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FANCM Mutations Linked to Early-Onset Familial Breast Cancer

NEW YORK (GenomeWeb) – In a case-control study, a team of German researchers has linked loss-of-function mutations in FANCM to early-onset familial breast cancer.

University Hospital Cologne's Eric Hahnen and his colleagues screened familial breast cancer patients along with people with ovarian cancer and geographically matched controls for loss-of-function mutations in FANCM. Since genes related to FANCM have been linked to increased breast or ovarian cancer risk, and as the FANCM protein and its binding partner FAAP24 are involved in DNA damage response, the gene has a plausible role in cancer, the researchers said.

As they reported today in JAMA Oncology, the researchers found that FANCM mutations were more common among patients with familial risk of disease, though they were particularly associated with people who developed the disease young or had triple-negative disease. This suggested to the researchers that FANCM testing should be included in breast cancer risk assessment testing.

"[B]ased on the present analyses and previously published findings, we recommend including FANCM in diagnostic gene panel testing," Hahnen and his colleagues wrote in their paper.

He and his colleagues examined exome-sequencing data from 2,047 familial breast cancer cases, 628 ovarian cancer cases, and 2,187 geographically matched controls. Overall, they reported that 21 of the 2,047 familial breast cancer cases had heterozygous truncating FANCM mutations, while six of the ovarian cancer patients and 11 of the controls had the mutations. They estimated that the familial breast cancer cases had a cumulative carrier frequency of 1.03 percent.

From this, they reported a weak, though significant, association between FANCM mutations and familial breast cancer.

When the researchers focused on patients with familial breast cancer who developed disease by the age of 51, they found an even stronger link. This subgroup had a cumulative carrier frequency of 1.22 percent. By contrast, the subgroup of patients who developed disease when they were 51 years old or older had a cumulative carrier frequency of 0.613 percent.

"Screening the entire coding sequence of the FANCM gene revealed its weak but overall significant association with familial [breast cancer]," Hahnen and his colleagues noted. "The study established an association between FANCM and early-onset [breast cancer] disease in familial index cases."

Similarly, the researchers reported that FANCM mutations were more common among patients with triple-negative disease. Four of the 215 triple-negative cancer cases in their cohort had FANCM mutations, giving a cumulative carrier frequency of 1.86 percent.

Hahnen and his colleagues did not uncover a link between FANCM and ovarian cancer, though they suggested that additional work using a larger sample size might clarify its role in ovarian cancer.

As their study focused on familial breast cancer and could thus have suffered from selection bias, the researchers noted that a follow-up study could involve analyzing unselected breast cancer cases and then stratifying them based on whether they have early-onset or triple-negative disease.

Still, Hahnen and his colleagues said that, based on their findings and previous findings, they "recommend including FANCM in diagnostic gene panel testing."