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Racial Differences in Lung Cancer Genetics
Editorial
Racial Differences in Lung Cancer Genetics Kenichi Suda, MD, and Tetsuya Mitsudomi, MD
T
he clinical application of gefitinib has unexpectedly highlighted racial differences among patients with non–small-cell lung cancers since its initial clinical development.1 This first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor demonstrated greater efficacy in East-Asian patients compared with white patients. Later studies revealed that this difference was on the basis of differences in EGFR mutation frequency between these two ethnic populations.2–4 Other studies further analyzed EGFR mutation frequencies in black patients, reporting a lower (or similar) frequency of this mutation compared with white patients.5–7 The cause of EGFR mutation is currently unclear. However, evidence suggests that racial or genetic differences may play a more important role in their occurrence than differences in lifestyle, such as diet, or geographic location. For example, East-Asians born or living in the United States have a high EGFR mutation rate, similar to that of East-Asians living in their native countries.8 In addition, the recent PIONEER study (NCT01185314) observed a lower EGFR mutation frequency in Indian patients (22.2%) comparable with that of white patients,9 both of which are classified as Caucasians. The frequencies of other mutations in non–small-cell lung cancers, such as KRAS or STK11, have also been reported to differ among ethnic groups.6,7,10 Recent developments in next-generation sequencing techniques have detected high rates of genetic alterations, including EGFR and KRAS mutations, in human lung cancers.11 Does the mutational profiling of lung cancers differ between ethnic groups? In this issue of the Journal of Thoracic Oncology, Bollig-Fischer et al.12 compared genetic differences between 335 white and 137 black patients using a matrix-assisted laser desorption/ionization time-of-flight mass-spectrometry approach in relation to 214 coding mutations in 26 cancer-related genes previously identified in non–small-cell lung cancers. Histologically, the black patient cohort demonstrated a higher rate of adenocarcinoma (67%) compared with the white patient cohort (48%). One of the most interesting findings was the difference in mutation rates between these two ethnic groups; 32% of black patients and 41% of white patients harbored at least one mutation in the 26 genes studied. The odds ratio of black patients having one or more mutations, adjusted for covariates using a logistic regression model, was 0.582 (95% confidence interval, 0.363–0.933; p = 0.025), suggesting a lower mutation rate in black patients compared with white patients. Although the reason for this discrepancy in mutation rates between black and white patients is unclear, it can be hypothesized that fewer accumulated mutations may be needed to cause lung cancers in black people compared with white people. This could at least partly explain the earlier onset of lung cancers in black patients12; the mean age at diagnosis was 66 years in African Americans compared with 71 years in whites.7 However, despite lower overall mutation rates in black patients, further analyses identified a higher incidence of EGFR exon 19 deletion in female black compared with female white patients (odds ratio, 3.914; p = 0.048). Although another study has shown similar result,13 the reason(s) underlying this phenomenon remain unclear.
Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. Disclosure: T. Mitsudomi has received honoraria from AstraZeneca, Chugai, Boehringer-Ingelheim, Pfizer, Roche, Novartis, and Taiho and has played advisory role for AstraZeneca, Chugai, Boehringer-Ingelheim, Pfizer, Roche, and Clovis Oncology. K. Suda has no conflicts of interest. Address for correspondence: Tetsuya Mitsudomi, MD, Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, 377-2 OhnoHigashi, Osaka-Sayama 589–8511, Japan. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000439 Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1002-0230
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Journal of Thoracic Oncology ® • Volume 10, Number 2, February 2015
Journal of Thoracic Oncology ® • Volume 10, Number 2, February 2015
Bollig-Fischer et al.12 also analyzed tumor specimens for single nucleotide polymorphisms. The frequencies of these single nucleotide polymorphisms in tumor samples from black and white patients correlated with their reported frequencies in the respective ethnic groups in the general population in the United States. However, NOTCH1 V1671I (p = 0.01) and MET N375S (p = 0.076) polymorphisms were more frequent in patients with cancer compared with the general population in black patients and white patients, respectively. Further studies are needed to explore the biological and clinical implications of these differences. One limitation of this study was that the cohort mainly consisted of smokers (<10% were never smokers in both ethnic groups). Tobacco smoke contains several carcinogens that can form stable covalent DNA adducts and induce DNA single-strand breaks, leading to higher mutation rates in lung cancers in smokers compared with nonsmokers. The genetic differences observed in the study by Bollig-Fischer et al. therefore represent a combination of racial differences in the lung cancers themselves and racial differences in susceptibility to tobacco smoking. It is also debatable whether lung cancers in black patients can be considered as a single disease, given that many studies, including genome-wide studies, have indicated higher levels of genetic diversity in African populations, including African Americans, compared with non-Africans. The genetic diversity among black patients may thus be higher than that within other ethnic groups.14 In summary, the study by Bollig-Fisher et al. represents an attractive approach; however, its findings are largely observational, and the underlying backgrounds and clinical implications of their findings are unclear. Further analyses based on their findings are necessary. Racial differences in physical features among humans can be large, despite very small genetic differences between ethnic groups. In contrast, it is interesting that racial differences in lung cancer genetics are relatively large, despite indistinguishably small differences in the microscopic morphologies of lung cancers among ethnic groups.
Racial Differences in Lung Cancer Genetics
ACKNOWLEDGMENTS
This work is supported in part by Grants-in-Aid of Cancer Research from the Ministry of Education, Science, Sports, and Culture of Japan (K. Suda, 25830119). REFERENCES 1. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-smallcell lung cancer (The IDEAL 1 Trial). J Clin Oncol 2003;21:2237–2246. 2. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139. 3. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500. 4. Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 2007;98:1817–1824. 5. Leidner RS, Fu P, Clifford B, et al. Genetic abnormalities of the EGFR pathway in African American Patients with non-small-cell lung cancer. J Clin Oncol 2009;27:5620–5626. 6. Bauml J, Mick R, Zhang Y, et al. Frequency of EGFR and KRAS mutations in patients with non small cell lung cancer by racial background: do disparities exist? Lung Cancer 2013;81:347–353. 7. El-Telbany A, Ma PC. Cancer genes in lung cancer: racial disparities: are there any? Genes Cancer 2012;3:467–480. 8. Tsao AS, Tang XM, Sabloff B, et al. Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung cancer. J Thorac Oncol 2006;1:231–239. 9. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-smallcell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154–162. 10. Suda K, Tomizawa K, Mitsudomi T. Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation. Cancer Metastasis Rev 2010;29:49–60. 11. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543–550. 12. Bollig-Fischer A, Chen W, Gadgeel SM, et al. Racial diversity of actionable mutations in non-small cell lung cancer. J Thorac Oncol 2014;10:245–250. 13. Cote ML, Haddad R, Edwards DJ, et al. Frequency and type of epidermal growth factor receptor mutations in African Americans with non-small cell lung cancer. J Thorac Oncol 2011;6:627–630. 14. Campbell MC, Tishkoff SA. The evolution of human genetic and phenotypic variation in Africa. Curr Biol 2010;20:R166–R173.
Copyright © 2014 by the International Association for the Study of Lung Cancer
231
Racial Differences in Lung Cancer Genetics Kenichi Suda, MD, and Tetsuya Mitsudomi, MD
T
he clinical application of gefitinib has unexpectedly highlighted racial differences among patients with non–small-cell lung cancers since its initial clinical development.1 This first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor demonstrated greater efficacy in East-Asian patients compared with white patients. Later studies revealed that this difference was on the basis of differences in EGFR mutation frequency between these two ethnic populations.2–4 Other studies further analyzed EGFR mutation frequencies in black patients, reporting a lower (or similar) frequency of this mutation compared with white patients.5–7 The cause of EGFR mutation is currently unclear. However, evidence suggests that racial or genetic differences may play a more important role in their occurrence than differences in lifestyle, such as diet, or geographic location. For example, East-Asians born or living in the United States have a high EGFR mutation rate, similar to that of East-Asians living in their native countries.8 In addition, the recent PIONEER study (NCT01185314) observed a lower EGFR mutation frequency in Indian patients (22.2%) comparable with that of white patients,9 both of which are classified as Caucasians. The frequencies of other mutations in non–small-cell lung cancers, such as KRAS or STK11, have also been reported to differ among ethnic groups.6,7,10 Recent developments in next-generation sequencing techniques have detected high rates of genetic alterations, including EGFR and KRAS mutations, in human lung cancers.11 Does the mutational profiling of lung cancers differ between ethnic groups? In this issue of the Journal of Thoracic Oncology, Bollig-Fischer et al.12 compared genetic differences between 335 white and 137 black patients using a matrix-assisted laser desorption/ionization time-of-flight mass-spectrometry approach in relation to 214 coding mutations in 26 cancer-related genes previously identified in non–small-cell lung cancers. Histologically, the black patient cohort demonstrated a higher rate of adenocarcinoma (67%) compared with the white patient cohort (48%). One of the most interesting findings was the difference in mutation rates between these two ethnic groups; 32% of black patients and 41% of white patients harbored at least one mutation in the 26 genes studied. The odds ratio of black patients having one or more mutations, adjusted for covariates using a logistic regression model, was 0.582 (95% confidence interval, 0.363–0.933; p = 0.025), suggesting a lower mutation rate in black patients compared with white patients. Although the reason for this discrepancy in mutation rates between black and white patients is unclear, it can be hypothesized that fewer accumulated mutations may be needed to cause lung cancers in black people compared with white people. This could at least partly explain the earlier onset of lung cancers in black patients12; the mean age at diagnosis was 66 years in African Americans compared with 71 years in whites.7 However, despite lower overall mutation rates in black patients, further analyses identified a higher incidence of EGFR exon 19 deletion in female black compared with female white patients (odds ratio, 3.914; p = 0.048). Although another study has shown similar result,13 the reason(s) underlying this phenomenon remain unclear.
Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. Disclosure: T. Mitsudomi has received honoraria from AstraZeneca, Chugai, Boehringer-Ingelheim, Pfizer, Roche, Novartis, and Taiho and has played advisory role for AstraZeneca, Chugai, Boehringer-Ingelheim, Pfizer, Roche, and Clovis Oncology. K. Suda has no conflicts of interest. Address for correspondence: Tetsuya Mitsudomi, MD, Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, 377-2 OhnoHigashi, Osaka-Sayama 589–8511, Japan. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000439 Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1002-0230
230
Journal of Thoracic Oncology ® • Volume 10, Number 2, February 2015
Journal of Thoracic Oncology ® • Volume 10, Number 2, February 2015
Bollig-Fischer et al.12 also analyzed tumor specimens for single nucleotide polymorphisms. The frequencies of these single nucleotide polymorphisms in tumor samples from black and white patients correlated with their reported frequencies in the respective ethnic groups in the general population in the United States. However, NOTCH1 V1671I (p = 0.01) and MET N375S (p = 0.076) polymorphisms were more frequent in patients with cancer compared with the general population in black patients and white patients, respectively. Further studies are needed to explore the biological and clinical implications of these differences. One limitation of this study was that the cohort mainly consisted of smokers (<10% were never smokers in both ethnic groups). Tobacco smoke contains several carcinogens that can form stable covalent DNA adducts and induce DNA single-strand breaks, leading to higher mutation rates in lung cancers in smokers compared with nonsmokers. The genetic differences observed in the study by Bollig-Fischer et al. therefore represent a combination of racial differences in the lung cancers themselves and racial differences in susceptibility to tobacco smoking. It is also debatable whether lung cancers in black patients can be considered as a single disease, given that many studies, including genome-wide studies, have indicated higher levels of genetic diversity in African populations, including African Americans, compared with non-Africans. The genetic diversity among black patients may thus be higher than that within other ethnic groups.14 In summary, the study by Bollig-Fisher et al. represents an attractive approach; however, its findings are largely observational, and the underlying backgrounds and clinical implications of their findings are unclear. Further analyses based on their findings are necessary. Racial differences in physical features among humans can be large, despite very small genetic differences between ethnic groups. In contrast, it is interesting that racial differences in lung cancer genetics are relatively large, despite indistinguishably small differences in the microscopic morphologies of lung cancers among ethnic groups.
Racial Differences in Lung Cancer Genetics
ACKNOWLEDGMENTS
This work is supported in part by Grants-in-Aid of Cancer Research from the Ministry of Education, Science, Sports, and Culture of Japan (K. Suda, 25830119). REFERENCES 1. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-smallcell lung cancer (The IDEAL 1 Trial). J Clin Oncol 2003;21:2237–2246. 2. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139. 3. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500. 4. Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 2007;98:1817–1824. 5. Leidner RS, Fu P, Clifford B, et al. Genetic abnormalities of the EGFR pathway in African American Patients with non-small-cell lung cancer. J Clin Oncol 2009;27:5620–5626. 6. Bauml J, Mick R, Zhang Y, et al. Frequency of EGFR and KRAS mutations in patients with non small cell lung cancer by racial background: do disparities exist? Lung Cancer 2013;81:347–353. 7. El-Telbany A, Ma PC. Cancer genes in lung cancer: racial disparities: are there any? Genes Cancer 2012;3:467–480. 8. Tsao AS, Tang XM, Sabloff B, et al. Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung cancer. J Thorac Oncol 2006;1:231–239. 9. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-smallcell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154–162. 10. Suda K, Tomizawa K, Mitsudomi T. Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation. Cancer Metastasis Rev 2010;29:49–60. 11. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543–550. 12. Bollig-Fischer A, Chen W, Gadgeel SM, et al. Racial diversity of actionable mutations in non-small cell lung cancer. J Thorac Oncol 2014;10:245–250. 13. Cote ML, Haddad R, Edwards DJ, et al. Frequency and type of epidermal growth factor receptor mutations in African Americans with non-small cell lung cancer. J Thorac Oncol 2011;6:627–630. 14. Campbell MC, Tishkoff SA. The evolution of human genetic and phenotypic variation in Africa. Curr Biol 2010;20:R166–R173.
Copyright © 2014 by the International Association for the Study of Lung Cancer
231