A new mutL homolog 1 c.1896+5G>A germline mutation detected in a Lynch syndrome-associated lung and gastric double primary cancer patient

Abstract

Background: Mismatch-repair genes (MMRs) ensure high fidelity in genome editing. Loss of function mutation of MMRs will lead to instability of the genome and increase the incidence of cancers. Human mutL homolog 1 (MLH1) is a member of the MMRs, and its mutation is found in Lynch syndrome (LS). In addition to the high incidence of colorectal cancer, LS patients often have other primary cancers. Here, a case of LS-associated lung and gastric double primary cancer was reported.

Methods: Diagnosis of lung and gastric double primary cancer was mainly based on clinical findings, imaging examination, and histopathological data. The tumor tissues and blood samples were collected, and then genomic DNA was extracted and 450 cancer-related gene alteration screening was conducted by next-generation sequencing and the functional verification of a mutant gene was carried out using the PCR method.

Results: We detected the epidermal growth factor receptor L858R, MSH2 R929* and telomerase reverse transcriptase amplification in the lung cancer specimen; CDH1 c.1320+1G>T mutation in the gastric cancer (GC) specimen; and MLH1 c.1896+5G>A germline mutation in the lung and GC specimens by 450 cancer-related gene mutations detection using next-generation sequencing technology. MLH1c.1896+5G>A is a novel germline mutation, and it was verified by the PCR subsequently. It was found that it could affect the splicing of intron 16. Nine relatives of three-generation of the patient were examined and the MLH1 c.1896+5G>A mutation and pedigree analysis were performed. The father's sister without cancer also carries this mutation.

Conclusion: Diagnosis of LS was mainly depended on the following: the cancer histories of his relatives, multi-primary cancers of lung and stomach in his own body, MLH1 and MSH2 gene mutations detected in the cancer tissues. The clinical significance of this new MLH1 c.1896+5G>A germline mutation detected in the LS-associated double primary cancer patient needed further study.

Keywords: Lynch syndrome; MLH1 c.1896+5G>A; germline mutation; mismatch-repair genes.