The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair-defective settings such as Fanconi anemia (FA). FA is an inherited bone marrow failure syndrome caused by defects in any one of so far identified 22 FANC genes including hereditary breast and ovarian cancer (HBOC) genes BRCA1 and BRCA2. We have previously reported that the progression of FA phenotypes is accelerated with the ALDH2 rs671 genotype. Individuals with HBOC are heterozygously mutated in either BRCA1 or BRCA2, and the cancer-initiating cells in these patients usually undergo loss of the wild-type BRCA1/2 allele, leading to homologous recombination defects. Therefore, we hypothesized that the ALDH2 genotypes may impact breast cancer development in BRCA1/2 mutant carriers. We genotyped ALDH2 in 103 HBOC patients recruited from multiple cancer centers in Japan. However, we were not able to detect any significant differences in clinical stages, histopathological classification, or age at clinical diagnosis across the ALDH2 genotypes. Unlike the effects in hematopoietic cells of FA, our current data suggest that there is no impact of the loss of ALDH2 function in cancer initiation and development in breast epithelium of HBOC patients.

Drs. Toyomasa Katagiri, Seishi Ogawa, Masakazu Toi, Hiroji Iwata, and Keitaro Matsuo are editorial board members of Cancer Science. The authors declare that there is no conflict of interest except for: the lecture fee for Masakazu Toi (Eli Lilly, AstraZeneca, Daiichi‐Sankyo), Eriko Tokunaga (AstraZeneca), Yasuo Miyoshi (AstraZeneca), Tomohiko Ohta (AstraZeneca), and Shozo Ohsumi (AstraZeneca); the research funds for Masakazu Toi (Taiho, AstraZeneca, Kyowa‐Kirin, Shimadzu, Astellas, JBCRG association, AFI Technology, Yakult, Luxonus, GL Science, KBCRN association), and Hiroyuki Kitao (Taiho); the scholarship endowment for Masakazu Toi (Chugai, Eisai, Nippon Kayaku). Hiroyuki Kitao belongs to an endowed chair funded by Taiho and accepted researchers from Taiho.