KRAS MUTATION IN FAMILIAL OVARIAN CANCER

MacConaill LE, Garraway LA
J Clin Oncol. 2010;28:5219-5228

Summary

Previous research identified an uncommon variant of the KRAS oncogene (rs61764370) that increases levels of KRAS in in vitro assays, suggesting that it may be associated with a biologically relevant increased risk for cancer development.^[1] Indeed, 2 case-control studies revealed a greater risk for the development of non-small cell lung cancer in individuals with this mutation vs those without the mutation. Although the variant is seen in fewer than 20% of patients with all solid tumors, it is present in more than 25% of patients with epithelial ovarian cancer.^[1]
In the analysis by Ratner and colleagues, investigators exploring an association between the presence of rs61764370 and the risk of developing ovarian cancer found the mutation in 25% of patients examined vs only 15% of individuals in a non-cancer "control" population. Of greatest interest, however, the KRAS mutation was found in 19 (61%) of 31 patients who appeared to have a familial history of ovarian cancer but no evidence of a BRCA1 or BRCA2 mutation. When compared with families with a BRCA association, patients in this group were less likely to have Jewish Ashkenazi ethnicity, and were more likely to be older and to have a history of lung cancer within the family.
In their review article, MacConaill and Garraway identify KRAS and BRCA as classic examples of synthetic lethality, in which cancer cell growth driven by expression of an oncogene is, in turn, dependent on expression of a second gene for survival. Whether a druggable target will be found for KRAS-mutated ovarian cancer similar to poly ADP ribose polymerase (PARP) inhibitors in BRCA-mutated breast cancer^[2] remains to be seen, but the identification of the KRAS mutation in this patient population certainly points to new possible avenues for therapeutic intervention.