Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
OBJECTIVE
Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain.


METHODS
Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway.


RESULTS
Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation.


CONCLUSIONS
Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials.
Authors' Affiliations: Division of Gynecologic Oncology; Division of Medical Genetics; Departments of Pathology and Laboratory Medicine, University of Washington Medical Center, Seattle, Washington.
Kathryn P
KP
Pennington
Tom
T
Walsh
Maria I
MI
Harrell
Ming K
MK
Lee
Christopher C
CC
Pennil
Mara H
MH
Rendi
Anne
A
Thornton
Barbara M
BM
Norquist
Silvia
S
Casadei
Alexander S
AS
Nord
Kathy J
KJ
Agnew
Colin C
CC
Pritchard
Sheena
S
Scroggins
Rochelle L
RL
Garcia
Mary-Claire
MC
King
Elizabeth M
EM
Swisher
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002277:Carcinoma / Q000235:genetics* / Q000401:mortality; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059765:Homologous Recombination / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D017671:Platinum Compounds / Q000627:therapeutic use
D000970:Antineoplastic Agents; D017671:Platinum Compounds