Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
Mayo Clinic, Rochester, Minnesota, USA.
Genet Med. 2014 Jan;16(1):101-16. doi: 10.1038/gim.2013.166. Epub 2013 Dec 5.
Lynch syndrome, familial adenomatous polyposis, and Mut Y homolog (MYH)-associated polyposis are three major known types of inherited colorectal cancer, which accounts for up to 5% of all colon cancer cases. Lynch syndrome is most frequently caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and is inherited in an autosomal dominant manner. Familial adenomatous polyposis is manifested as colonic polyposis caused by mutations in the APC gene and is also inherited in an autosomal dominant manner. Finally, MYH-associated polyposis is caused by mutations in the MUTYH gene and is inherited in an autosomal recessive manner but may or may not be associated with polyps. There are variants of both familial adenomatous polyposis (Gardner syndrome--with extracolonic features--and Turcot syndrome, which features medulloblastoma) and Lynch syndrome (Muir-Torre syndrome features sebaceous skin carcinomas, and Turcot syndrome features glioblastomas). Although a clinical diagnosis of familial adenomatous polyposis can be made using colonoscopy, genetic testing is needed to inform at-risk relatives. Because of the overlapping phenotypes between attenuated familial adenomatous polyposis, MYH-associated polyposis, and Lynch syndrome, genetic testing is needed to distinguish among these conditions. This distinction is important, especially for women with Lynch syndrome, who are at increased risk for gynecological cancers. Clinical testing for these genes has progressed rapidly in the past few years with advances in technologies and the lower cost of reagents, especially for sequencing. To assist clinical laboratories in developing and validating testing for this group of inherited colorectal cancers, the American College of Medical Genetics and Genomics has developed the following technical standards and guidelines. An algorithm for testing is also proposed.
林奇综合征、家族性腺瘤性息肉病和 MutY 同源物（MYH）相关息肉病是三种已知的主要遗传性结直肠癌类型，占所有结肠癌病例的 5% 左右。林奇综合征最常由错配修复基因 MLH1、MSH2、MSH6 和 PMS2 的突变引起，以常染色体显性遗传方式遗传。家族性腺瘤性息肉病表现为 APC 基因突变引起的结肠息肉，也以常染色体显性遗传方式遗传。最后，MYH 相关息肉病由 MUTYH 基因突变引起，以常染色体隐性遗传方式遗传，但可能与息肉无关。家族性腺瘤性息肉病（伴结肠外特征的 Gardner 综合征和有髓母细胞瘤的 Turcot 综合征）和林奇综合征（有皮脂癌的 Muir-Torre 综合征和有胶质母细胞瘤的 Turcot 综合征）都有变异。虽然家族性腺瘤性息肉病可以通过结肠镜检查做出临床诊断，但需要进行基因检测以告知有风险的亲属。由于轻度家族性腺瘤性息肉病、MYH 相关息肉病和林奇综合征之间存在重叠的表型，因此需要进行基因检测以区分这些疾病。这种区分很重要，尤其是对于林奇综合征的女性，她们患妇科癌症的风险增加。随着技术的进步和试剂成本的降低，尤其是测序技术的进步，过去几年中这些基因的临床检测取得了快速进展。为了帮助临床实验室开发和验证这些遗传性结直肠癌的检测，美国医学遗传学与基因组学学院制定了以下技术标准和指南。还提出了一种测试算法。
