Novel Lynch syndrome-causing mutation in the MLH1 gene accompanied by a p.R283C mutation in TP53: A case report

Targeted gene panel testing has the power to interrogate hundreds of genes simultaneously and evaluate the genetic risk for many types of hereditary cancers at the same time. Herein, we applied gene panel sequencing and identified a frameshift mutation c.333_334delTC; p.His112CysfsTer9 in the MLH1 gene accompanied by a known missense variant of unknown significance c.847C>T; p.Arg283Cys in the TP53 gene in a young patient with glioblastoma multiforme. The MLH1 variant was also found in the patient’s mother, who was diagnosed with breast cancer in the year preceding his diagnosis. To the best of our knowledge, this is the first study reporting the co-occurrence of a Lynch syndrome causing genetic mutation accompanied by a rare functionally relevant variant in the TP53 gene. It is conceivable that the combination of both variants might have a synergistic effect and influence the onset and the tissue specificity of cancer. This report underlines the need for broad panel gene testing in lieu of single-gene or syndrome focused gene screening and evaluation of the effects of multiple pathogenic or modifier variants on the phenotypic spectrum of the disease.

靶向基因面板检测（Targeted gene panel testing）可同时并行分析数百个基因，并同步评估多种遗传性癌症的遗传风险。本研究中，我们采用基因面板测序技术，对一例年轻多形性胶质母细胞瘤患者进行检测，在其MLH1基因中检出移码突变c.333_334delTC；p.His112CysfsTer9，同时检出TP53基因中1个已知意义未明的错义变异c.847C>T；p.Arg283Cys。该MLH1变异同时在患者母亲体内被检出，其母亲在患者确诊前一年被诊断为乳腺癌。据我们所知，本研究是首项报道致林奇综合征（Lynch syndrome）的基因突变与TP53基因罕见功能相关变异共现的研究。可以推测，两种变异的联合作用可能产生协同效应，并影响癌症的发病时机与组织特异性。本研究强调，相较于单基因检测或针对单一综合征的靶向基因筛查，应采用广谱基因面板检测，并需评估多个致病性或修饰性变异对疾病表型谱的影响。