Common Variant in ALDH2 Modifies the Risk of Breast Cancer Among Carriers of the p.K3326* Variant in BRCA2.

Autor:	Kluźniak W; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland., Szymiczek A; Women's College Research Institute, University of Toronto, Toronto, Canada., Rodrigue A; Genome Stability Laboratory, CHU de Québec Research Center, Oncology Axis, Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, Québec, Canada., Wokołorczyk D; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland., Rusak B; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland., Stempa K; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland., Huzarski T; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.; Department of Clinical Genetics and Pathology, University of Zielona Góra, Poland., Gronwald J; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland., Lubiński J; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland., Zamani N; Women's College Research Institute, University of Toronto, Toronto, Canada.; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada., Zhang S; Women's College Research Institute, University of Toronto, Toronto, Canada., Masson JY; Genome Stability Laboratory, CHU de Québec Research Center, Oncology Axis, Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, Québec, Canada., Narod SA; Women's College Research Institute, University of Toronto, Toronto, Canada.; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada.; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada., Cybulski C; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland., Akbari MR; Women's College Research Institute, University of Toronto, Toronto, Canada.; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada.; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
Jazyk:	angličtina
Zdroj:	JCO precision oncology [JCO Precis Oncol] 2022 Apr; Vol. 6, pp. e2100450.
DOI:	10.1200/PO.21.00450
Abstrakt:	Purpose: The BRCA2 p.K3326* variant is considered a low-penetrance variant for breast cancer. Aldehydes that accumulate in cells under insufficient aldehyde oxidation were most recently shown to trigger carcinogenesis by promoting depletion of BRCA2 protein. Allele T of the common variant rs10744777 in the ALDH2 gene was associated with reduced expression of aldehyde dehydrogenase, the main enzyme in aldehyde oxidation. We hypothesized that this allele could modify breast cancer risk in women with the BRCA2 p.K3326* low-penetrance variant through reduced function of ALDH2, increased accumulation of cellular aldehydes, and depletion of BRCA2 protein. Materials and Methods: We genotyped 11,873 Polish women diagnosed with breast cancer and 7,615 ethnically matched controls for these two variants. Next, we extended our analysis of rs10744777 to 231 carriers of pathogenic BRCA2 mutations. Results: BRCA2 p.K3326* variant was associated with significant increase in breast cancer risk only in those who were homozygous for the T allele of the ALDH2 rs10744777 variant (odds ratio = 1.72; 95% CI, 1.19 to 2.48; P = .003). The BRCA2 p.K3326* variant did not increase the risk of breast cancer among those who were heterozygous or homozygous for the C allele of the ALDH2 rs10744777 variant (odds ratio = 1.05; 95% CI, 0.73 to 1.51; P = .81). In the carriers of high-risk BRCA2 mutations, the TT genotype of rs10744777 conferred a modest (18%) and not significant increase in breast cancer risk. Conclusion: Our results suggest that BRCA2 p.K3326* variant, which is low-penetrance by itself, confers increased breast cancer risk on the background of the TT genotype of the ALDH2 rs10744777 variant in the Polish population. Competing Interests: Mohammad R. AkbariStock and Other Ownership Interests: GenewisePatents, Royalties, Other Intellectual Property: Breast Cancer Biomarkers (RECQL) and Methods of Diagnosis, Patent No. US 10,131,957 B2 (Inst), Breast Cancer Biomarkers (RECQL) and Methods of Treatment, Patent No. US 9,926,607 B2 (Inst)No other potential conflicts of interest were reported.
Databáze:	MEDLINE
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