Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing

Tom Walsh, Silvia Casadei, Ming K. Lee, Christopher C. Pennil, Alexander Nord, Anne M. Thornton, Wendy Roeb, Kathy J. Agnew, Sunday M. Stray, Anneka Wickramanayake, Barbara Norquist, Kathryn P. Pennington, Rochelle L. Garcia, Mary Claire King, Elizabeth M. Swisher

Research output: Contribution to journalArticle

477 Citations (Scopus)

Abstract

Inherited loss-of-function mutations in BRCA1 and BRCA2 and other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due to inherited mutations is not known. Using targeted capture and massively parallel genomic sequencing, we screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma. Subjects were consecutively enrolled at diagnosis and not selected for age or family history. All classes of mutations, including point mutations and large genomic deletions and insertions, were detected. Of 360 subjects, 24% carried germ-line loss-of-function mutations: 18% in BRCA1 or BRCA2 and 6% in BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53. Six of these genes were not previously implicated in inherited ovarian carcinoma. Primary carcinomas were generally characterized by genomic loss of normal alleles of the mutant genes. Of women with inherited mutations, >30% had no family history of breast or ovarian carcinoma, and >35% were 60 y or older at diagnosis. More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost.

Original languageEnglish (US)
Pages (from-to)18032-18037
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number44
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

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High-Throughput Nucleotide Sequencing
Fallopian Tubes
Carcinoma
Mutation
Genes
Genetic Testing
Tumor Suppressor Genes
Germ-Line Mutation
Point Mutation
Germ Cells
Breast
Alleles
Costs and Cost Analysis
DNA

ASJC Scopus subject areas

  • General

Cite this

Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. / Walsh, Tom; Casadei, Silvia; Lee, Ming K.; Pennil, Christopher C.; Nord, Alexander; Thornton, Anne M.; Roeb, Wendy; Agnew, Kathy J.; Stray, Sunday M.; Wickramanayake, Anneka; Norquist, Barbara; Pennington, Kathryn P.; Garcia, Rochelle L.; King, Mary Claire; Swisher, Elizabeth M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 44, 01.11.2011, p. 18032-18037.

Research output: Contribution to journalArticle

Walsh, T, Casadei, S, Lee, MK, Pennil, CC, Nord, A, Thornton, AM, Roeb, W, Agnew, KJ, Stray, SM, Wickramanayake, A, Norquist, B, Pennington, KP, Garcia, RL, King, MC & Swisher, EM 2011, 'Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 44, pp. 18032-18037. https://doi.org/10.1073/pnas.1115052108
Walsh, Tom ; Casadei, Silvia ; Lee, Ming K. ; Pennil, Christopher C. ; Nord, Alexander ; Thornton, Anne M. ; Roeb, Wendy ; Agnew, Kathy J. ; Stray, Sunday M. ; Wickramanayake, Anneka ; Norquist, Barbara ; Pennington, Kathryn P. ; Garcia, Rochelle L. ; King, Mary Claire ; Swisher, Elizabeth M. / Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 44. pp. 18032-18037.
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