NEW YORK (GenomeWeb) – The National Cancer Institute has awarded University of Washington researcher Mary-Claire King a $4.2 million grant to support her use of next-generation sequencing technology to uncover the genetic causes of inherited breast and ovarian cancer.
The seven-year grant comes through the agency's Outstanding Investigator Award program. King, a Lasker Foundation Award winner, is perhaps best known for her discovery of BRCA1, a homologous recombination repair gene that significantly increases breast cancer risk when mutated.
Despite the clinical value of BRCA1 and the handful of other genes found to harbor mutations that predispose women to breast and ovarian cancer, most women with familial forms of the diseases do not carry a mutation in these genes, King told GenomeWeb this week.
Even whole-exome and complete-locus sequencing studies of such patients, culled from more than 4,000 families with histories of breast and ovarian cancer that King has been studying since the early 1970s, have failed to turn up much more than a few additional homologous recombination repair gene mutations, she explained.
"If you look at [the families'] pedigrees … you think, 'How can this be? How can there be this much breast cancer in this family … and we don't find mutations?'" she said.
King has come to believe that these unresolved cancer cases are the result of rare mutations in distant regulatory regions of known breast and ovarian cancer genes — those that lie beyond the coding sequences and nearby regions that have already been well examined — as well as in genes not yet known to be involved in inherited predisposition to the diseases.
To uncover these mutations, and with the support of the NCI grant, King has begun an effort to apply whole-genome sequencing to as many as 3,000 individuals from families with a very high incidence of breast and ovarian cancer with no known genetic cause.
"It's a big genome out there and we have to start somewhere," she said. "So we'll start with megabases going north and south from each of the known [susceptibility] genes, and we'll see what we find that co-segregates … [working] out from there."
King also aims to discover founder mutations in early-onset breast cancer patients of Ashkenazi Jewish ancestry who have normal sequences of all known breast and ovarian cancer genes. The frequencies of potentially critical founder alleles will then be compared in independent cases and controls from the same population.
King noted that she has previously worked with collaborators in Israel on breast and ovarian cancer in the Ashkenazi Jewish population, reporting last year that BRCA1 and BRCA2 mutations confer the same disease risk regardless of family history.
Having built an extensive collection of patient and control DNA samples through that study, "We're in a position to be able, in that historically demographically very well-defined population, to look at … essentially one huge family that goes back thousands of years," King noted. "It's another approach to the same question: Do we see any founder alleles in that population that are regulatory in nature?"
By the end of the grant project, King said she hopes to have identified the genetic mutations behind resolved breast and ovarian cancer cases so that "women, their families, and their physicians have the opportunity to know who is at increased inherited risk for breast and ovarian cancer [and] the degree of that risk.
"I advocate for sequencing of BRCA1 and BRCA2 to be offered to all women at age 30," she added. "By the end of seven years, I would like to see that extended to far more genes and far more mutational mechanisms."