Analysis of mutation and loss of heterozygosity by whole-exome sequencing yields insights into pseudomyxoma peritonei

Pseudomyxoma peritonei is a clinical syndrome characterized by gross mucinous ascites originating from a disseminated intraperitoneal neoplasm. Although typically confined to the abdomen, mortality is high if untreated. Biomarkers, including genetic mutation profiles, may aid treatment selection and decision making. In order to investigate this, we have applied whole-exome sequencing to five patients diagnosed with low grade appendiceal mucinous neoplasms, utilising paired tumour and germline samples. Multiple bioinformatic approaches were applied to these data and assess both somatic mutation profiles and loss of heterozygosity events. Mutation profiles of the tumours were consistent with deamination of methylcytosine being the prevailing mechanism. We identify pathogenic mutations in both KRAS and GNAS in all samples, as well as further mutations in genes implicated in PMP, namely FGFR2, APC, SMAD2 and FAT4. No TP53 somatic mutations were identified, matching expectations for low-grade tumours. Four of five samples exhibited clonal loss of heterozygosity; these regions were further examined and found to contain genes harbouring pathogenic somatic mutations in some samples. RNF43 was hereby implicated in the pathogenesis of PMP of appendiceal origin, having previously been demonstrated to increase sensitivity to Wnt signalling and have involvement in similar mucinous tumours. In conclusion, we have investigated the mutation profile of pseudomyxoma peritonei of appendiceal origin, and provided the first report of RNF43 involvement in its progression