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Routine genomic screening could help identify otherwise undetected cancer risk
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Most carriers of genetic mutations known to increase the risk for breast, ovarian, prostate and pancreatic cancers appeared unaware of their mutation carrier status despite frequent interactions with the health care system, according to results of a cross-sectional study published in JAMA Network Open.
Exome sequencing-based screening may help identify BRCA1- and BRCA2-associated cancer risk that otherwise might go undetected within health care systems, results showed.
“As a colleague said, it usually takes a tragedy for people to get tested,” Michael Murray, MD, professor of genetics at Yale School of Medicine, said in a press release. “Our reliance on a documented personal or family history as a trigger to offer testing is not working. Hopefully, one day we can change that with effective DNA-based screening for everyone.”
Investigators studied 50,726 adult volunteers (mean age, 60 years) in the ongoing DiscovEHR cohort identified through the Geisinger My Code Community Health Initiative. All participants underwent exome sequencing-based screening between Jan. 1, 2014, and March 1, 2016.
Main outcomes of the study included prevalence of BRCA1/BRCA2 variants, proportion of BRCA carriers not previously ascertained through clinical testing, and personal and family history of relevant cancers among carriers and noncarriers.
Results showed that while nearly all (99.5%) participants did not expect to have a pathogenic mutation, 267 (0.5%; women, 55.4%; mean age, 58.9 years) harbored BRCA1 or BRCA2 mutations.
Eighty-two percent of those with pathogenic and likely pathogenic BRCA1 (n = 95) and BRCA2 (n = 172) mutations reported no prior clinical testing during the course of their ongoing health care.
Nearly 17% of those living with a BRCA mutation had a BRCA-associated cancer, and nearly 48% of those who died before the study concluded had a BRCA-associated cancer.
“Once risk is identified, we can apply proven tools for early diagnosis and prevention, and we believe that the ... difference in cancer incidence in these two groups is a window into an opportunity to decrease cancer and cancer deaths through genomic screening approaches,” Murray said in the release.
Thirty-one of 148 (20.9%) female variant carriers had a personal history of breast cancer, compared with 1,554 of 29,880 (5.2%) noncarriers (OR = 5.95; 95% CI, 3.88-9.13). A greater proportion of variant carriers also had ovarian cancer history (10.1% vs. 0.6%; OR = 18.3; 95% CI, 10.48-31.41).
In a subcohort of 89 participants with detailed personal and family history data, about half (n = 45) met current National Comprehensive Cancer Network criteria for testing but had never been screened, whereas 44 participants (49.4%) who did not meet the NCCN criteria had pathogenic variants.
Limitations of the study include being skewed toward those who received regular health care, increasing their opportunity to be enrolled in the biobank research.
“Our evidence demonstrates that this clinical underascertainment may be associated with both the failure to apply criteria-based referral for BRCA1 and BRCA2 testing strategies to individuals with high pretest probabilities, and the failure of such criteria-based strategies to be sufficiently sensitive to identify all true positives,” the researchers wrote. – by Jennifer Southall
Disclosures: The study was funded by institutional support from Geisinger and grants from the Horace W. Goldsmith Foundation, the Mericle Foundation, the Robert Wood Johnson Foundation, and the Commonwealth of Pennsylvania Department of Community and Economic Development. Murray reports grants from Regeneron Pharmaceuticals during the study period, and personal fees from Invitae outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.
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