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Genomic Profiles Specific to Patient Ethnicity in Lung Adenocarcinoma Running Title: Ethnic-Specific Chromosomal Aberrations in NSCLC

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Genomic Profiles Specific to Patient Ethnicity in Lung Adenocarcinoma Running Title: Ethnic-Specific Chromosomal Aberrations in NSCLC Author Manuscript Published OnlineFirst on April 26, 2011; DOI: 10.1158/1078-0432.CCR-10-2185 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ethnic-specific chromosomal aberrations in NSCLC 1 Genomic Profiles Specific to Patient Ethnicity in Lung Adenocarcinoma Running title: Ethnic-specific chromosomal aberrations in NSCLC Philippe Broët1,2,3, Cyril Dalmasso1, Eng Huat Tan4, Marco Alifano3, Shenli Zhang5, Jeanie Wu6, Ming Hui Lee6, Jean-François Régnard3,7, Darren Lim4, Heng Nung Koong4, Thirugnanam Agasthian8, Lance D. Miller1,9, Elaine Lim5, Sophie Camilleri-Broët2, Patrick Tan1,6,10 1 Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome, Singapore 138672; 2 Univ Paris-Sud, JE2492, Villejuif, 12 Avenue Paul-Vaillant-Couturier, Villejuif F-94807, France; 3 APHP (Assistance Publique Hôpitaux de Paris), 3 Avenue Victoria, 75004 Paris, France; 4 National Cancer Centre, 11 Hospital Drive Singapore 169610; 5 Yong Loo Lin School of Medicine, NUS; 10 Medical Drive, Singapore 117597; 6 Duke-NUS Graduate Medical School; 8 College Road Singapore 169857; 7 Faculty of Medicine Paris-Descartes, 15 rue de l’Ecole de Médecine, 75006 Paris, France; 8 Singapore General Hospital, Outram Road Singapore 169608; 9 Wake Forest University School of Medicine, Medical Center Boulevard Winston-Salem, N.C. 27157, USA; 10 Cancer Sciences Institute of Singapore, NUS, 28 Medical Drive, Singapore 117456. Address for reprint requests: Dr. Philippe Broët Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome, Singapore 138672 Tel: (65) 6808 8000; E-mail: [email protected], [email protected] Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 26, 2011; DOI: 10.1158/1078-0432.CCR-10-2185 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ethnic-specific chromosomal aberrations in NSCLC 2 Abstract Purpose: East-Asian (EA) patients with Non Small Cell Lung Cancer (NSCLC) are associated with a high proportion of non-smoking women, EGFR activating somatic mutations, and clinical responses to tyrosine kinase inhibitors. We sought to identify novel molecular differences between EA and Western European (WE) NSCLCs. Experimental Design: 226 EA (90) and WE (136) lung adenocarcinomas were analyzed for copy-number aberrations (CNAs) using a common high resolution SNP microarray platform. Univariate and multivariate analyses were performed to identify CNAs specifically related to smoking history, EGFR mutation status and ethnicity. Results: The overall genomic profiles of EA and WE adenocarcinomas were highly similar. Univariate analyses revealed several CNAs significantly associated with ethnicity, EGFR mutation and smoking, but not to gender, KRAS or p53 mutations. A multivariate model identified four ethnic-specific recurrent CNAs - Significantly higher rates of copy number gain were observed on 16p13.13 and 16p13.11 in EA tumors, while higher rates of genomic loss on 19p13.3 and 19p13.11 were observed in WE tumors. We identified several potential driver genes in these regions, showing a positive correlation between cis-localized copy number changes and transcriptomic changes. Conclusion: 16p copy number gains (EA) and 19p losses (WE) are ethnic-specific chromosomal aberrations in lung adenocarcinoma. Patient ethnicity should be considered when evaluating future NSCLC therapies targeting genes located on Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 26, 2011; DOI: 10.1158/1078-0432.CCR-10-2185 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ethnic-specific chromosomal aberrations in NSCLC 3 these areas. Keywords: Lung Cancer, Comparative Genomic, Gene amplification Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 26, 2011; DOI: 10.1158/1078-0432.CCR-10-2185 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ethnic-specific chromosomal aberrations in NSCLC 4 Statement of Translational Relevance East-Asian (EA) and Western European (WE) patients with Non Small Cell Lung Cancer (NSCLC) several exhibit epidemiologic and molecular differences, including a high proportion of non-smoking women, EGFR activating somatic mutations, and clinical responses to tyrosine kinase inhibitor therapy in EA cancers. However, whether differences exist in the pattern of copy-number alterations (CNAs) between EA and WE populations is currently unknown. We report the first large scale comparative analysis of genomic alteration profiles between lung adenocarcinomas from EA and WE populations. We identify two ethnic-specific CNAs: 16p13 amplification (Asian-specific) and 19p13 deletion (Caucasian specific). We discuss candidate copy-number driven genes located on these areas. Our findings emphasize the need to take into account ethnicity in the design of future NSCLC clinical trials evaluating targeted therapies involving copy-number driven candidate genes located on those ethnic-specific genomic regions. Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 26, 2011; DOI: 10.1158/1078-0432.CCR-10-2185 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ethnic-specific chromosomal aberrations in NSCLC 5 Introduction Lung cancer is a common malignancy worldwide and the leading cause of global cancer mortality in both males and females (1). Clinical and epidemiological studies on non small cell lung carcinomas (NSCLC) from patients of Asian and Caucasian origin have revealed substantial clinical and molecular differences between the two populations, with the former exhibiting a higher proportion of non-smoking females, adenocarcinomas and epidermal growth factor receptor (EGFR) mutations (2-5). Some studies have shown that EGFR mutations, which are currently used as predictive markers of clinical response to EGFR tyrosine kinase inhibitors (TKis), are linked with EGFR gene amplifications (6-7). Since Asian patients are known to exhibit higher response rates to EGFR TKis, these findings raise the possibility that in addition to DNA mutations, recurrent copy-number aberrations (CNAs) (amplifications/deletions) specific to Asian and Caucasian NSCLC patients may also exist. To date, most reported large CNA analyses of NSCLC have largely comprised tumors of Caucasian origin, identifying important oncogenic loci such as Myc, TTF-1 (NKX2-1), and E2F (8-12). In contrast, similar CNA data on Asian NSCLCs has either been sparse, unavailable, or only available as small patient populations or low resolution technologies. Identifying discrete CNA differences between Asian and Caucasian NSCLCs would suggest that these two conditions represent distinct biological and clinical entities. The discovery of ethnic-specific CNAs would also argue for patient ethnicity being an important consideration in the design and evaluation of future targeted therapies in lung cancer, if the targeted genes involve ethnic specific CNAs. Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 26, 2011; DOI: 10.1158/1078-0432.CCR-10-2185 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ethnic-specific chromosomal aberrations in NSCLC 6 Here, we report the first large scale comparative analysis of genomic alteration profiles between lung adenocarcinomas from East-Asian (EA) and Western Europe (WE). Using a common high-resolution SNP microarray platform, we found that the genomic profiles of lung adenocarcinomas from both populations were highly similar, except for a limited number of chromosomal aberrations that could be ascribed to specific differences in smoking history, EGFR mutation status or ethnicity. We also identified interesting copy-number driven candidate genes located on these ethnic-specific chromosomal aberrations 16p13 (EA) and 19p13 (WE). These results emphasize the need to take into account ethnicity in future lung adenocarcinoma clinical trials targeting oncogenic pathways that involve copy-number driven candidate genes located on those ethnic-specific genomic areas. Material and Methods Patients & Procedures Frozen samples of 318 lung carcinomas were processed. Tumors from Western European patients (n=157, WE series) were collected at the Hotel-Dieu hospital (Paris, France) between 2000 and 2005. Tumors from East-Asian patients (n=162, predominantly Asian-Chinese, EA series) were collected at four centres (National University Hospital, Tan Tock Seng Hospital, National Cancer Centre Singapore, and Singapore General Hospital) between 2002 and 2006. All samples were surgical specimens and underwent pathological review. Tumor samples were immediately frozen at –80°C until retrieved. Only tissue samples with tumor cells >50% were selected. The two series were initially collected from different perspectives Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2011 American Association
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