We've heard a lot about the impact of KRAS in colorectal cancer as a useful biomarker for determining whether or not to treat with EGFR therapy, depending on whether the mutation is wild-type or mutated, but now new evidence has emerged for it's possible role in ovarian cancer.

A paper by Ratner et al., from Yale University, looked at the relationship between an increased risk of OC and a KRAS variant.

Overall, the data demonstrated that a variant of the KRAS oncogene was present in 25% of all ovarian cancer patients. The same variant was also found in 61% of ovarian cancer patients with a family history of breast and ovarian cancer. Up until now though, it has proven impossible to tell which women with a strong family history of breast and ovarian cancers would go on to develop the disease. These results therefore offer some new clues in the puzzle.

Related research from another team from the UK, Denmark and US, published last year, looked at tagging single-nucleotide polymorphisms (SNPs) in candidate oncogenes and the susceptibility to ovarian cancer in approx. 1,800 women with invasive ovarian cancer compared with controls (n=3,000). The goal was to identify moderate/low-risk susceptibility alleles of the proto-oncogenes BRAF, ERBB2, KRAS, NMI, and PIK3CA, but no evidence of ovarian cancer association was found with these SNPs. When stratified by
histologic subtype, however, one common variant allele have borderline evidence of association with epithelial ovarian cancer.

What was interesting to me in the latest research from Yale is that all the women in the study had a strong family history of cancer, but only half had known genetic markers of ovarian cancer risk such as BRCA1 or BRCA2 mutations. The results, albeit from a small sample (n=157), suggest that the KRAS variant may offer a more sensitive than currently available. 

The Yale group had previously established that the KRAS-variant is not somatic but germline, meaning it is identical in person's normal and tumour tissues, thereby enabling the researchers to collect primarily germline DNA from either blood or saliva, rather than from tumour biopsy samples.  This is huge from a patient perspective and physician point of view in terms of ease of use and convenience.

This study is important because ovarian cancer is the single most deadly form of women's cancer and is usually diagnosed in advanced stage disease.  Part of the reason is because of the lack of known risk factors or genetic markers of risk.  To this end, the authors concluded:

"Our findings strongly support the hypothesis that the KRAS-variant is a genetic marker for increased risk of developing ovarian cancer, and they suggest that the KRAS-variant may be a new genetic marker of cancer risk for hereditary breast and ovarian cancer families without other known genetic abnormalities."

What we now need is validation in large scale clinical trials to determine whether the genetic marker can be used commercially to determine prognostic risk for ovarian cancer earlier.  If the results ultimately prove useful in clinical trials, then this finding relating to the KRAS variant may well have important implications for future therapeutic strategies and pipeline development in ovarian cancer as well as for prognostic testing and earlier detection for improved outcomes. 

Ratner, E., Lu, L., Boeke, M., Barnett, R., Nallur, S., Chin, L., Pelletier, C., Blitzblau, R., Tassi, R., Paranjape, T., Hui, P., Godwin, A., Yu, H., Risch, H., Rutherford, T., Schwartz, P., Santin, A., Matloff, E., Zelterman, D., Slack, F., & Weidhaas, J. (2010). A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk Cancer Research DOI: 10.1158/0008-5472.CAN-10-0689 

Quaye, L., Song, H., Ramus, S., Gentry-Maharaj, A., Høgdall, E., DiCioccio, R., McGuire, V., Wu, A., Van Den Berg, D., Pike, M., Wozniak, E., Doherty, J., Rossing, M., Ness, R., Moysich, K., Høgdall, C., Blaakaer, J., Easton, D., Ponder, B., Jacobs, I., Menon, U., Whittemore, A., Krüger-Kjaer, S., Pearce, C., Pharoah, P., & Gayther, S. (2009). Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer British Journal of Cancer, 100 (6), 993-1001 DOI: 10.1038/sj.bjc.6604947

Chin, L., Ratner, E., Leng, S., Zhai, R., Nallur, S., Babar, I., Muller, R., Straka, E., Su, L., Burki, E., Crowell, R., Patel, R., Kulkarni, T., Homer, R., Zelterman, D., Kidd, K., Zhu, Y., Christiani, D., Belinsky, S., Slack, F., & Weidhaas, J. (2008). A SNP in a let-7 microRNA Complementary Site in the KRAS 3' Untranslated Region Increases Non-Small Cell Lung Cancer Risk Cancer Research, 68 (20), 8535-8540 DOI: 10.1158/0008-5472.CAN-08-2129