which the frequency of HLA in a certain disease was compared to that in a normal population. Such studies appear to be of relatively limited value and probably reflect linkage disequilibrium in a certain population. Koenig and Miier [6,7] showed in similar studies that in patients with the localized form of cervical carcinoma a decrease of HLA-Al and an increase in HLA-A3 and HLA-A28 could be found. A different, and probably more valuable design is the study of a family by which a possible linkage between a certain haplotype and disease can be determined. We used this approach when we came across a family in which three sisters were suffering from the localized form of cervical carcinoma. MATERIALS
AND METHODS
The family we studied consisted of a mother, seven daughters, and two sons (Table 1). Three of the daughters were found to have cervical carcinoma stage 0. In the first patient (49 years of age) a carcinoma in situ was diagnosed cytologically and confirmed histologically in 1974. She was treated by conization but the surgical margins contained tumor tissue; consequently a hysterectomy was performed, in which no tumor was found.
RESULTS OF
A2--SW51 A3--37
daughter son 1
(a) Cc) 1*(49)
TABLE 1 HLA TYPING IN A FAMILY
n2--a~51 A3--BW51
daughter son 2
(a) Cd)
A28--B40 A3--B7
2 (45)
daughter daughter
WITH CERVICAL
(b) (c)
4*(42) 6 (31)
CANCER
A28--B40 A3--BW51
daughter daughter daughter
(b) Cd)
3*(43) 5 (34) 7 (25)
Note. Daughters with cervical cancer are marked by asterisks. The present age is indicated in oarentheses.
HLA
PATTERNS
IN
CERVICAL
CANCER
251
In the second patient (43 years of age) cytological and histological evidence of a carcinoma in situ was present in the same year. She was treated in a similar way by conization and hysterectomy for surgical margins of the cone contained tumor tissue. Also in 1974 a carcinoma in situ was diagnosed by biopsy in the third sister (40 years of age). Four years later a hysterectomy was performed because of irregular bleeding. No evidence of disease was found in the uterus. For the purpose of this study the operation specimens were recently reviewed and the diagnosis of cervical carcinoma stage 0 could be confirmed. At the same time the mother and all of her daughters were examined cytologically and colposcopically. No evidence of disease has been discovered so far. This study concerns a respectable family of conservative catholic traditions with stable marriages in which promiscuity is out of the question to the best of our knowledge. HLA typing was carried out by standard lymphocytotoxicity methods [8]. HLA-D typing was not performed. Since the father was not alive his HLA pattern had to be composed in retrospect. We demonstrated that all three cervical cancer patients had different HLA patterns. DISCUSSION It has been well established that the epidemiological pattern of cervical carcinoma is directly related to factors of young age of sexual activity, first pregnancy, promiscuity and multiparity [93. However, these factors were absent in the members of this family which place them in the low risk group from an epidemiological point of view. It was argued therefore, that some genetic variation may contribute to the susceptibility of the disease in this family. Several hypothetic models have been designed to explain associations between HLA patterns and disease. In one of them it is proposed that certain HLA antigens may serve as receptors for (oncogenic) viruses and other microorganisms [ 10, Ill. Circumstantial evidence has been accumulated which implicates herpes simplex virus type 2 with carcinoma of the uterine cervix [12]. Moreover the oncogenic potential of herpes virus in other animal hosts suggests the possibility of a similar role in human beings [13]. Since the minority of patients suffering from genital herpes eventually develop cervical cancer an individual susceptibility appears to be important [14]. In this respect it would be conceivable that certain HLA combine with the herpes virus, consequently transforming the cell. In this family study no association between cervical cancer and HLA-haplotype pattern was found, casting some doubt on this theory. It does not exclude, however, some unexplained genetic susceptibility in this family. Therefore we will follow the younger sisters of the patients with interest and care. ACKNOWLEDGMENTS The authors wish to thank Miss D. Go, cytopathologist at the Institute of Pathology of the Academisch Ziekenhuis in Utrecht, for revising all the specimens.
252
BRUINSE,
TE VELDE,
AND
DE GAST
REFERENCES 1. Dausset, J. Leuco-agglutinius IV. Leuco-agglutinius and blood transfusion, VOX Sanguinis 6, 190 (1954). 2. van Rood, J. J. Leucocyte grouping: A method and its application, Thesis, University of Leiden (1962). 3. Batchelor, J. R., and Chapman, B. A. Genetic background and transplantation antigens, J. Clin. Z’athol. 20, 415 (1967). 4. Bach, F. H., van Rood, J. J. The major histocompatibility complex. Genetics and biology, N. Engl. Journal of Medicine, 295, 806, 872, (1976). 5. MC Intyre, J. A., Turner, R. E., and Carwile, E. Human leucocyte antigens (HLA), South. Med. J. 71, 10, 1269 (1978). 6. Koenig, V. D., and Mtiller, N. Untersuchungen zur Bedeutung der Histocomptabilitats antigene bei Zervix Karzinom patientinnen, Geburtshilfe Frauenheilkunde 36, 416 (1976). 7. Koenig, V. D., and Mtiller, N. Der HLA-Polymor fismus und seine Beziehung zur ZervixNeoplasie, Fortschritten Medizin 95, 9, 565 (1977). 8. Teresaki, P. I., MC Clelland, J. D. Microdroplets assay of human serum cytotoxins, Nature (London) 204, 998 (1964). 9. Beral, Y. Cancer of the cervix: A sexually transmitted infection? Lancet I, 1037 (1974). 10. McDavitt, H. O., and Benacerraf, B. Genetic control of specific immuneresponses, Advan. Zmmunol. 11, 31 (1969). 11. Lawler Sylvia, D. HLA-antigens and malignant disease, Brit. J. Cancer 28 (Suppl.) 243 (1973). 12. Aurelian, L. The “viruses of love” and cancer, Amer. .Z. Med. Technol. 40, 11, 496 (1974). 13. Rapp, F., Reed, C. Experimental evidence for the oncogenic potential of herpes simplex virus, Cancer Res. 36, 800 (1976). 14. Naib, Z. M., Nahmias, A. J., Josey, W. E., et al. Relation of cyto-histopathology of genital herpes virus infection to anaplasia, Cancer Res. 33, 1452 (1973).