Key Points
Question
Which cancer types and their clinical characteristics are associated with pathogenic variants in
BRCA1
and
BRCA2
in addition to breast, ovarian, prostate, and pancreatic cancers?
Findings
In this case-control study of 63 828 patients with 14 common cancer types and 37 086 controls, pathogenic variants in
BRCA1
were associated with biliary tract cancer, in
BRCA2
with esophageal cancer, and in
BRCA1/2
with gastric cancer.
Meaning
The study results suggest that the range of cancer types associated with pathogenic variants in
BRCA1
and
BRCA2
is broader than that determined from previous analyses, potentially indicating the broader clinical relevance of
BRCA1/2
genetic testing.
A genetic variant on aldehyde dehydrogenase 2 (ALDH2 rs671, Glu504Lys) contributes to carcinogenesis after alcohol consumption. Somewhat conversely, the ALDH2 Lys allele also confers a protective effect against alcohol-induced carcinogenesis by decreasing alcohol consumption due to acetaldehyde-related adverse effects. Here, we applied a mediation analysis to five case-control studies for head and neck, esophageal, stomach, small intestine, and colorectal cancers, with 4,099 cases and 6,065 controls, and explored the potentially heterogeneous impact of alcohol drinking on digestive tract carcinogenesis by decomposing the total effect of the ALDH2 Lys allele on digestive tract cancer risk into the two opposing effects of the carcinogenic effect (direct effect) and the protective effect (indirect effect mediated by drinking behavior). Alcohol was associated with an increased risk of most digestive tract cancers, but significant direct effects were observed only for upper gastrointestinal tract cancer risk, and varied substantially by site, with ORs (95% confidence interval) of 1.83 (1.43-2.36) for head and neck cancer, 21.15 (9.11-49.12) for esophageal cancer, and 1.65 (1.38-1.96) for stomach cancer. In contrast, a significant protective indirect effect was observed on risk for all cancers, except small intestine cancer. These findings suggest that alcohol is a major risk factor for digestive tract cancers, but its impact as a surrogate for acetaldehyde exposure appears heterogeneous by site. Meanwhile, the behavior-related effect of the ALDH2 Lys allele results in a decreased risk of most digestive tract cancers.Significance: These findings support that genetic alcohol avoidance is a factor against alcohol-induced cancers.
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