Integrated genomic and molecular characterization of cervical cancer

Robert D. Burk; Zigui Chen; Saller Cf; Katherine Tarvin; André L. Carvalho; Cristovam Scapulatempo-Neto; Henrique C. Silveira; José H. Fregnani; Chad J. Creighton; Matthew L. Anderson; Patricia Castro; Sophia S. Wang; C Yau; Christopher Benz; A. Gordon Robertson; Karen Mungall; Lynette Lim; Reanne Bowlby; Sara Sadeghi; Denise Brooks; Payal Sipahimalani; Richard Mar; Ally Ai; Amanda Clarke; Andrew J. Mungall; Angela Tam; Darlene Lee; Eric Chuah; Jacqueline E. Schein; Kane Tse; Katayoon Kasaian; Yussanne Ma; Marco A. Marra; Michael Mayo; Miruna Balasundaram; Nina Thiessen; Noreen Dhalla; Rebecca Carlsen; Richard A. Moore; Robert A. Holt; Steven J.M. Jones; Tina Wong; Angeliki Pantazi; Michael Parfenov; Raju Kucherlapati; Angela Hadjipanayis; J G Seidman; Melanie Kucherlapati; Xiaojia Ren; Andrew W. Xu; Lixing Yang; Peter J. Park; So Lee; Brenda Rabeno; Lori Huelsenbeck-Dill; Mark Borowsky; Mark Cadungog; Mary Iacocca; Nicholas Petrelli; Patricia Swanson; Akinyemi I. Ojesina; Bradley A. Murray; Hailei Zhang; Andrew D. Cherniack; Carrie Sougnez; Chandra Sekhar Pedamallu; Lee Lichtenstein; M. Meyerson; Michael S. Noble; David I. Heiman; Doug Voet; Getz Gs; Gordon Saksena; Jaegil Kim; Juliann Shih; Juok Cho; Michael S. Lawrence; Nils Gehlenborg; Pei Lin; Rameen Beroukhim; Scott Frazer; Stacey B. Gabriel; Steven E. Schumacher; Xuan Le; George Sandusky; Sally N. Adebamowo; Teniola Akeredolu; Clement Adebamowo; Sheila M. Reynolds; Ilya Shmulevich; Candace Shelton; Daniel Crain; David Mallery; Erin Curley; Johanna Gardner; Robert Penny; Scott Morris; Troy Shelton; J B Liu; Laxmi Lolla

doi:10.1038/nature21386

Abstract

Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers. This paper describes molecular subtypes of cervical cancers, including squamous cell carcinoma and adenocarcinoma clusters defined by HPV status and molecular features, and distinct molecular pathways that are activated in cervical carcinomas caused by different somatic alterations and HPV types. Cervical cancer is one of the main causes of cancer-related deaths worldwide, and 95% of cases result from human papilloma virus (HPV) infection. The Cancer Genome Atlas Research Network now reports the genomic and molecular characterization of 228 primary cervical cancers. The authors identify significantly mutated genes and pathways that differ by cervical cancer subtype, and find that keratin-low squamous, keratin-high squamous and adenocarcinoma-rich clusters are marked by different HPV types and molecular features.

Research topics

Cancer Immunotherapy and Biomarkers Cancer-related molecular mechanisms research Cervical Cancer and HPV Research

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