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.

Germline and somatic genetic alterations in two first‐degree relatives with appendiceal low‐grade mucinous carcinoma peritonei

“…Recently, Lung et al performed germline whole exome sequencing on a father/daughter pair with LGMCP and HGMCP, respectively, and identified 15 matching mutations. 22 Although none matched our cases, this could be due to histopathologic differences. However, these sporadic cases can provide important information about disease mechanisms and need further investigation.…”

“…There are few reports of germline genetic testing in appendiceal tumors. Recently, Lung et al performed germline whole exome sequencing on a father/daughter pair with LGMCP and HGMCP, respectively, and identified 15 matching mutations 22 . Although none matched our cases, this could be due to histopathologic differences.…”

“…To our knowledge, this is the fifth report of familial appendiceal neoplasms, and the third report of first-degree relatives with appendiceal cancer: a father/daughter with appendiceal carcinoid neoplasms, identical twin brothers with mucinous adenomas, a brother and sister with mucinous adenocarcinoma, and a father/daughter with LGMCP and HGMCP, respectively. 16,[20][21][22] By evaluating both germline and somatic genetic factors, these cases may elucidate the molecular factors that contribute to and guide further investigation of appendiceal cancer and treatment response in larger cohorts. Identifying differences in molecular alterations between exceptional and poor responders in a larger cohort may elucidate targeted therapies and additional treatment options.…”

“…The possibility of a germline susceptibility to appendiceal cancer has yet to be fully investigated. To our knowledge, there are four reported familial instances of appendiceal neoplasms, none of which had complete genomic testing (germline and somatic) on both patients 16,20‐22 . Understanding appendiceal LGMCP pathogenesis is essential in early diagnosis and development of effective treatments.…”

Exonucleases: Degrading DNA to Deal with Genome Damage, Cell Death, Inflammation and Cancer

“…EXOG removes this dinucleotide of the RNA/DNA hybrid duplex, maintaining mitochondrial genome integrity [ 118 ]. Since the identification of EXOG in 2008, only one report has associated EXOG with cancer: a missense mutation was found in a familiar case of appendiceal mucinous tumours, an extremely rare disease with uncertain genetic aetiology [ 119 ].…”