Abstract:
Objective Lynch syndrome is a malignant tumor syndrome with autosomal dominant inheritance. Preliminary screening of patients based on family history of tumor is currently the main method for Lynch syndrome screening. This study aimed to determine the proportion of colorectal cancer patients who met the clinical criteria of Lynch syndrome in China and were finally diagnosed with Lynch syndrome, as well as the opportunities and challenges that next-generation sequencing brought to the clinical diagnosis of Lynch syndrome.
Methods From February 2017 to October 2019, 85 unrelated patients were enrolled in 7 hospitals (The Second Affiliated Hospital, Zhejiang University School of Medicine; Peking Union Medical College Hospital; Jiangsu Province Hospital; Peking University First Hospital; Liaoning Cancer Hospital & Institute; West China Hospital; Wenzhou Central Hospital) with colorectal cancer who met the Chinese clinical criteria for Lynch syndrome, and detected the germline variants using a next-generation sequencing panel containing 61 genes that have been reported to be related to hereditary tumors. For the variants of uncertain clinical significance, the pathogenic significance of the variants is determined by Sanger sequencing and multiplex fluorescent PCR capillary electrophoresis to detect microsatellite status of tumor tissues.
Results Among the colorectal cancer patients who met Chinese clinical criteria for Lynch syndrome, 28.2% were detected with pathogenic or likely pathogenic germline variants in Lynch syndrome-related genes, and 15.3% of patients carried variants of uncertain clinical significance of these genes. In the analysis of variants of uncertain significance, we suppose that the MLH1 read-through variant (c.2240_2255 delCTGATCTATACAAAGT) is a pathogenic variant of Lynch syndrome. Additionally, there is still insufficient evidence to show that MLH3 gene exon 2-11 duplication is closely related to the occurrence of hereditary colorectal cancer.
Conclusions This study found that, also based on colorectal cancer patients who met the Chinese clinical criteria of Lynch syndrome, next-generation sequencing did not improve the diagnosis rate of Lynch syndrome compared with previous researches using Sanger sequencing. At the same time, it also brought a large number of variants of uncertain significance. Therefore, we need to be cautious about the results of genetic test. If necessary, in-depth pedigree research and comprehensive molecular testing should be carried out to clarify the clinical significance of these variants.
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