Department of Medical Oncology, Josephine Nefkens Institute Be414, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
Breast Cancer Res Treat. 2010 Sep;123(2):315-20. doi: 10.1007/s10549-009-0634-4. Epub 2009 Nov 19.
Germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 predispose to Lynch syndrome (also known as hereditary non-polyposis colorectal cancer). Recently, we have shown that the CHEK2 1100delC mutation also is associated with Lynch syndrome/Lynch syndrome-associated families albeit in a polygenic setting. Two of the ten CHEK2 1100delC positive Lynch syndrome families additionally carried a pathogenic MLH1 or MSH6 mutation, suggesting that mutations in mismatch repair genes may be involved in CHEK2 1100delC-associated cancer phenotypes. A phenotype of importance is hereditary breast and colorectal cancer (HBCC), with the CHEK2 1100delC mutation present in almost one-fifth of the families-again in a polygenic setting. In order to evaluate the involvement of MSH6 in polygenic CHEK2 cancer susceptibility, we, here, have analyzed the entire MSH6 coding sequence for genetic alterations in 68 HBCC breast cancer families. Rare MSH6 variants, with population frequencies below 1%, were identified in 11.8% of HBCC breast cancer families, whereas the same variants were identified in only 1.5% of population controls, suggesting that rare MSH6 variants are associated with HBCC breast cancer (P < or = 0.00001). However, screening of the entire MSH6 coding sequence in 68 non-HBCC breast cancer families showed a similar association (8.8 vs. approximately 1.4% in controls, P < or = 0.001), suggesting that rare MSH6 variants are not confined to HBCC breast cancer. Together, our data suggest that rare MSH6 variants may predispose to familial breast cancer. However, none of the rare MSH6 variants are obviously pathogenic, suggesting that a more subtle disease mechanism may operate in breast carcinogenesis.
错配修复基因 MLH1、MSH2、MSH6 和 PMS2 的种系突变使 Lynch 综合征（也称为遗传性非息肉病性结直肠癌）易感性增加。最近，我们发现 CHEK2 1100delC 突变也与 Lynch 综合征/Lynch 综合征相关家族相关，尽管是在多基因背景下。在十个 CHEK2 1100delC 阳性 Lynch 综合征家族中，有两个家族还携带致病性 MLH1 或 MSH6 突变，这表明错配修复基因的突变可能与 CHEK2 1100delC 相关的癌症表型有关。一个重要的表型是遗传性乳腺癌和结直肠癌（HBCC），在 CHEK2 1100delC 突变中，近五分之一的家族——同样是在多基因背景下。为了评估 MSH6 在多基因 CHEK2 癌症易感性中的作用，我们在此分析了 68 个 HBCC 乳腺癌家族中 MSH6 编码序列的所有遗传改变。在 11.8%的 HBCC 乳腺癌家族中发现了罕见的 MSH6 变体，其在人群中的频率低于 1%，而在人群对照中只发现了 1.5%的相同变体，这表明罕见的 MSH6 变体与 HBCC 乳腺癌相关（P<0.00001）。然而，在 68 个非 HBCC 乳腺癌家族的整个 MSH6 编码序列筛查中显示出类似的关联（8.8%与对照组的约 1.4%相比，P<0.001），这表明罕见的 MSH6 变体不仅局限于 HBCC 乳腺癌。总之，我们的数据表明，罕见的 MSH6 变体可能使家族性乳腺癌易感。然而，罕见的 MSH6 变体都不是明显的致病性，这表明在乳腺癌发生过程中可能存在更微妙的疾病机制。
