Zetner Diana Bregner, Bisgaard Marie Luise
Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Curr Genomics. 2017 Aug;18(4):341-359. doi: 10.2174/1389202918666170307161643.
The genetic background is unknown for the 50-60% of the HNPCC families, who fulfill the Amsterdam criteria, but do not have a mutation in an MMR gene, and is referred to as FCCTX. This study reviews the clinical, morphological and molecular characteristics of FCCTX, and discusses the molecular genetic methods used to localize new FCCTX genes, along with an overview of the genes and chromosomal areas that possibly relate to FCCTX. FCCTX is a heterogeneous group, mainly comprising cases caused by single high-penetrance genes, or by multiple low-penetrance genes acting together, and sporadic CRC cases. FCCTX differs in clinical, morphological and molecular genetic characteristics compared to LS, including a later age of onset, distal location of tumours in the colon, lower risk of developing extracolonic tumours and a higher adenoma/carcinoma ratio, which indicates a slower progression to CRC. Certain characteristics are shared with sporadic CRC, e.g. similarities in gene expression and a high degree of CIN+, with significanly increased 20q gain in FCCTX. Other molecular characteristics of FCCTX include longer telomere length and hypomethylation of LINE-1, both being a possible explanation for CIN+. Some genes in FCCTX families (RPS20, BMPR1A, SEMA4A) have been identified by using a combination of linkage analysis and sequencing. Sequencing strategies and subsequent bioinformatics are improving fast. Exome sequencing and whole genome sequencing are currently the most promising tools. Finally, the involvement of CNV's and regulatory sequences are widely unexplored and would be interesting for further investigation in FCCTX.
50% - 60%符合阿姆斯特丹标准但错配修复（MMR）基因无突变的遗传性非息肉病性结直肠癌（HNPCC）家系，其遗传背景未知，被称为家族性结直肠癌X型（FCCTX）。本研究回顾了FCCTX的临床、形态学和分子特征，讨论了用于定位新的FCCTX基因的分子遗传学方法，以及可能与FCCTX相关的基因和染色体区域概述。FCCTX是一个异质性群体，主要包括由单个高外显率基因、或多个低外显率基因共同作用引起的病例，以及散发性结直肠癌病例。与林奇综合征（LS）相比，FCCTX在临床、形态学和分子遗传学特征方面存在差异，包括发病年龄较晚、肿瘤位于结肠远端、发生结外肿瘤的风险较低以及腺瘤/癌比例较高，这表明其向结直肠癌的进展较慢。FCCTX与散发性结直肠癌有某些共同特征，例如基因表达相似和高度的染色体不稳定（CIN +），FCCTX中20号染色体长臂增加显著。FCCTX的其他分子特征包括端粒长度较长和LINE-1低甲基化，两者都可能是CIN +的原因。通过连锁分析和测序相结合的方法，已经在FCCTX家系中鉴定出一些基因（RPS20、BMPR1A、SEMA4A）。测序策略和后续的生物信息学正在快速发展。外显子组测序和全基因组测序目前是最有前景的工具。最后，拷贝数变异（CNV）和调控序列的参与在很大程度上尚未被探索，对FCCTX进行进一步研究将很有意义。
