Review ArticleNo clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
Introduction
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that negatively regulate gene expression by binding partially complementary sites in the 3′ untranslated regions (UTRs) of their target mRNAs. In this way, miRNAs control many cancer-related biological pathways involved in cell proliferation, differentiation, and apoptosis [1]. To date, several inherited variants in microRNAs or miRNA target sites have been reported to confer increased cancer risks [2]. One such variant is located in the 3′ UTR of the KRAS gene (rs61764370 T > G) for which the rarer G allele has been reported to confer an increased risk of ovarian, breast, and lung cancer [3], [4], [5], [6], [7] as well as endometriosis [8], although not consistently [9], [10], [11].
For ovarian cancer, the rs61764370 G allele was also reported to be associated with increased risk (320 cases, 328 controls). Further increased risks were observed among 23 BRCA1 mutation carriers and 31 women with familial ovarian cancer, but without BRCA1 or BRCA2 mutations [3]. In contrast, no association with ovarian cancer risk was seen in another, much larger study, based on 8669 cases, 10,012 controls, and 2682 BRCA1 mutation carriers [9]. One criticism on the latter study was that some of the genotype data were for rs17388148, an imputed proxy for rs61764370; even though rs17388148 is highly correlated with rs61764370 (r2 = 0.97) and was imputed with high accuracy (r2 = 0.977) [12], [13]. The minor allele of rs61764370 was also associated with shorter survival time in a study of 279 ovarian cancer patients diagnosed after age 52 years with platinum-resistant disease (28 resistant, 263 not resistant) and with sub-optimal debulking surgery after neoadjuvant chemotherapy (7 sub-optimal, 109 optimal) [14]. However, another study observed no association between rs61764370 and ovarian cancer outcome (329 cases) [15].
For breast cancer, a borderline significant increased frequency of the rs61764370 G allele was observed in 268 BRCA1 mutation carriers with breast cancer, but not in 127 estrogen receptor (ER)-negative familial non-BRCA1/BRCA2 breast cancer patients [5]. However, in a subsequent study, the variant was reported to be associated with increased risk of ER/PR negative disease (80 cases, 470 controls), as well as with triple negative breast cancer diagnosed before age 52 (111 cases, 250 controls), regardless of BRCA1 mutation status [6]. The validity of these findings has been questioned given the very small sample sizes and the number of subgroups tested [16], [17]. Another report found no association with sporadic or familial breast cancer risk (695 combined cases, 270 controls), but found that the variant was associated with ERBB2-positive and high grade disease, based on 153 cases who used post-menopausal hormone replacement therapy [18].
It has also been reported, based on 232 women with both primary ovarian and breast cancer, that the frequency of the G allele at rs61764370 was increased for those who were screened negative for BRCA1 and BRCA2 (92 cases), particularly among those enrolled within two years of their ovarian cancer diagnosis (to minimize survival bias, 30 cases), those diagnosed with post-menopausal ovarian cancer (63 cases), those with a family history of ovarian or breast cancer (24 cases), and those with a third primary cancer (16 cases) [4].
This notable lack of consistency in findings between studies might be expected when appropriate levels of statistical significance are not used to declare positive findings from multiple small subgroup comparisons or post-hoc hypotheses [19]. In this respect, the dangers of subgroup analyses in the context of clinical trials are well-recognized [20]. These are important caveats, particularly since a genetic test for rs61764370 is currently marketed in the US for risk prediction testing to women who are at increased risk for developing ovarian and/or breast cancer or women who have been diagnosed with either ovarian or breast cancer themselves [21]. In general, much larger studies, with sufficient power to detect positive findings at much more stringent levels of statistical significance ought to be required to establish the clinical validity of a genetic test. Therefore, we conducted centralized genotyping of rs61764370 and other variants in the genomic region around the KRAS gene in 140,012 women to examine associations with risk and clinical outcome of ovarian and breast cancer.
Section snippets
Study participants
The following three consortia contributed to these analyses: the Ovarian Cancer Association Consortium (OCAC: 41 studies, Supplementary Table S1) [22], the Breast Cancer Association Consortium (BCAC: 37 studies, Supplementary Table S2) [23], and the Consortium of Modifiers of BRCA1 and BRCA2 (CIMBA: 55 studies, Supplementary Table S3) [24], [25]. OCAC and BCAC consisted of case–control studies of unrelated women, and CIMBA consisted of studies of women with germline deleterious BRCA1 or BRCA2
Results
The results of the overall analysis as well as the subgroup analyses investigating the association between the minor allele at rs61764370 and ovarian cancer risk, breast cancer risk, and ovarian and breast cancer risks in BRCA1 and BRCA2 mutation carriers are shown in Table 1. Associations with clinical outcomes in and ovarian and breast cancer patients including BRCA1 and BRCA2 mutation carriers are shown in Table 2 and Supplementary Table S4.
We found no evidence for association between the
Discussion
Our analysis of 140,012 women genotyped for inherited variants in the KRAS region provides definitive clarification of the role of these variants in ovarian and breast cancer susceptibility and outcome. We have found no evidence to support an association between rs61764370 and ovarian or breast cancer risk, or clinical outcomes in patients with ovarian or breast cancer. In the absence of any association and with ORs close to unity we would not typically consider sub-group analyses, particularly
Conflict of interest statement
There are no conflicts of interest to disclose.
Antoinette Hollestelle and Ellen L. Goode had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Acknowledgments
We thank all the individuals who took part in this study and all the researchers, clinicians and administrative staff who have made possible the many studies contributing to this work.
The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 — HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek
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Equal contributions.