By Doug Macron
Genomics startup Mira Dx announced this week that it has launched a new test designed to identify women at increased risk of developing ovarian cancer based on a genetic variant that affects a key microRNA.
While two other companies — Rosetta Genomics and Asuragen — have launched diagnostics based on miRNA technology, their assays analyze the signatures of the small, non-coding RNAs themselves.
In contrast, Mira Dx's test is based on the discovery of "several important genetic variants that, by disrupting miRNA pathways, predispose certain individuals to develop cancer,” Joanne Weidhaas, a Yale University researcher and Mira Dx co-founder, said in a statement. “We believed that these markers could have significant clinical value, and were pleased to work with Yale to license the technology to Mira Dx for development and commercialization.”
The test, called PreOvar, is designed to identify a variant allele of the oncogene KRAS that Weidhaas and Frank Slack, another Yale researcher and company co-founder, found to interfere with the miRNA let-7.
In a paper published this week in the online edition of Cancer Research, Weidhaas, Slack, and colleagues reported how a KRAS variant was present in more than 60 percent of cases of hereditary breast and ovarian cancer syndrome.
"One of the best-studied hereditary syndromes linked to familial [ovarian cancer] is hereditary breast and ovarian cancer syndrome," which is associated with mutations in the tumor-suppressor genes BRCA1 and BRCA2, they wrote in the paper.
Though the discovery of these genes was a "significant advance" in understanding familial ovarian cancer predisposition, they account for "less than half of familial excess risk" of the disease, they added.
"Additional gene alterations explaining any significant proportion of the remaining familial risk for [ovarian cancer] have not been identified."
Recent research has identified miRNAs as possible players in this situation because, as "global gene regulators, even small aberrations in miRNA levels or their target sites can lead to important cellular changes," Weidhaas and her colleagues noted in Cancer Research. "Emerging evidence shows than [single nucleotide polymorphisms] within miRNAs or miRNA binding sites can be functional and act as powerful biomarkers of cancer risk when one allele alters miRNA function or binding characteristics."
In the paper, the investigators focused on let-7, one of the earliest identified miRNAs and the subject of much research in Slack's lab. Members of this miRNA family have been shown to play important roles in cancer, and let-7 is known to regulate a number of ovarian cancer-related oncogenes including KRAS, they wrote.
"We previously identified a germline SNP in the 3' UTR of the KRAS oncogene," they stated. While "relatively uncommon," the KRAS variant is functional and has been shown in vitro to disrupt the binding of let-7 to KRAS, leading to increased levels of the oncogene.
The KRAS variant was also found to be a genetic marker for increased susceptibility to non-small cell lung cancer, and tumors with the variant were found to have lower let-7 levels, according to the paper. It was also later shown to be a marker of poor outcomes in head and neck cancer.
"Because of the importance of both let-7 and KRAS in human solid tumors, we evaluated the frequency of the KRAS variant in patients with other solid tumor types," the investigators wrote in their paper.
While present in less than 18 percent of all patients with solid tumors and in control populations, the variant was found in more than 25 percent of those with epithelial ovarian cancer, and was shown to be a genetic marker for developing the diseases in the general female population, according to the Cancer Research report.
Furthermore, the KRAS variant was present in 61 percent of ovarian cancer patients with hereditary breast and ovarian cancer syndrome but lacking BRCA1 or BRCA2 mutations, as well as in their family members with cancer.
"These findings suggest that the KRAS variant represents a new genetic marker of [ovarian cancer] risk," the paper states.
"Although it may seem surprising that a single-nucleotide variant could have such predictive power for disease risk, the KRAS variant represents an entirely different entity than tagging SNPs studied and used in" genome-wide association studies, the authors conclude.
Although they concede that the Cancer Research study is "somewhat limited … the frequent association of the KRAS variant with [hereditary breast and ovarian cancer syndrome] patients and their family members with cancer further strengthens the hypothesis that the KRAS variant is a generic marker" of ovarian cancer risk, the team states.
According to Mira Dx, the PreOvar test uses either salvia or blood samples, which are analyzed for the KRAS variant at the firm's Clinical Laboratory Improvement Amendments-certified laboratory in Connecticut.
Earlier this month, quasi-public investment group Connecticut Innovations announced that it had invested $1 million into Mira Dx to support the launch of PreOvar, capping a $4 million Series A round for the company.