|
|
|
|
|
|
|
|
abstract
Purpose: 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 (HR) DNA repair genes is uncertain.
Experimental Design: 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 HR
pathway.
Results: 31% of ovarian carcinomas had a
deleterious germline (24%) and/or somatic (9%) mutation in one or more
of the 13
HR genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1,
CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Non-serous
ovarian
carcinomas had similar rates of HR mutations to
serous carcinomas (28% vs. 31%, p=0.6), including clear cell,
endometrioid,
and carcinosarcoma. The presence of germline and
somatic HR mutations was highly predictive of primary platinum
sensitivity
(p=0.0002) and improved overall survival
(p=0.0006), with median overall survival 66 months in germline HR
mutation carriers,
59 months in cases with a somatic HR mutation, and
41 months for cases without an HR mutation.
Conclusions: Germline or somatic mutations in HR
genes are present in almost one-third of ovarian carcinomas, including
both
serous and non-serous histologies. Somatic BRCA1/2
mutations and mutations in other HR genes have a similar positive impact
on overall survival and platinum responsiveness as
germline BRCA1/2 mutations. The similar rate of HR mutations in
non-serous
carcinomas supports their inclusion in PARP
inhibitor clinical trials.
0 comments :
Post a Comment
Your comments?
Note: Only a member of this blog may post a comment.