Dovrat Shiri, Figer Arie, Fidder Herma H, Neophytou Pavlos, Fireman Zvi, Geva Ravit, Zidan Jamal, Flex Dov, Meir Shimon Bar, Friedman Eitan
Head of the Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Genetics, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel.
Fam Cancer. 2005;4(4):291-4. doi: 10.1007/s10689-005-1255-7.
Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly hMlh1 and hMsh2, underlie Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Germline hMSH6 gene mutations have been reported in a small subset of HNPCC families. In the present study, ethnically diverse individuals with HNPCC and HNPCC-like features were genotyped for hMsh6 germline mutations using exon-specific PCR, DGGE, and DNA sequencing. The study encompassed 92 individuals representing 88 unrelated families who were previously analyzed for Msh2 and Mlh1 mutations: Jewish Ashkenazim (n = 44), non-Ashkenazim (n = 27), Israeli Moslem-Arab (n = 15), Druze (n=3), and Cypriot non-Jews (n = 3). Of the study population, 71 had colon cancer (CRC), mean age at diagnosis was 50.9+/-13.2 years (range 16-73 years), 5 had endometrial cancer (two with concurrent CRC), (mean 43.6+/-3.26 years, range 38-45 years), and unaffected individuals (n = 18) were first degree relatives within HNPCC families and were genotyped at a mean age of 48.3+/-11.7 years (range 30-69 years). Of the 92 individuals analyzed, none showed a truncating hMsh6 mutation, and 6 (6.6%) harbored one of three germline missense mutations: a previously reported one (V878A), and two novel mutations (V509A, S227I). The pathogenic significance of these three missense mutations is yet unclear. In addition, 5 polymorphisms were detected, 2 of which were novel. We conclude that the rate of pathogenic hMsh6 mutations in HNPCC families of Jewish and Mediterranean origin is low, and that mutations in other genes probably account for the phenotype in these families.
DNA错配修复（DNA-MMR）基因的种系突变，主要是hMlh1和hMsh2，是遗传性非息肉病性结直肠癌（HNPCC）的基础。在一小部分HNPCC家族中已报道有种系hMSH6基因突变。在本研究中，使用外显子特异性PCR、变性梯度凝胶电泳（DGGE）和DNA测序对具有HNPCC及HNPCC样特征的不同种族个体进行hMsh6种系突变基因分型。该研究涵盖了代表88个无关家族的92名个体，这些家族之前已进行过Msh2和Mlh1突变分析：犹太阿什肯纳兹人（n = 44）、非阿什肯纳兹人（n = 27）、以色列穆斯林阿拉伯人（n = 15）、德鲁兹人（n = 3）以及塞浦路斯非犹太人（n = 3）。在研究人群中，71人患有结肠癌（CRC），诊断时的平均年龄为50.9±13.2岁（范围16 - 73岁），5人患有子宫内膜癌（两人同时患有CRC），（平均43.6±3.26岁，范围38 - 45岁），未受影响的个体（n = 18）是HNPCC家族中的一级亲属，基因分型时的平均年龄为48.3±11.7岁（范围30 - 69岁）。在分析的92名个体中，没有人显示出hMsh6截短突变，6人（6.6%）携带三种种系错义突变之一：一种先前报道的突变（V878A），以及两种新突变（V509A、S227I）。这三种错义突变的致病意义尚不清楚。此外，检测到5种多态性，其中2种是新的。我们得出结论，犹太人和地中海血统的HNPCC家族中致病性hMsh6突变的发生率较低，并且其他基因的突变可能是这些家族中该表型的原因。
