The KRAS-variant is associated with risk of developing double primary breast and ovarian cancer.
OBJECTIVE
A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is associated with an increased risk of developing several cancers. Because this variant is most strongly associated with ovarian cancer risk in patients from hereditary breast and ovarian families (HBOC), and with the risk of premenopausal triple negative breast cancer, we evaluated the association of the KRAS-variant with women with personal histories of both breast and ovarian cancer, referred to as double primary patients.


METHODS
Germline DNA from double primary patients was tested for the KRAS-variant (n = 232). Confirmation of pathologic diagnoses, age of diagnoses, interval between ovarian cancer diagnosis and sample collection, additional cancer diagnoses, and family history were obtained when available. All patients were tested for deleterious BRCA mutations.


RESULTS
The KRAS-variant was significantly enriched in uninformative (BRCA negative) double primary patients, being found in 39% of patients accrued within two years of their ovarian cancer diagnosis. Furthermore, the KRAS-variant was found in 35% of uninformative double primary patients diagnosed with ovarian cancer post-menopausally, and was significantly associated with uninformative double primary patients with a positive family history. The KRAS-variant was also significantly enriched in uninformative patients who developed more then two primary cancers, being found in 48% of women with two breast primaries plus ovarian cancer or with triple primary cancers.


CONCLUSIONS
These findings further validate the importance of the KRAS-variant in breast and ovarian cancer risk, and support the association of this variant as a genetic marker for HBOC families previously considered uninformative.
The Ohio State University Comprehensive Cancer Center and Department of Internal Medicine, Columbus, Ohio, United States of America. Robert.Pilarski@osumc.edu
Robert
R
Pilarski
Divya A
DA
Patel
Jeffrey
J
Weitzel
Terri
T
McVeigh
Jemima J
JJ
Dorairaj
Helen M
HM
Heneghan
Nicola
N
Miller
Joanne B
JB
Weidhaas
Michael J
MJ
Kerin
Megan
M
McKenna
Xifeng
X
Wu
Michelle
M
Hildebrandt
Daniel
D
Zelterman
Sharon
S
Sand
Lee P
LP
Shulman
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D011905:Genes, ras; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009378:Neoplasms, Multiple Primary / Q000453:epidemiology / Q000235:genetics; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D015995:Prevalence; D012306:Risk