Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer syndrome
(HNPCC) is a common genetic predisposition to cancer due to germline mutations in
genes affecting DNA mismatch repair. Due to mismatch repair deficiency, developing
tumors are characterized by microsatellite instability (MSI-H), high frequency of
expressed neoantigens and good clinical response to immune checkpoint inhibitors.
Granzyme B (GrB) is the most abundant serine protease in the granules of cytotoxic
T-cells and natural killer cells, mediating anti-tumor immunity. However, recent results
confirm a diverse range of physiological functions of GrB including that in extracellular
matrix remodelling, inflammation and fibrosis. In the present study, our aim was to
investigate whether a frequent genetic variation of GZMB , the gene encoding GrB,
constituted by three missense single nucleotide polymorphisms (rs2236338, rs11539752
and rs8192917) has any association with cancer risk in individuals with LS. In silico
analysis and genotype calls from whole exome sequencing data in the Hungarian population
confirmed that these SNPs are closely linked. Genotyping results of rs8192917 on a
cohort of 145 individuals with LS demonstrated an association of the CC genotype with
lower cancer risk. In silico prediction proposed likely GrB cleavage sites in a high
proportion of shared neontigens in MSI-H tumors. Our results propose the CC genotype
of rs8192917 as a potential disease-modifying genetic factor in LS.
