Background: Pseudomyxoma peritonei (PMP) is a rare abdominal malignancy of mucin-producing cells arising from an appendiceal mucinous neoplasm(AMN). Two familial cases of AMNs have been described, however, only selected genes have been tested for germline predisposition. We set out to identify potential predisposing mutations in a third familial case through whole exome sequencing(WES) of germline DNA, and correlated germline variants with regions of loss of heterozygosity(LOH) in the tumours.
Methods: We performedWES on germline DNA from a father and daughter who had developed PMP. We identified shared heterozygous loss of function and non-synonymous variants which were not present in the 1000 Genomes Project[1], GO Exome Sequencing Project[2] or in-house germline exomes(N=147) and validated those with a Combined Annotation Dependent Depletion(CADD) Phred score[3] of >10. SNP array analysis was performed on the tumour tissue from both individuals to identify common regions of LOH.
Results: We identified 16 shared variants with CADD Phred scores of >10: a nonsense mutation in REEP5, an essential splice site mutation in THOP1, and 14 non-synonymous missense variants.
No variants were located in regions of LOH shared by the father and daughter. Three genes(RANBP2, RANBP6 and TNFRSF1B) contained missense variants that fell in a region of LOH in the father's tumour , however, none of these had loss of the wild-type allele in tumour tissue.
Conclusions: GermlineWES of a father and daughter with PMP identified a candidate list of genes which may predispose to AMNs and PMP. Further studies are required to clarify the role of these genes in familial or sporadic PMP.
2. Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA (http://evs.gs.washington.edu/EVS/), Accessed 6th March 2014