A novel STK11 gene mutation (c.388dupG, p.Glu130Glyfs∗33) in a Peutz-Jeghers family and evidence of higher gastric cancer susceptibility associated with alterations in STK11 region aa 107-170

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation and gastrointestinal (GI) hamartomatous polyposis and is associated with a markedly increased risk of (extra-)GI malignancies. STK11 has been identified as a pathogenic factor in PJS. STK11 is a tumor suppressor gene located on chromosome 19p13.3 and includes 9 coding exons. STK11 plays an important role in tumorigenesis since it is implicated in numerous biological processes. STK11 germline mutations have a wide genetic heterogeneity, and genotype-phenotype associations are not yet clearly established. In the current study, we examined an Italian family with a clinical diagnosis of PJS. The index case is a 42-year-old woman with several GI hamartomatous polyps. The patient had a positive family history of gastric cancer and colon polyposis. The index patient underwent a molecular study of the STK11 gene (NM_000455.4). The molecular analysis of the STK11 gene identified a novel heterozygous frameshift variant, c.388dupG, in exon 3. STK11 c.388dupG was found to be rare since it was not listed in the global population and major disease-associated databases. The STK11 c.388dupG mutation is located in the core of the catalytic site (aa 123–148) and causes a frameshift in the coding sequence at codon 130, leading to premature termination of translation at codon 163 (p.Glu130Glyfs*33), with loss of the STK11 catalytic domain and C-terminal non-catalytic regulatory region. Based on the family history of gastric lesions reported in the examined Italian family, we correlated the location of STK11 nonsense and frameshift mutations with gastric cancer susceptibility by performing a meta-analysis of published studies comprising relevant clinical data. These data revealed a trend toward a higher risk of developing GC in PJS patients with STK11 truncating mutations in region aa 107-170. The STK11 c.388dupG leads to premature termination of translation at codon 163 (p.Glu130Glyfs*33), which contributes to the PJS phenotype. Furthermore, we found that PJS patients carrying STK11 nonsense and frameshift germline mutations in region aa 107-170 seem to have increased susceptibility to developing GC. This finding may have a significant impact on the surveillance, tailored management, and overall quality of life of PJS patients.