Barreiro Rodrigo Araujo Sequeira, Sabbaga Jorge, Rossi Benedito M, Achatz Maria Isabel W, Bettoni Fabiana, Camargo Anamaria A, Asprino Paula F, A F Galante Pedro
Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil.
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Sao Paulo, Brazil.
J Pathol. 2022 Feb;256(2):214-222. doi: 10.1002/path.5829. Epub 2021 Nov 23.
MUTYH encodes a glycosylase involved in the base excision repair of DNA. Biallelic pathogenic germline variants in MUTYH cause an autosomal recessive condition known as MUTYH-associated adenomatous polyposis and consequently increase the risk of colorectal cancer. However, reports of increased cancer risk in individuals carrying only one defective MUTYH allele are controversial and based on studies involving few individuals. Here, we describe a comprehensive investigation of monoallelic pathogenic MUTYH germline variants in 10,389 cancer patients across 33 different tumour types and 117,000 healthy individuals. Our results indicate that monoallelic pathogenic MUTYH germline variants can lead to tumorigenesis through a mechanism of somatic loss of heterozygosity of the functional MUTYH allele in the tumour. We confirmed that the frequency of monoallelic pathogenic MUTYH germline variants is higher in individuals with cancer than in the general population, although this frequency is not homogeneous among tumour types. We also demonstrated that the MUTYH mutational signature is present only in tumours with loss of the functional allele and found that the characteristic MUTYH base substitution (C>A) increases stop-codon generation. We identified key genes that are affected during tumorigenesis. In conclusion, we propose that carriers of the monoallelic pathogenic MUTYH germline variant are at a higher risk of developing tumours, especially those with frequent loss of heterozygosity events, such as adrenal adenocarcinoma, although the overall risk is still low. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
MUTYH编码一种参与DNA碱基切除修复的糖基化酶。MUTYH的双等位基因致病性种系变异会导致一种常染色体隐性疾病，称为MUTYH相关腺瘤性息肉病，从而增加患结直肠癌的风险。然而，关于仅携带一个缺陷MUTYH等位基因的个体癌症风险增加的报道存在争议，且基于涉及个体较少的研究。在此，我们描述了对10389例患有33种不同肿瘤类型的癌症患者和117000名健康个体中MUTYH单等位基因致病性种系变异的全面调查。我们的结果表明，MUTYH单等位基因致病性种系变异可通过肿瘤中功能性MUTYH等位基因的体细胞杂合性缺失机制导致肿瘤发生。我们证实，癌症患者中MUTYH单等位基因致病性种系变异的频率高于一般人群，尽管该频率在不同肿瘤类型中并不均匀。我们还证明，MUTYH突变特征仅存在于功能性等位基因缺失的肿瘤中，并发现特征性的MUTYH碱基替换（C>A）会增加终止密码子的产生。我们确定了肿瘤发生过程中受影响的关键基因。总之，我们提出，MUTYH单等位基因致病性种系变异的携带者患肿瘤的风险更高，尤其是那些杂合性缺失事件频繁的肿瘤，如肾上腺腺癌，尽管总体风险仍然较低。© 2021年英国和爱尔兰病理学会。由约翰·威利父子有限公司出版。
