Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer

Abstract

BackgroundThe reported penetrance of germline CDH1 mutations is high in families with hereditary diffuse gastric cancer (HDGC). Men and women have a 70% and 56%, respectively, cumulative risk of developing diffuse gastric cancer by age 80. Women additionally have a 42% cumulative risk of developing breast cancer. Due to the high penetrance of these mutations, prophylactic total gastrectomy is currently recommended for CDH1 mutation carriers. However, whether everyone with a CDH1 gene mutation is at risk for HDGC is not clear.MethodsMutation identification was performed by next‐generation sequencing. Mutations and variant status was confirmed by Sanger sequencing in 11 family members.ResultsWe present two families with pathogenic CDH1 mutations. The first family carries a novel truncating, nonsense CDH1 mutation that we were able to trace for three generations, but reports no family history of diffuse gastric cancer. The occurrence of cancer in this family deviates significantly from the expectation for HDGC. The proband from the second family presents with breast cancer and carries a previously reported pathogenic CDH1 mutation, but also reports no family history of diffuse gastric cancer.ConclusionsOur study demonstrates the need for further analysis of CDH1 mutation penetrance in order to better counsel asymptomatic CDH1 mutation carriers on preventative measures and general care.

Genetic and histological subtypes of gastric cancer reviewed, particularly emphasising on microsatellite instability and E-cadherin gene mutation

“…Clinical manifestations, (a family history, the presence of potential risk factors of GC, patient age, a macroscopic tumour image), and the histological type of cancer may help to determine those patients who might need future treatment because of their genetic predisposition to GC. Finally, as aforementioned in detail, the two principal subtypes of GC with MSI-H and CDH1 mutation evolve through different pathways, and those differences in molecular pathogenesis translate into a morphological distinction, which merits our attention [48,49].…”

CDH1‐related blepharocheilodontic syndrome is associated with diffuse gastric cancer risk

“…CDH1 variants have also been reported in nonsyndromic CLP (NSCLP) without cancer, as well as in families with both NSCLP and HDGC (Benusiglio et al, 2013;Brito et al, 2015;Frebourg et al, 2006;Huynh & Laukaitis, 2016;Kluijt et al, 2012;Vogelaar et al, 2013).…”

Contemporary paradigm for the evaluation and treatment of hereditary gastric cancer

“…Independent of epidemiologic trends is a population of patients with hereditary gastric cancer syndromes (24,25). Recent improvement in molecular genetics has refined our understanding of the mutations causing hereditary gastric cancer (26). Since these patients are most often asymptomatic, guidelines for surveillance, indications for intervention, and long-term quality of life studies are in the medical literature (27).…”