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Researchers From Canada, Poland Uncover New Breast Cancer Susceptibility Gene

NEW YORK (GenomeWeb) – A team of researchers from Canada and Poland has uncovered variants in the RECQL gene that are linked to breast cancer susceptibility.

A team led by the University of Toronto's Mohammad Akbari performed whole-exome sequencing on 195 patients with familial breast cancer from Polish and French-Canadian founder populations. From this, the researchers uncovered rare, recurrent RECQL gene mutations in both populations that they then confirmed in some 25,000 additional cases and controls, as they reported in Nature Genetics today.

"This study showed that studying specific founder populations like Polish and French-Canadian women is an excellent approach for identifying disease-associated genes," co-author Steven Narod from Toronto said in a statement.

While breast cancer susceptibility genes like BRCA1 and BRCA2 account for a portion of inherited breast cancers, the researchers noted all the known susceptibility genes together are estimated to account for about half of hereditary breast cancer cases. To search for additional breast cancer susceptibility genes, they turned to Polish and Quebecois populations, both of whom harbor multiple founder mutations in known breast cancer susceptibility genes.

Akbari, Narod, and their colleagues sequenced the exomes of 144 Polish and 51 French-Canadian women with breast cancer, but who lacked known breast cancer susceptibility variants.

Five patients from this discovery set, or 2.6 percent, carried other truncating mutations within RECQL, which the researchers confirmed through Sanger sequencing. By contrast, they found only eight truncating mutation carriers within the 4,300 European-American individuals of the National Heart, Lung, and Blood Institute exome database, or about 0.2 percent.

To validate these findings, the researchers sequenced the entire 14 coding exons of RECQL in 475 Polish and 475 French-Canadian breast cancer patients who were negative for known population-specific founder mutations. While the researchers didn't see any of the RECQL mutations they identified in the discovery cohort, they did observe two other truncating mutations in this cohort — namely c.1667_1667+3delAGTA in two Polish patients and c.643C>T (p.Arg215*) in two French-Canadian patients.

For their second validation phase, Akbari and his colleagues focused on the recurrent mutations they'd found, reasoning that they might better represent founder mutations than the ones they'd identified through exome sequencing.

They thus genotyped the recurrent c.1667_1667+3delAGTA RECQL mutation they found in Polish women in 13,136 patients with breast cancer and 4,702 controls, and found the mutation in 30 cases, or 0.23 percent, and two controls, or 0.04 percent.

Similarly, they genotyped the recurrent French-Canadian c.634C>T (p.Arg215*) RECQL mutation in 538 cases and 7,136 controls and found the mutation in five cases and one control.

RECQL is located on chromosome 12p12 and encodes a DNA helicase, the researchers noted. This helicase, Akbari and his colleagues added, is thought to have a role in preserving the integrity of the genome.

For instance, cells lacking RECQL have a higher rate of spontaneous sister chromatid exchange, are more sensitive to ionizing radiation, and undergo more double-stranded DNA breaks. RECQL, the researchers said, seems to prevent such DNA breaks by stabilizing stalled or regressed replication forks. It also appears to be involved in non-homologous end joining DNA repair and lengthening of telomeres without telomerase, they added. All together, this suggested to the researchers that RECQL has a tumor-suppressor role.

Though these mutations are themselves rare, the researchers noted in a statement that they have a high penetrance — they estimated that about half of the women with one of the mutations would develop breast cancer.