MLH1 Exon 12 Gene Deletion Leading to Lynch Syndrome: A Case Report

Abstract

Introduction: Deleterious heterozygous mutation of the MLH1 gene is an important cause of Lynch syndrome (LS), an autosomal dominant cancer caused by functional defects in the DNA mismatch repair (MMR) complex.

Case report: The proband was a 35-year-old patient with confirmed colorectal cancer (CRC). Immunohistochemical (IHC) staining revealed the absence of MLH1 and PMS2 expression in the colorectal tissue specimens of the patient. Genetic counselling and tumor gene testing were performed using next-generation sequencing technology. The genetic tumor verification report showed the deletion of 4 bases in exon 12 of the tested MLH1 gene and a transcoding mutation. To our knowledge, this germline splice site mutation of MLH1 has not been reported before. The proband accepted several therapeutic regimens including PD-1 inhibitor and ultimately died of multiple organ failure.

Conclusion: Nonsense mutations and frameshift mutations of MMR genes are the most common causes of LS. Common mutations include those in MSH2, MLH1, MSH6, and PMS2. We report a mutation of MLH1 that has never been reported before. We recommend that patients with a history of colon or rectal cancer receive universal MMR or MSI testing and checkpoint inhibitor therapy for the first-line treatment of deficient MMR CRC.

Keywords: Colorectal cancer; Germline mutation; Lynch syndrome; Mismatch repair; PD-1 inhibitors.

Fig. 1

Hematoxylin-eosin (HE) staining and IHC staining of colon cancer tissue specimens. Magnification ×100. A HE staining. B Negative MHL1 expression. C Positive MSH2 expression. D Positive MSH6 expression. E Negative PMS2 expression. F IHC staining of PD-1.

Fig. 2

Pedigree of the patient. The arrow indicates the proband. Squares and circles denote males and females, respectively. Closed symbols indicate persons with cancer.

Fig. 3

CT images of the patient. A First progression. B Second progression.

Fig. 4

A Results of gene detection (Sanger sequencing). The frameshift mutation c.1057_1060delGCTG (p.gly354profs *12) was detected in the MHL1 gene of the proband (arrows). B Outcomes of high-throughput genome sequencing; the red vertical line represents gene mutation sites.

Fig. 5

The results of family gene detection were analyzed by Sanger sequencing. A Heterozygous (Het) mutations were observed in the proband. B Het mutations were observed in the proband's uncle. C Genetic tests on the proband's maternal aunt showed normal results. D Het mutations were observed in the proband's mother. The red arrows show the Het mutation c.1057_1060delGCTG (p.gly354profs *12).