期刊
BMC CANCER
卷 20, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12885-020-6705-y
关键词
Pseudomyxoma peritonei; Appendiceal tumour; Familial; Germline predisposition; Exome sequencing
类别
资金
- Australian National Health and Medical Research Council
- Victorian Cancer Council [APP1028374]
- Australian Postgraduate Award through the University of Melbourne, Australia
- U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- Cancer Council Victoria, Queensland Cancer Fund
- Cancer Council New South Wales
- Cancer Council South Australia
- Cancer Foundation of Western Australia
- Cancer Council Tasmania
- National Health and Medical Research Council of Australia (NHMRC) [ID400413, ID400281]
- Ovarian Cancer Australia (OCA)
- Peter MacCallum Foundation
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.
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