Department of Medical Genetics, St. Olavs Hospital, Trondheim, Norway.
Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
BMC Med Genomics. 2023 Jun 9;16(1):126. doi: 10.1186/s12920-023-01562-3.
Hereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch repair genes, causing one of several types of familial colorectal cancer (CRC) syndromes. Most of the mutations are low-penetrant variants, contributing to an increased risk of familial colorectal cancer, and they are often found in additional genes and pathways not previously associated with CRC. The aim of this study was to identify such variants, both high-penetrant and low-penetrant ones.
We performed whole exome sequencing on constitutional DNA extracted from blood of 48 patients suspected of familial colorectal cancer and used multiple in silico prediction tools and available literature-based evidence to detect and investigate genetic variants.
We identified several causative and some potentially causative germline variants in genes known for their association with colorectal cancer. In addition, we identified several variants in genes not typically included in relevant gene panels for colorectal cancer, including CFTR, PABPC1 and TYRO3, which may be associated with an increased risk for cancer.
Identification of variants in additional genes that potentially can be associated with familial colorectal cancer indicates a larger genetic spectrum of this disease, not limited only to mismatch repair genes. Usage of multiple in silico tools based on different methods and combined through a consensus approach increases the sensitivity of predictions and narrows down a large list of variants to the ones that are most likely to be significant.
导致结直肠癌易感性的遗传性基因突变约占所有结直肠癌病例的 30%。然而，这些基因突变中只有一小部分是发生在 DNA 错配修复基因中的高外显率突变，导致几种家族性结直肠癌（CRC）综合征之一。大多数突变是低外显率的变体，导致家族性结直肠癌的风险增加，并且它们通常存在于以前与 CRC 无关的其他基因和途径中。本研究的目的是识别这些高外显率和低外显率的变体。
我们对 48 名疑似家族性结直肠癌患者的血液中的基因组 DNA 进行了全外显子组测序，并使用多种基于计算的预测工具和可用的文献证据来检测和研究遗传变异。
我们在与结直肠癌相关的已知基因中发现了一些致病和一些潜在的致病种系变体。此外，我们在通常不包含在结直肠癌相关基因面板中的基因中发现了一些变体，包括 CFTR、PABPC1 和 TYRO3，它们可能与癌症风险增加有关。
在可能与家族性结直肠癌相关的其他基因中识别出变体表明该疾病的遗传谱更大，不仅限于错配修复基因。使用基于不同方法的多种基于计算的工具，并通过共识方法进行组合，可以提高预测的敏感性，并将大量变体缩小到最有可能具有重要意义的变体。
