Dataset Information

Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei.

ABSTRACT:

Background

Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours.

Methods

Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ?10. Genome-wide copy number analysis was performed on tumour tissue from both individuals to identify regions of LOH.

Results

Fifteen novel variants in 15 genes were shared by the father and daughter, including a nonsense mutation in REEP5. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes (EXOG, RANBP2, RANBP6 and TNFRSF1B) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 individuals with presumed sporadic AMTs or PMP; no LoF or rare missense germline variants were identified.

Conclusion

Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.

SUBMITTER: Lung MS

PROVIDER: S-EPMC7195761 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei.

Lung Mei Sim MS Mitchell Catherine A CA Doyle Maria A MA Lynch Andrew C AC Gorringe Kylie L KL Bowtell David D L DDL Campbell Ian G IG Trainer Alison H AH

BMC cancer 20200501 1

<h4>Background</h4>Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours.<h4>Methods</h4>Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, framesh ...[more]

PMID: 32357859

Similar Datasets

Project description:BackgroundPseudomyxoma peritonei (PMP) is a malignancy characterized by dissemination of mucus-secreting cells throughout the peritoneum. This disease is associated with significant morbidity and mortality and despite effective treatment options for early-stage disease, patients with PMP often relapse. Thus, there is a need for additional treatment options to reduce relapse rate and increase long-term survival. A previous study identified the presence of both typed and non-culturable bacteria associated with PMP tissue and determined that increased bacterial density was associated with more severe disease. These findings highlighted the possible role for bacteria in PMP disease.MethodsTo more clearly define the bacterial communities associated with PMP disease, we employed a sequenced-based analysis to profile the bacterial populations found in PMP tumor and mucin tissue in 11 patients. Sequencing data were confirmed by in situ hybridization at multiple taxonomic depths and by culturing. A pilot clinical study was initiated to determine whether the addition of antibiotic therapy affected PMP patient outcome.Main resultsWe determined that the types of bacteria present are highly conserved in all PMP patients; the dominant phyla are the Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. A core set of taxon-specific sequences were found in all 11 patients; many of these sequences were classified into taxonomic groups that also contain known human pathogens. In situ hybridization directly confirmed the presence of bacteria in PMP at multiple taxonomic depths and supported our sequence-based analysis. Furthermore, culturing of PMP tissue samples allowed us to isolate 11 different bacterial strains from eight independent patients, and in vitro analysis of subset of these isolates suggests that at least some of these strains may interact with the PMP-associated mucin MUC2. Finally, we provide evidence suggesting that targeting these bacteria with antibiotic treatment may increase the survival of PMP patients.ConclusionsUsing 16S amplicon-based sequencing, direct in situ hybridization analysis and culturing methods, we have identified numerous bacterial taxa that are consistently present in all PMP patients tested. Combined with data from a pilot clinical study, these data support the hypothesis that adding antimicrobials to the standard PMP treatment could improve PMP patient survival.

Dataset Information

Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei.

Background

Methods

Results

Conclusion

Publications

Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets