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 t...
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| Format: | Article |
| Language: | English |
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BMC
2020-05-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-020-6705-y |
| _version_ | 1818147922856902656 |
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| author | Mei Sim Lung Catherine A. Mitchell Maria A. Doyle Andrew C. Lynch Kylie L. Gorringe David D. L. Bowtell Australian Ovarian Cancer Study Group Ian G. Campbell Alison H. Trainer |
| author_facet | Mei Sim Lung Catherine A. Mitchell Maria A. Doyle Andrew C. Lynch Kylie L. Gorringe David D. L. Bowtell Australian Ovarian Cancer Study Group Ian G. Campbell Alison H. Trainer |
| author_sort | Mei Sim Lung |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T12:42:57Z |
| format | Article |
| id | doaj.art-dd423ce9e9bb43bfa0607007b1b914c2 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-11T12:42:57Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-dd423ce9e9bb43bfa0607007b1b914c22022-12-22T01:06:55ZengBMCBMC Cancer1471-24072020-05-012011910.1186/s12885-020-6705-yGermline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritoneiMei Sim Lung0Catherine A. Mitchell1Maria A. Doyle2Andrew C. Lynch3Kylie L. Gorringe4David D. L. Bowtell5Australian Ovarian Cancer Study GroupIan G. Campbell6Alison H. Trainer7Research Division, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre BuildingDepartment of Pathology, Peter MacCallum Cancer CentreResearch Computing Facility, Peter MacCallum Cancer CentreDepartment of Surgical Oncology, Peter MacCallum Cancer CentreCancer Genomics Program, Peter MacCallum Cancer CentreCancer Genetics and Genomics Laboratory, Peter MacCallum Cancer CentreResearch Division, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre BuildingResearch Division, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre BuildingAbstract 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.http://link.springer.com/article/10.1186/s12885-020-6705-yPseudomyxoma peritoneiAppendiceal tumourFamilialGermline predispositionExome sequencing |
| spellingShingle | Mei Sim Lung Catherine A. Mitchell Maria A. Doyle Andrew C. Lynch Kylie L. Gorringe David D. L. Bowtell Australian Ovarian Cancer Study Group Ian G. Campbell Alison H. Trainer Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei BMC Cancer Pseudomyxoma peritonei Appendiceal tumour Familial Germline predisposition Exome sequencing |
| title | Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei |
| title_full | Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei |
| title_fullStr | Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei |
| title_full_unstemmed | Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei |
| title_short | Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei |
| title_sort | germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei |
| topic | Pseudomyxoma peritonei Appendiceal tumour Familial Germline predisposition Exome sequencing |
| url | http://link.springer.com/article/10.1186/s12885-020-6705-y |
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