Identification of a Germline XAF1 Mutation in Patients With Gastrointestinal Cancers

Gastrointestinal (GI) cancers can be attributed to the interplay between genetic and environmental factors. To date, apart from certain cancer syndromes, the genetic factors underlying familial GI cancers have not been clearly elucidated.

Blood samples were collected from six members of a family with GI cancer for whole exome sequencing to identify suspicious germline mutations. Subsequently, 148 patients with GI cancers (including esophageal and gastric cancers) and 283 cancer-free patients were recruited. The frequency of the suspected mutations in both groups was determined using Sanger sequencing. Furthermore, immunofluorescence (IF) assays for XAF1 protein expression were performed in paraffin-embedded surgically resected tumor tissues from patients with GI cancer, with or without the mutation.

In a family with GI cancer, we identified a mutation of XAF1 (c.454+1372G>A), which is a nonsense mutation in Exon 4b that results in a truncated XAF1 Isoform 5. Sanger sequencing of sporadic cancer patients and cancer-free populations further verified that the frequency of this mutation was enriched in patients with GI cancer. Additionally, IF assays revealed that XAF1 protein expression was lower in the mutated group than in the nonmutated group.

Our study provides evidence that a XAF1 mutation (c.454+1372G>A) leads to repressed expression of XAF1 and is associated with a predisposition to GI tumorigenesis, especially in esophageal and gastric cancers.