大酒家の食道扁平上皮癌におけるアルコール代謝酵素の関連からみた多発癌および口腔咽喉と胃の他臓器重複癌

Alcohol and Aldehyde Dehydrogenase Gene Polymorphisms and Multiple Cancers Associated with Esophageal Squamous Cell Carcinoma in Japanese Alcoholics

　本研究では，アルコール依存症男性の食道ヨ－ド染色検診で診断した食道扁平上皮癌患者143例を対象に、食道内多発癌と口腔咽喉や胃の重複癌のリスクを，アルコール代謝酵素の遺伝子多型との関連から検討した．48例に同時性食道内多発癌を認め，同時性多発癌のオッズ比は，アルデヒド脱水素酵素-2(ALDH2)ヘテロ欠損型で2.54倍(95％ CI＝1.20-5.39)となった．22例に異時性原発食道癌を認め，ALDH2ヘテロ欠損者と同時性多発癌患者で，その発生率が高く，ハザード比はそれぞれ3.61倍(1.20-10.8)と3.12倍(1.28-7.61)であった．口腔咽喉や胃の同時性重複癌は21例，異時性重複癌は16例で認めた．ALDH2ヘテロ欠損者と同時性多発癌患者で累積重複癌発生率が高い傾向にあり，ALDH2ヘテロ欠損型とADH2非活性型の両者を有する者で有意に累積重複率が高かった．特に下咽頭領域では，これらの関連がすべて有意で強かった．大酒家の多発重複食道発癌は，アルコール代謝酵素遺伝子多型と関連した高度のアセトアルデヒド暴露と関連すると考えられた．

　Multiple intraesophageal cancers and oropharyngolaryngeal and/or stomach cancers associated with esophageal cancer are common, especially in Japanese alcoholics. Inactive heterozygous aldehyde dehydrogenase-2 (ALDH 2^*1/2^*2) and the less active form of alcohol dehydrogenase-2 (ADH 2^*1/2^*2) are risk factors for esophageal cancer in both alcoholic and general Japanese male members of the population. In this study, we undertook a comprehensive study of ALDH 2/ADH 2 genotypes and multiple cancers associated with esophageal cancer in Japanese alcoholics. Of 143 male alcoholics who did not have any history of cancer in the oropharyngolarynx, esophagus, or stomach, and were newly diagnosed as having esophageal squamous cell carcinoma, 48 had synchronous multiple intraesophageal cancers and 22 had metachronous ones. In the presence of ALDH 2^*1/2^*2, the risk for synchronous multiple intraesophageal cancers was higher (odds ratio＝2.54,95 ％ CI＝1.20-5.39) than the risk for solitary esophageal cancer. Kaplan-Meier estimates of the proportion of patients with metachronous primary esophageal cancers showed that patients with ALDH 2＊1/2＊2 (hazard ratio＝3.61, 1.20-10.8) or synchronous multiple intraesophageal cancers (hazard ratio＝3.12, 1.28-7.61) had a significantly increased likelihood to develop metachronous cancer. Concurrent oropharyngolaryngeal and/or stomach cancers were synchronously diagnosed in 21 patients and metachronously in 16 ones. Estimated cumulative rates of oropharyngolaryngeal and/or stomach cancers and hypopharyngeal/epilaryngeal cancers showed that those with ALDH 2^*1/2^*2 (p＝0.080 and 0.022, respectively), a combination of ALDH 2^*1/2^*2 and ADH 2^*1/2^*1(p＝0.048 and 0.0019, respectively), or synchronous multiple intraesophageal cancers (p＝0.059 and 0.0070, respectively) had an increased likelihood to develop these multiorgan cancers. These results suggest that acetaldehyde plays a critical role in multicentric or field cancerization associated with esophageal cancer in Japanese alcoholics. The results also point to the need for a careful search for multiple-field cancerization both before and after beginning treatment of the index cancer in high-risk patients.