Ferreira Ana M, Westers Helga, Sousa Sónia, Wu Ying, Niessen Renée C, Olderode-Berends Maran, van der Sluis Tineke, Reuvekamp Peter T W, Seruca Raquel, Kleibeuker Jan H, Hollema Harry, Sijmons Rolf H, Hofstra Robert M W
Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
J Pathol. 2009 Sep;219(1):96-102. doi: 10.1002/path.2573.
A progressive accumulation of genetic alterations underlies the adenoma-carcinoma sequence of colorectal cancer. This accumulation of mutations is driven by genetic instability, of which there are different types. Microsatellite instability (MSI) is the predominant type present in the tumours of Lynch syndrome patients and in a subset of sporadic tumours. It is generally accepted that MSI can be found in the early stages of tumour progression, such as adenomas; however, the frequencies reported vary widely among studies. Moreover, data on the qualitative differences between adenomas and carcinomas, or between tumours of hereditary and sporadic origin, are scarce. We compared MSI in samples of colorectal adenoma and colorectal carcinoma in order to identify possible differences along the adenoma-carcinoma sequence. We compared germline mismatch repair (MMR) gene mutation carriers and non-carriers, to address possible differences of instability patterns between Lynch syndrome patients and patients with sporadic tumours. We found a comparable relative frequency of mono- and dinucleotide instability in sporadic colorectal adenomas and carcinomas, dinucleotide instability being observed most frequently in these sporadic tumours. In MMR gene truncating mutation carriers, the profile was different: colorectal adenomas showed predominantly mononucleotide instability and in colorectal carcinomas, also more mononucleotide than dinucleotide instability was detected. We conclude that MSI profiles differ between sporadic and Lynch syndrome tumours, and that mononucleotide marker instability precedes dinucleotide marker instability during colorectal tumour development in Lynch syndrome patients. As mononucleotide MSI proves to be highly sensitive for detecting mutation carriers, we propose the use of mononucleotide markers for the identification of possible Lynch syndrome patients.
遗传改变的逐步积累是结直肠癌腺瘤-癌序列的基础。这种突变的积累是由遗传不稳定性驱动的，遗传不稳定性有不同类型。微卫星不稳定性（MSI）是林奇综合征患者肿瘤以及一部分散发性肿瘤中存在的主要类型。一般认为，MSI可在肿瘤进展的早期阶段如腺瘤中发现；然而，不同研究报道的频率差异很大。此外，关于腺瘤与癌之间，或遗传性与散发性起源肿瘤之间定性差异的数据很少。我们比较了结直肠腺瘤和结直肠癌样本中的MSI，以确定沿腺瘤-癌序列可能存在的差异。我们比较了种系错配修复（MMR）基因突变携带者和非携带者，以探讨林奇综合征患者与散发性肿瘤患者之间不稳定模式的可能差异。我们发现散发性结直肠腺瘤和癌中，单核苷酸和二核苷酸不稳定性的相对频率相当，二核苷酸不稳定性在这些散发性肿瘤中最常观察到。在MMR基因截短突变携带者中，情况不同：结直肠腺瘤主要表现为单核苷酸不稳定性，在结直肠癌中，检测到的单核苷酸不稳定性也比二核苷酸不稳定性更多。我们得出结论，散发性肿瘤和林奇综合征肿瘤的MSI谱不同，并且在林奇综合征患者的结直肠肿瘤发生过程中，单核苷酸标记不稳定性先于二核苷酸标记不稳定性。由于单核苷酸MSI被证明对检测突变携带者高度敏感，我们建议使用单核苷酸标记来识别可能的林奇综合征患者。
