NEW YORK – Rare, loss-of-function mutations in the DNA damage checkpoint gene ATRIP appear to coincide with higher-than-usual breast cancer risk in European individuals, according to new research from investigators at the University of Toronto, Pomeranian Medical University in Szczecin, and elsewhere.
As they reported in the American Journal of Human Genetics on Monday, the researchers turned to exome sequencing to search for genetic breast cancer risk factors in 510 women from breast cancer-affected families that could not be explained by known risk variants in genes such as BRCA1, BRCA2, or TP53, comparing their germline sequences to those from more than 300 women from breast cancer-free families from the same founder population from Poland.
"Founder populations have founder mutations, which are more frequent than non-founder mutations and also have a lower background genetic variation that would increase the chance of identifying new breast cancer susceptibility genes," senior and corresponding author Mohammad Akbari, a researcher at the University of Toronto, explained in an email. "Therefore, we have formed a strong collaboration with our colleagues at Pomeranian Medical School in Poland to search for new breast cancer susceptibility genes."
In that cohort, the researchers tracked down the same rare mutation in two participants with breast cancer, prompting additional analyses in germline sequences for 450,000 UK Biobank participants. Among the 15,643 UK Biobank participants with breast cancer, they found 13 individuals who carried loss-of-function ATRIP mutations.
Similar ATRIP risk variants have since been identified in patients from the Middle East affected by familial breast cancer, Akbari noted.
"Replication and validation of our findings in future studies may prompt consideration of clinical testing for mutations in this breast cancer susceptibility gene candidate," the researchers suggested.
With a series of follow-up experiments, including loss-of-heterozygosity testing on 10 tumor samples from breast cancer patients carrying germline ATRIP alterations, the team linked the variants to higher-than-usual homologous recombination deficiency (HRD) scores, suggesting that these patients may respond to PARP inhibitors.
"HRD seems to be a common characteristic of the breast tumors with ATRIP germline mutations," Akbari said, noting that HRD "is a strong indicator of response to [PARP inhibitor (PARPi)] drugs."
Consequently, he explained, breast cancer patients carrying ATRIP mutations may be particularly apt to respond to PARPi treatments, though this hypothesis is yet to be tested in randomized clinical trials.
Based on their results so far, the researchers suggested that ATRIP can be considered a moderately penetrant cancer susceptibility gene that may explain some familial breast cancer cases that do not involve alterations in more well-characterized risk genes.
"This will help to identify carriers and offer them preventive measures or intensive screening to detect their cancer in earlier stages," Akbari said, noting that "the benefits are not limited to the hereditary cases."
"Every new gene we identify will improve our knowledge about the biology of breast cancer in general that could eventually help us in developing more efficient targeted therapies for sporadic cancer cases, as well," he added.