The KRAS-Variant Is Associated with Risk of Developing Double Primary Breast and Ovarian Cancer

Abstract

PurposeA 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.Experimental DesignGermline 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.ResultsThe 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.ConclusionsThese 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.

Estrogen withdrawal, increased breast cancer risk and the KRAS-variant

“…In addition, although KRASvariant patients were not significantly more likely to have a family history of breast or ovarian cancer than non-variant BC patients (62.66% vs 64.01%, NS), they were significantly more likely to have a family history of a relative with multiple primary cancers than non-variant BC patients (4.98% vs 0.92%, P < 0.0001), in agreement with our prior findings of increased multiple primary cancer risk. 6 The association of HRT with BC subtype and grade We next evaluated the association of hormone replacement therapy (HRT) use and tumor biology in women with the KRAS-variant. We grouped post-menopausally diagnosed BC patients into 3 HRT use groups based on their HRT use at the time of their diagnosis.…”

“…This evidence includes: a higher risk of nonsmall cell lung cancer in women versus men with the KRAS-variant (unpublished data); ovarian cancer almost exclusively postmenopausally for women with the KRAS-variant; 6 an increased risk of estrogen receptor (ER) negative tumor development in KRAS-variant patients (TNBC and type II uterine cancer, 32 ) and; the finding that post-menopausal KRAS-variant BC patients with a history of HRT use are more likely to develop biologically aggressive BC. 33 Although it may seem unusual that an external exposure, such as estrogen, could impact the function of an inherited 3 0 UTR variant like the KRAS-variant, there is in fact strong evidence that such miRNA binding site mutations are "influenced" by external exposures.…”

“…2 This mutation predicts an increased risk of several cancers, including non-small cell lung cancer, 2 triple negative breast cancer (TNBC) in premenopausal women 3 and ovarian cancer. [4][5][6] The KRAS-variant also predicts unique tumor biology, with tumors in KRAS-variant patients exhibiting a KRAS-addicted signature, as well as an estrogen negative, basal-like gene expression pattern. 3,5 Perhaps most powerful is the extensive evidence that the KRAS-variant is biologically functional, as exemplified by its role as a strong biomarker of response to cancer therapy.…”

“…8 Women with the KRAS-variant are also at a significantly increased risk of developing multiple primary cancers, including breast and ovarian cancer, as well as a third independent cancer in their lifetime. 6 Multiple primary cancer, although difficult to predict, is not rare, as one in 8 cancer patients will be diagnosed with a new primary cancer after their first cancer diagnosis (metachronous cancer), and one in 40 patients will be diagnosed with 2 cancers at the same time (synchronous cancer). 10 While it is hypothesized that some metachronous cancers are caused by primary cancer treatment, it is also thought that genetics may play a significant role in the development of both synchronous and metachronous cancers.…”

“…21 Most recently, the KRAS-variant was found to also be associated with MPBC in a small case series, as it was found in 57.1% (4/7) of patients who developed bilateral BC and ovarian cancer who were uninformative (BRCA negative). 6 Factors thought to decrease MPBC risk have also been identified, and include menarche after age 13, multiparity, 17 treatment with anti-hormonal agents or chemotherapy 22,23 and prophylactic surgical intervention. 24 These findings suggest that multiple primary BC risk can be impacted by estrogen alterations either before or after the first BC diagnosis.…”