Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Instituto de Investigacion Sanitaria de Santiago, Grupo de Medicina Xenomica, Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
Gastroenterology. 2023 Jul;165(1):162-172.e5. doi: 10.1053/j.gastro.2023.03.006. Epub 2023 Mar 11.
BACKGROUND & AIMS: Colorectal cancer (CRC) is one of the most prevalent tumors worldwide, with incidence quickly increasing (particularly in the context of early-onset cases), despite important prevention efforts, mainly in the form of population-wide screening programs. Although many cases present a clear familial component, the current list of hereditary CRC genes leaves a considerable proportion of the cases unexplained.
In this work, we used whole-exome sequencing approaches on 19 unrelated patients with unexplained colonic polyposis to identify candidate CRC predisposition genes. The candidate genes were then validated in an additional series of 365 patients. CRISPR-Cas9 models were used to validate BMPR2 as a potential candidate for CRC risk.
We found 8 individuals carrying 6 different variants in the BMPR2 gene (approximately 2% of our cohort of patients with unexplained colonic polyposis). CRISPR-Cas9 models of 3 of these variants showed that the p.(Asn442Thrfs∗32) truncating variant completely abrogated BMP pathway function in a similar way to the BMPR2 knockout. Missense variants p.(Asn565Ser), p.(Ser967Pro) had varying effects on cell proliferation levels, with the former impairing cell control inhibition via noncanonical pathways.
Collectively, these results support loss-of-function BMPR2 variants as candidates to be involved in CRC germline predisposition.
结直肠癌（CRC）是全球最常见的肿瘤之一，尽管采取了重要的预防措施（主要以人群筛查计划的形式），但其发病率仍在迅速上升（尤其是在早发病例的情况下）。尽管许多病例具有明显的家族成分，但目前遗传性 CRC 基因列表仍有相当一部分病例无法解释。
在这项工作中，我们使用外显子组测序方法对 19 名无明显家族史的结肠息肉病患者进行了研究，以鉴定候选的 CRC 易感性基因。然后在另外 365 名患者的系列中验证候选基因。使用 CRISPR-Cas9 模型验证 BMPR2 是否为 CRC 风险的潜在候选基因。
我们发现 8 名个体携带 BMPR2 基因中的 6 种不同变体（约占我们无明显家族史结肠息肉病患者队列的 2%）。这 3 种变体的 CRISPR-Cas9 模型表明，p.(Asn442Thrfs∗32) 截断变体完全消除了 BMP 通路功能，与 BMPR2 敲除的方式相似。错义变体 p.(Asn565Ser)、p.(Ser967Pro) 对细胞增殖水平有不同的影响，前者通过非经典途径损害细胞控制抑制。
综上所述，这些结果支持 BMPR2 功能丧失变体作为参与 CRC 种系易感性的候选基因。
