Multisite analysis of high‐grade serous epithelial ovarian cancers identifies genomic regions of focal and recurrent copy number alteration in 3q26.2 and 8q24.3

High‐grade serous epithelial ovarian cancer (HGS‐EOC) is a systemic disease, with marked intra and interpatient tumor heterogeneity. The issue of spatial and temporal heterogeneity has long been overlooked, hampering the possibility to identify those genomic alterations that persist, before and after therapy, in the genome of all tumor cells across the different anatomical districts. This knowledge is the first step to clarify those molecular determinants that characterize the tumor biology of HGS‐EOC and their route toward malignancy. In our study, ‐omics data were generated from 79 snap frozen matched tumor biopsies, withdrawn before and after chemotherapy from 24 HGS‐EOC patients, gathered together from independent cohorts. The landscape of somatic copy number alterations depicts a more homogenous and stable genomic portrait than the single nucleotide variant profile. Genomic identification of significant targets in cancer analysis identified two focal and minimal common regions (FMCRs) of amplification in the cytoband 3q26.2 (region α, 193 kb long) and 8q24.3 (region β, 495 kb long). Analysis in two external databases confirmed regions α and β are features of HGS‐EOC. The MECOM gene is located in region α, and 15 genes are in region β. No functional data are yet available for the genes in the β region. In conclusion, we have identified for the first time two FMCRs of amplification in HGS‐EOC, opening up a potential biological role in its etiopathogenesis.

[1]  Oliver Hofmann,et al.  Copy-number signatures and mutational processes in ovarian carcinoma , 2017, Nature Genetics.

[2]  L. Chin,et al.  PRKCI promotes immune suppression in ovarian cancer , 2017, Genes & development.

[3]  M D'Incalci,et al.  Profiling cancer gene mutations in longitudinal epithelial ovarian cancer biopsies by targeted next-generation sequencing: a retrospective study. , 2015, Annals of Oncology.

[4]  Joshy George,et al.  Whole–genome characterization of chemoresistant ovarian cancer , 2015, Nature.

[5]  Evis Sala,et al.  Spatial and Temporal Heterogeneity in High-Grade Serous Ovarian Cancer: A Phylogenetic Analysis , 2015, PLoS medicine.

[6]  M. D’Incalci,et al.  Regional and temporal heterogeneity of epithelial ovarian cancer tumor biopsies: implications for therapeutic strategies , 2014, Oncotarget.

[7]  Yan Guo,et al.  Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk , 2014, Nature Genetics.

[8]  J. Pringle,et al.  Plasticity of melanoma and EMT-TF reprogramming , 2013, Oncotarget.

[9]  Ali Bashashati,et al.  Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling , 2013, The Journal of pathology.

[10]  J. George,et al.  Nonequivalent Gene Expression and Copy Number Alterations in High-Grade Serous Ovarian Cancers with BRCA1 and BRCA2 Mutations , 2013, Clinical Cancer Research.

[11]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[12]  G. Getz,et al.  GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers , 2011, Genome Biology.

[13]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[14]  A. Whittemore,et al.  A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24 , 2010, Nature Genetics.

[15]  Deborah Hughes,et al.  Genome-wide association study identifies five new breast cancer susceptibility loci , 2010, Nature Genetics.

[16]  Derek Y. Chiang,et al.  The landscape of somatic copy-number alteration across human cancers , 2010, Nature.

[17]  J. Staaf,et al.  High-Resolution Genomic Profiling of Carboplatin Resistance in Early-Stage Epithelial Ovarian Carcinoma , 2009, Cytogenetic and Genome Research.

[18]  Chris Sander,et al.  An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors , 2009, Oncogene.

[19]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[20]  Derek Y. Chiang,et al.  Characterizing the cancer genome in lung adenocarcinoma , 2007, Nature.

[21]  Steven Gallinger,et al.  Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24 , 2007, Nature Genetics.

[22]  D. Gudbjartsson,et al.  Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24 , 2007, Nature Genetics.

[23]  Peter Kraft,et al.  A common 8q24 variant in prostate and breast cancer from a large nested case-control study. , 2007, Cancer research.

[24]  A. Whittemore,et al.  Multiple regions within 8q24 independently affect risk for prostate cancer , 2007, Nature Genetics.

[25]  Gordon B Mills,et al.  Atypical PKCiota contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  W. Sauerbrei,et al.  Reporting recommendations for tumor marker prognostic studies (REMARK). , 2005, Journal of the National Cancer Institute.

[27]  N. Carter,et al.  Array Comparative Genomic Hybridization Analysis of Colorectal Cancer Cell Lines and Primary Carcinomas , 2004, Cancer Research.

[28]  Yu Shyr,et al.  Significance of p63 amplification and overexpression in lung cancer development and prognosis. , 2003, Cancer research.

[29]  J. Inazawa,et al.  TERC identified as a probable target within the 3q26 amplicon that is detected frequently in non-small cell lung cancers. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[30]  J. Inazawa,et al.  Identification of ZASC1 encoding a Krüppel-like zinc finger protein as a novel target for 3q26 amplification in esophageal squamous cell carcinomas. , 2003, Cancer research.

[31]  J. Shah,et al.  The role of novel oncogenes squamous cell carcinoma-related oncogene and phosphatidylinositol 3-kinase p110alpha in squamous cell carcinoma of the oral tongue. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[32]  Heinz Becker,et al.  Gain of chromosome 8q23-24 is a predictive marker for lymph node positivity in colorectal cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  J. Shah,et al.  Amplification of the 3q26.3 locus is associated with progression to invasive cancer and is a negative prognostic factor in head and neck squamous cell carcinomas. , 2002, The American journal of pathology.

[34]  B. Wullich,et al.  Novel amplification unit at chromosome 3q25–q27 in human prostate cancer , 2000, The Prostate.

[35]  N. Tanaka,et al.  Molecular definition of a small amplification domain within 3q26 in tumors of cervix, ovary, and lung. , 2000, Cancer genetics and cytogenetics.

[36]  D. Bostwick,et al.  Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma. , 1999, Journal of the National Cancer Institute.

[37]  S. Cannistra Cancer of the ovary. , 1993, The New England journal of medicine.

[38]  E. Berns,et al.  Genetic heterogeneity after first-line chemotherapy in high-grade serous ovarian cancer. , 2016, European journal of cancer.