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胆道癌における遺伝性腫瘍関連遺伝子バリアントと相同組換え欠損についての研究

大川, 裕貴 北海道大学

2023.12.25

概要

【背景と目的】胆道癌は診断時には切除不能進行癌として発見されることが多
く, 高い浸潤性を持つ予後不良の悪性腫瘍である。胆道癌発症の危険因子とし
ては, 胆石による胆道の炎症, ウイルス性肝炎, 原発性硬化性胆管炎, 代謝性疾
患, アフラトキシンなどの化学物質への曝露などが挙げられるが, これらの危
険因子が胆道癌の発癌に必須ではない。一方, 乳癌や卵巣癌, 大腸癌において
遺伝性を有する遺伝性乳癌卵巣癌症候群やリンチ症候群に寄与する生殖遺伝子
変異は胆道癌の発癌にも関連するという報告が散見される。しかし, 胆道癌は
比較的稀な疾患であり, 遺伝性がん素因遺伝子の胆道癌への寄与度は未だ不明
である。また, 遺伝性乳癌卵巣癌症候群の原因遺伝子である BRCA1/2 の遺伝子
変異によって引き起こされる相同組換え修復欠損(HRD, homologous
recombination deficiency)の検討は胆道癌において行われていない。胆道癌にお
ける遺伝性の解明は, 癌スクリーニングおよび新規治療ターゲットの同定につ
ながると考えられる。
【対象と方法】バイオバンク・ジャパンに登録された胆道癌症例と北海道大学
病院で切除された胆道癌症例を併せた 1,292 症例を対象に解析を行った。胆道
癌における生殖細胞変異の寄与度を検討するためにバイオバンク・ジャパンに
登録されている癌の既往歴と家族歴のない対照者 37,583 人についても解析を行
った。合計 38,875 症例の血液サンプルもしくは正常組織サンプルに対してター
ゲットシークエンスを行い, 27 のがん素因遺伝子の生殖細胞変異(APC, ATM,
BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2,
EPCAM, HOXB13, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN,
RAD51C, RAD51D, SMAD4, STK11, TP53. 以降, 生殖細胞変異と記載)を検出し
た。胆道癌症例と対照者の間で生殖細胞変異の頻度を比較し, 胆道癌の発癌に
寄与する生殖細胞変異を明らかにした。次に, 生殖細胞変異をもつ胆道癌症例
と生殖細胞変異を持たない胆道癌を比較し, 生殖細胞変異をもつ胆道癌症例の
臨床的特徴を検討した。さらに, 胆道癌が HRD の状態であるかの評価を行うた
めに北海道大学病院で切除された胆道癌症例の腫瘍組織を用いて 52 例の胆道
癌に対して全ゲノムシークエンスを行った。解析された遺伝子変異情報をもと
に, 機械学習を用いて胆道癌が HRD の状態であるかを評価した。また, HRD の
状態がどの遺伝子異常によって引き起こされているか確認するために, 全ゲノ
ムシークエンスのデータを用いて各胆道癌症例の遺伝子異常を確認した。 ...

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