Ferreira Sara, Lage Pedro, Sousa Rita, Claro Isabel, Francisco Inês, Filipe Bruno, Suspiro Alexandra, Chaves Paula, Rodrigues Paula, Albuquerque Cristina, Nobre Leitão C
Instituto Português de Oncologia, Lisboa.
Acta Med Port. 2009 May-Jun;22(3):207-14. Epub 2009 Jul 15.
Some families fulfilling the Amsterdam Criteria (AC) differ from the Lynch syndrome (LS) in that colorectal cancers (CRC) do not present microsatellite instability (MSI) and DNA mismatch repair gene mutations are not found. These families have been designated as Familial Colorectal Cancer type X (XS) and their genetic basis remains unknown.
In families fulfilling AC for LS: 1) To perform MSI testing in CRC and to correlate it with clinical and pathological characteristics and with the mutational analysis in the DNA mismatch repair genes; 2) In cases suggestive of XS, to study the suppressor pathway (SP) of carcinogenesis.
45 patients with CRC, from 41 families fulfilling AC, were included. Clinical and pathological data were recorded. MSI testing was performed with the Bethesda marker panel and mutational analysis in MLH1, MSH2 and MSH6 genes was undertaken by DGGE, MLPA and direct sequencing. To study the SP, loss of heterozigoty was evaluated at the following loci: APC, p53, DCC and SMAD4 genes.
33/41 (80%) and 8/41 (20%) families presented high-grade microsatellite instability (MSI-H) and microsatellite stable (MSS) CRC, respectively. In families suggestive of XS, a smaller number of CRC and less frequent spectrum associated tumors were detected. In comparison with MSI-H CRC, MSS CRC were preferentially located at the distal colon/rectum and less often presented mucous production or lymphocytic infiltrate. In 70% of families with MSI-H CRC, a pathogenic mutation in one of the DNA mismatch repair genes was identified, as opposed to none in the group with MSS CRC. The SP was followed in 2 cases and an alternative one in other two. The remaining 4 cases were noninformative; however, 5/8 (63%) presented allelic losses in the APC gene.
一些符合阿姆斯特丹标准（AC）的家族与林奇综合征（LS）不同，其结直肠癌（CRC）不存在微卫星不稳定性（MSI），且未发现DNA错配修复基因突变。这些家族被指定为X型家族性结直肠癌（XS），其遗传基础仍不清楚。
在符合LS的AC标准的家族中：1）对CRC进行MSI检测，并将其与临床和病理特征以及DNA错配修复基因的突变分析相关联；2）在疑似XS的病例中，研究致癌作用的抑制途径（SP）。
纳入了来自41个符合AC标准的家族的45例CRC患者。记录临床和病理数据。使用贝塞斯达标记物面板进行MSI检测，并通过变性梯度凝胶电泳（DGGE）、多重连接探针扩增（MLPA）和直接测序对MLH1、MSH2和MSH6基因进行突变分析。为了研究SP，在以下位点评估杂合性缺失：APC、p53、DCC和SMAD4基因。
41个家族中分别有33个（80%）和8个（20%）家族的CRC表现为高度微卫星不稳定（MSI-H）和微卫星稳定（MSS）。在疑似XS的家族中，检测到的CRC数量较少，且与谱相关肿瘤的发生频率较低。与MSI-H CRC相比，MSS CRC更倾向于位于结肠远端/直肠，且较少出现黏液分泌或淋巴细胞浸润。在70%的MSI-H CRC家族中，在DNA错配修复基因之一中鉴定出致病突变，而MSS CRC组中未发现。对2例患者进行了SP追踪，另外2例患者进行了替代追踪。其余4例无信息；然而，8例中有5例（63%）在APC基因中出现等位基因缺失。
1）符合AC标准且患有MSS CRC的家族具有特殊特征，这进一步证明了存在一种不同于LS的新实体；2）X型家族性结直肠癌的命名似乎适合对一种CRC遵循不明致癌途径且遗传基础未知的实体进行分类；3）LS的命名应仅限于已鉴定出致病DNA错配修复基因突变的家族。
