Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma

Zhao S.; Choi M.; Overton J.D.Bellone S.Roque D.M.Cocco E.Guzzo F.English D.P.Varughese J.Gasparrini S.Bortolomai I.Buza N.Hui P.Abu-Khalaf M.Ravaggi A.Bignotti E.Bandiera E.Romani C.Todeschini P.Tassi R.Zanotti L.Carrara L.Pecorelli S.Silasi D.-A.Ratner E.

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Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma

机译：Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma

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Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape of USC by whole-exome sequencing of 57 cancers, most of which were matched to normal DNA from the same patients. The distribution of the number of protein-altering somatic mutations revealed that 52 USC tumors had fewer than 100 (median 36), whereas 5 had more than 3,000 somatic mutations. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch repair. Among the remainder, we found a significantly increased burden ofmutation in 14 genes. In addition to well-known cancer genes (i.e., TP53, PIK3CA, PPP2R1A, KRAS, FBXW7), there were frequent mutations in CHD4/Mi2b, a member of the NuRD-chromatin-remodeling complex, and TAF1, an element of the core TFIID transcriptional machinery. Additionally, somatic copy-number variation was found to play an important role inUSC, with 13 copy-number gains and 12 copy-number losses that occurred more often than expected by chance. In addition to loss of TP53, we found frequent deletion of a small segment of chromosome 19 containing MBD3, also a member of the NuRD-chromatin-modification complex, and frequent amplification of chromosome segments containing PIK3CA, ERBB2 (an upstream activator of PIK3CA), and CCNE1 (a target of FBXW7-mediated ubiquitination). These findings identify frequent mutation of DNA damage, chromatin remodeling, cell cycle, and cell proliferation pathways in USC and suggest potential targets for treatment of this lethal variant of endometrial cancer.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第8期|2916-2921|共6页
作者
Zhao S.; Choi M.; Overton J.D.Bellone S.Roque D.M.Cocco E.Guzzo F.English D.P.Varughese J.Gasparrini S.Bortolomai I.Buza N.Hui P.Abu-Khalaf M.Ravaggi A.Bignotti E.Bandiera E.Romani C.Todeschini P.Tassi R.Zanotti L.Carrara L.Pecorelli S.Silasi D.-A.Ratner E.;
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作者单位

Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, United States;

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, United States;

Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, United StatesDepartment of Internal Medicine and Oncology, Yale University School of Medicine, New Haven, CT 06510, United StatesDepartment of Obstetrics, and Gynecology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, 25123 Brescia, Italy;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Cancer genomics; Endometrial carcinoma; Uterine serous papillary cancer;

Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma

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