Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands.
Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands.
J Natl Cancer Inst. 2023 Jul 6;115(7):853-860. doi: 10.1093/jnci/djad063.
Individuals with Lynch syndrome are at increased hereditary risk of colorectal and endometrial carcinomas with microsatellite instability (MSI-H) and mismatch repair-deficiency (dMMR), which make these tumors vulnerable to therapy with immune checkpoint inhibitors. Our aim is to assess how often other tumor types in these individuals share these characteristics.
We retrieved the full tumor history of a historical clinic-based cohort of 1745 individuals with Lynch syndrome and calculated the standardized incidence ratio for all tumor types. MSI status, somatic second hit alterations, and immunohistochemistry-based MMR status were analyzed in 236 noncolorectal and nonendometrial malignant tumors.
In individuals with Lynch syndrome MSI-H/dMMR occurred both in Lynch-spectrum and in non-Lynch-spectrum malignancies (85% vs 37%, P < .01). MSI-H/dMMR malignancies were found in nearly all non-Lynch-spectrum tumor types. Almost all breast carcinomas had medullary features, and most of them were MSI-H/dMMR. Breast carcinoma with medullary features were shown to be associated with Lynch syndrome (standardized incidence ratio = 38.8, 95% confidence interval = 16.7 to 76.5).
In individuals with Lynch syndrome, MSI-H/dMMR occurs in more than one-half of the malignancies other than colorectal and endometrial carcinomas, including tumor types without increased incidence. The Lynch-spectrum tumors should be expanded to breast carcinomas with medullary features. All malignancies in patients with Lynch syndrome, independent of subtype, should be tested for MSI-H/dMMR in case therapy with immune checkpoint inhibitors is considered. Moreover, Lynch syndrome should be considered an underlying cause of all MSI-H/dMMR malignancies other than colorectal and endometrial carcinomas.
具有微卫星不稳定性（MSI-H）和错配修复缺陷（dMMR）的林奇综合征个体患结直肠癌和子宫内膜癌的遗传风险增加，这使得这些肿瘤容易受到免疫检查点抑制剂的治疗。我们的目的是评估这些个体中的其他肿瘤类型有多少次具有这些特征。
我们检索了 1745 名林奇综合征患者的历史临床队列的完整肿瘤史，并计算了所有肿瘤类型的标准化发病比。在 236 种非结直肠和非子宫内膜恶性肿瘤中分析了 MSI 状态、体细胞二次打击改变和基于免疫组化的 MMR 状态。
在林奇综合征个体中，MSI-H/dMMR 既存在于林奇谱恶性肿瘤中，也存在于非林奇谱恶性肿瘤中（85% vs 37%，P<.01）。几乎所有非林奇谱肿瘤类型都存在 MSI-H/dMMR 恶性肿瘤。几乎所有乳腺癌都具有髓样特征，其中大多数是 MSI-H/dMMR。具有髓样特征的乳腺癌与林奇综合征相关（标准化发病比=38.8，95%置信区间=16.7 至 76.5）。
在林奇综合征个体中，除了结直肠癌和子宫内膜癌以外，超过一半的恶性肿瘤存在 MSI-H/dMMR，包括发病率没有增加的肿瘤类型。林奇谱肿瘤应扩展到具有髓样特征的乳腺癌。应考虑对所有具有林奇综合征的恶性肿瘤，无论亚型如何，均进行 MSI-H/dMMR 检测，以考虑免疫检查点抑制剂治疗。此外，所有除结直肠癌和子宫内膜癌以外的 MSI-H/dMMR 恶性肿瘤都应考虑为林奇综合征的潜在原因。
