Unit of Pathology, Institute for Cancer Research and Treatment, Candiolo, (Torino), Italy.
Mod Pathol. 2013 Oct;26(10):1371-81. doi: 10.1038/modpathol.2013.66. Epub 2013 Apr 19.
MUTYH is a DNA-base-excision-repair gene implicated in the activation of nuclear and mitochondrial cell-death pathways. MUTYH germline mutations cause an inherited polyposis, MUTYH-associated-polyposis, characterized by multiple adenomas and increased susceptibility to colorectal cancer. Since this carcinogenesis remains partially unknown, we searched for nuclear and mitochondrial gene alterations that may drive the tumorigenic process. Ninety-six adenomas and 7 carcinomas from 12 MUTYH-associated-polyposis and 13 classical/attenuated adenomatous polyposis patients were investigated by sequencing and pyrosequencing for the presence of mutations in KRAS, BRAF, MT-CO1/MT-CO2 and MT-TD genes. KRAS mutations were identified in 24% MUTYH-associated-polyposis vs 15% classical/attenuated familial polyposis adenomas; mutated MUTYH-associated-polyposis adenomas exhibited only c.34G>T transversions in codon 12, an alteration typically associated with oxidative DNA damage, or mutations in codon 13; neither of these mutations was found in classical/attenuated familial polyposis adenomas (P<0.001). Mutated MUTYH-associated-polyposis carcinomas showed KRAS c.34G>T transversions, prevalently occurring with BRAFV600E; none of the classical/attenuated familial polyposis carcinomas displayed these alterations. Comparing mitochondrial DNA from lymphocytes and adenomas of the same individuals, we detected variants in 82% MUTYH-associated-polyposis vs 38% classical/attenuated familial polyposis patients (P=0.040). MT-CO1/MT-CO2 missense mutations, which cause aminoacid changes, were only found in MUTYH-associated-polyposis lesions and were significantly associated with KRAS mutations (P=0.0085). We provide evidence that MUTYH-associated-polyposis carcinogenesis is characterized by the occurrence of specific mutations in both KRAS and phylogenetically conserved genes of mitochondrial DNA which are involved in controlling oxidative phosphorylation; this implies the existence of a colorectal tumorigenesis in which changes in mitochondrial functions cooperate with RAS-induced malignant transformation.
MUTYH 是一种 DNA 碱基切除修复基因，参与核和线粒体细胞死亡途径的激活。MUTYH 种系突变导致遗传性息肉病，即 MUTYH 相关息肉病，其特征为多发性腺瘤和结直肠癌易感性增加。由于这种致癌作用仍部分未知，我们寻找可能驱动肿瘤发生过程的核和线粒体基因改变。通过测序和焦磷酸测序，研究了 12 例 MUTYH 相关息肉病和 13 例经典/减轻型腺瘤性息肉病患者的 96 个腺瘤和 7 个癌组织中 KRAS、BRAF、MT-CO1/MT-CO2 和 MT-TD 基因的突变情况。MUTYH 相关息肉病腺瘤中 KRAS 突变发生率为 24%，而经典/减轻型家族性息肉病腺瘤为 15%；突变的 MUTYH 相关息肉病腺瘤仅在密码子 12 中显示 c.34G>T 颠换，这种改变通常与氧化 DNA 损伤相关，或在密码子 13 中发生突变；经典/减轻型家族性息肉病腺瘤中均未发现这些突变（P<0.001）。突变的 MUTYH 相关息肉病癌显示 KRAS c.34G>T 颠换，主要与 BRAFV600E 同时发生；经典/减轻型家族性息肉病癌均未显示这些改变。比较同一患者淋巴细胞和腺瘤中的线粒体 DNA，我们发现 MUTYH 相关息肉病患者中有 82%存在变体，而经典/减轻型家族性息肉病患者中有 38%存在变体（P=0.040）。仅在 MUTYH 相关息肉病病变中发现导致氨基酸改变的 MT-CO1/MT-CO2 错义突变，并且与 KRAS 突变显著相关（P=0.0085）。我们提供的证据表明，MUTYH 相关息肉病的癌变特征为 KRAS 和线粒体 DNA 中进化上保守的基因均发生特定突变，这些基因参与控制氧化磷酸化；这意味着存在结直肠肿瘤发生，其中线粒体功能的改变与 RAS 诱导的恶性转化协同作用。
