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

Mei Sim Lung,Maria A Doyle,Kylie L Gorringe,Catherine A Mitchell,David D L Bowtell,Andrew C Lynch,Alison H Trainer,Ian G Campbell

doi:10.1186/s12885-020-6705-y

Abstract

BackgroundFamilial 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.MethodsThrough 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.ResultsFifteen 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.ConclusionGermline 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.

Highlights

Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain
Analysis of genes associated with known familial colorectal cancer syndromes Prior to analysis for novel shared germline variants, a targeted analysis was undertaken of 17 genes associated with an increased familial colorectal cancer risk: APC, MUTYH, MLH1, MSH2, MSH6, PMS2, BMPR1A, SMAD4, STK11, EPCAM [32], GREM1, POLE [33], POLD1 [33], BUB1 [34], BUB1B [35], BUB3 [34] and NTHL1 [36]
After excluding any variant previously reported in the 1000 Genomes Project or the NHLBI Grand Opportunity (GO) Exome Sequencing Project, or a local cohort of 147 familial breast cancer exomes, a total of 106 and 110 variants remained in P1 and P2, respectively

Summary

Introduction

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. Appendiceal mucinous tumours (AMTs) are rare, occurring at an age-adjusted incidence of 0.12 per million individuals, with a median age at diagnosis of 59 years and no gender bias [1]. Molecular studies of PMP and AMTs are limited, but somatic mutations have been identified in KRAS (60– 100% of sequenced cases), GNAS (30–74%), SMAD4 (16%), and TP53 (5–14%) [3,4,5,6,7,8,9]. In 5 LAMNs, a mutation signature consistent with deamination of 5-methylcytosine was commonly detected [10]

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