The widespread use of tumor DNA mismatch repair (MMR) protein immunohistochemistry in gastrointestinal tract (GIT) carcinomas has unveiled cases where the MMR protein status differs between synchronous/metachronous tumors from the same patients. This study aims at examining the frequency, patterns and molecular etiologies of such inter-tumoral MMR discordances. We analyzed a cohort of 2159 colorectal cancer (CRC) patients collected over a 5-year period and found that 1.3% of the patients (27/2159) had ≥ 2 primary CRCs, and 25.9% of the patients with ≥ 2 primary CRCs (7/27) exhibited inter-tumoral MMR discordance. We then combined the seven MMR-discordant CRC patients with three additional MMR-discordant GIT carcinoma patients and evaluated their discordant patterns and associated molecular abnormalities. The 10 patients consisted of 3 patients with Lynch syndrome (LS), 1 with polymerase proofreading-associated polyposis (PAPP), 1 with familial adenomatous polyposis (FAP), and 5 deemed to have no cancer disposing hereditary syndromes. Their MMR discordances were associated with the following etiologies: (1) PMS2-LS manifesting PMS2-deficient cancer at an old age when a co-incidental sporadic MMR-proficient cancer also occurred; (2) microsatellite instability-driven secondary somatic MSH6-inactivation occurring in only one—and not all—PMS2-LS associated MMR-deficient carcinomas; (3) “compound LS” with germline mutations in two MMR genes manifesting different tumors with deficiencies in different MMR proteins; (4) PAPP or FAP syndrome-associated MMR-proficient cancer co-occurring metachronously with a somatic MMR-deficient cancer; and (5) non-syndromic patients with sporadic MMR-proficient cancers co-occurring synchronously/metachronously with sporadic MMR-deficient cancers. Our study thus suggests that inter-tumoral MMR discordance is not uncommon among patients with multiple primary GIT carcinomas (25.9% in patients with ≥ 2 CRCs), and may be associated with widely varied molecular etiologies. Awareness of these patterns is essential in ensuring the most effective strategies in both LS detection and treatment decision-making. When selecting patients for immunotherapy, MMR testing should be performed on the tumor or tumors that are being treated.

肿瘤 DNA 错配修复 (MMR) 蛋白免疫组织化学在胃肠道 (GIT) 癌中的广泛应用揭示了来自同一患者的同步/异时肿瘤之间 MMR 蛋白状态不同的病例。本研究旨在检查这种肿瘤间 MMR 不一致的频率、模式和分子病因。我们分析了 5 年期间收集的 2159 名结直肠癌 (CRC) 患者队列，发现 1.3% 的患者 (27/2159) 有 ≥ 2 个原发性 CRC，25.9% 的患者有 ≥ 2 个原发性 CRC。 7/27）表现出肿瘤间 MMR 不一致。然后，我们将七名 MMR 不一致的 CRC 患者与另外三名 MMR 不一致的 GIT 癌患者结合起来，并评估了他们的不一致模式和相关的分子异常。10 名患者包括 3 名 Lynch 综合征 (LS) 患者、1 名聚合酶校对相关息肉病 (PAPP) 患者、1 名家族性腺瘤性息肉病 (FAP) 患者和 5 名被认为没有癌症处置遗传综合征的患者。他们的 MMR 不一致与以下病因有关：（1）PMS2-LS 在老年时表现为 PMS2 缺陷型癌症，同时也发生了偶发的散发性 MMR 成熟型癌症；(2) 微卫星不稳定性驱动的次级体细胞 (1) PMS2-LS 在老年时表现出 PMS2 缺陷型癌症，同时同时发生散发性 MMR 丰富型癌症；(2) 微卫星不稳定性驱动的次级体细胞 (1) PMS2-LS 在老年时表现出 PMS2 缺陷型癌症，同时同时发生散发性 MMR 丰富型癌症；(2) 微卫星不稳定性驱动的次级体细胞MSH6-仅在一个——而非所有——PMS2-LS相关的MMR缺陷癌中发生失活；（3）“复合LS”在两个MMR基因中具有种系突变，表现为不同的肿瘤，具有不同的MMR蛋白缺陷；(4) PAPP 或 FAP 综合征相关的 MMR-proficient 癌症与体细胞 MMR-deficient 癌症同时发生；(5) 患有散发性 MMR 熟练性癌症的非综合征患者与散发性 MMR 缺陷性癌症同步/异时同时发生。因此，我们的研究表明，肿瘤间 MMR 不一致在多发原发性 GIT 癌患者中并不少见（≥ 2 例 CRC 患者中为 25.9%），并且可能与广泛不同的分子病因有关。了解这些模式对于确保 LS 检测和治疗决策制定最有效的策略至关重要。