, according to findings from a large population-based cohort study.
Similar results were seen for patients with Lynch syndrome.
The findings suggest that a first-degree family history confers much of the risk that is associated with pathogenic variants associated with hereditary breast, ovarian, and colorectal cancers. Furthermore, to avoid overtreatment in those without a first-degree family history who undergo genetic testing, that history should be considered when discussing potential follow-up care, the investigators argue.
“This difference in penetrance in carrier individuals, if replicated in larger studies, could be sufficient to justify stratifying just individuals with a family history into high-risk groups currently eligible for specialist clinical care,” Leigh Jackson, PhD, of the University of Exeter College of Medicine and Health, Royal Devon and Exeter Hospital, England, and his colleagues noted.
To assess how population penetrance of familial cancer syndromes varies based on family history, researchers analyzed exome sequences and clinical data collected between March 2006 and June 25, 2021, from 454,712 UK Biobank participants with either breast or colorectal cancer, a self-reported family history of breast or colorectal cancer, and a pathogenic/likely pathogenic variant in the major genes associated with hereditary breast cancer or Lynch syndrome.
After researchers controlled for sex, death, recruitment center, screening, and prophylactic surgery, those with a pathogenic BRCA1 (n = 230) or BRCA2 (n = 611) variant had an increased risk of breast cancer, and the risk was higher in those with a first-degree family history (relative hazard, 10.3 and 7.8, respectively), than in those without a first-degree family history (relative hazard, 7.2 and 4.7), the investigators reported.
Penetrance to age 60 years was also higher in those with vs. without a first-degree family history (44.7% and 24.1% vs 22.8% and 17.9%, respectively).
Similarly, patients with Lynch syndrome and a pathogenic MLH1, MSH2, or MSH6 variant (n = 89, 71, and 421, respectively) had an increased risk of colorectal cancer, and that risk was higher in those with vs. without a family history (relative hazard, 35.6, 48.0, and 9.9 vs. 13.0, 15.4, and 7.2). Penetrance to age 60 was higher for those with a pathogenic MLH1 and MSH2 variant with vs. without a family history (30.9% and 38% vs. 20.5% and 8.3%).
The study results were published online in eClinicalMedicine, part of The Lancet Discovery Science.
“The findings of this study suggest that any universal policy of returning pathogenic cancer predisposing genetic variants found incidentally or through direct-to-consumer genetic testing of asymptomatic individuals should consider family history and other factors when counseling patients on the risks and benefits of follow-up care,” the investigators recommended. “It will be very difficult to counsel individuals as to their particular risk profile without further pedigree construction or investigations.
“If penetrance estimates from affected families are used, there is a danger of overmanagement of asymptomatic individuals with no family history of disease. These ‘patients-in-waiting’ may be exposed to unnecessary surveillance or more invasive prophylactic procedures,” they added.
This study was supported by an MRC grant. The authors reported having no competing interests.