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Analysis of mutation and loss of heterozygosity by whole-exome sequencing yields insights into pseudomyxoma peritonei

Analysis of mutation and loss of heterozygosity by whole-exome sequencing yields insights into pseudomyxoma peritonei
Analysis of mutation and loss of heterozygosity by whole-exome sequencing yields insights into pseudomyxoma peritonei
Pseudomyxoma peritonei is a clinical syndrome characterized by gross mucinous ascites originating from a disseminated intraperitoneal neoplasm. Although typically confined to the abdomen, mortality is high if untreated. Biomarkers, including genetic mutation profiles, may aid treatment selection and decision making. In order to investigate this, we have applied whole-exome sequencing to five patients diagnosed with low grade appendiceal mucinous neoplasms, utilising paired tumour and germline samples. Multiple bioinformatic approaches were applied to these data and assess both somatic mutation profiles and loss of heterozygosity events. Mutation profiles of the tumours were consistent with deamination of methylcytosine being the prevailing mechanism. We identify pathogenic mutations in both KRAS and GNAS in all samples, as well as further mutations in genes implicated in PMP, namely FGFR2, APC, SMAD2 and FAT4. No TP53 somatic mutations were identified, matching expectations for low-grade tumours. Four of five samples exhibited clonal loss of heterozygosity; these regions were further examined and found to contain genes harbouring pathogenic somatic mutations in some samples. RNF43 was hereby implicated in the pathogenesis of PMP of appendiceal origin, having previously been demonstrated to increase sensitivity to Wnt signalling and have involvement in similar mucinous tumours. In conclusion, we have investigated the mutation profile of pseudomyxoma peritonei of appendiceal origin, and provided the first report of RNF43 involvement in its progression.
1525-1578
635-642
Pengelly, Reuben
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Rowaiye, Babatunde
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Pickard, Karen
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Moran, Brendan J.
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Dayal, Sanjeev
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Tapper, William
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Mirnezami, Alexander
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Cecil, Tom
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Mohamed, Faheez
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Carr, Norman
561fffe8-2b94-415d-a556-2d3d9acf3d2a
Ennis, Sarah
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Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Rowaiye, Babatunde
8983ebe0-4974-48fd-9cde-d924017c88c2
Pickard, Karen
e5188669-dff1-49c7-9c6f-8122b0c74bd9
Moran, Brendan J.
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Dayal, Sanjeev
b22b44bc-1c90-405c-91d8-effee2546991
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Mirnezami, Alexander
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Cecil, Tom
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Mohamed, Faheez
11e760f5-fd56-4f32-9264-22a2e710b365
Carr, Norman
561fffe8-2b94-415d-a556-2d3d9acf3d2a
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9

Pengelly, Reuben, Rowaiye, Babatunde, Pickard, Karen, Moran, Brendan J., Dayal, Sanjeev, Tapper, William, Mirnezami, Alexander, Cecil, Tom, Mohamed, Faheez, Carr, Norman and Ennis, Sarah (2018) Analysis of mutation and loss of heterozygosity by whole-exome sequencing yields insights into pseudomyxoma peritonei. Journal of Molecular Diagnostics, 20 (5), 635-642. (doi:10.1016/j.jmoldx.2018.05.002).

Record type: Article

Abstract

Pseudomyxoma peritonei is a clinical syndrome characterized by gross mucinous ascites originating from a disseminated intraperitoneal neoplasm. Although typically confined to the abdomen, mortality is high if untreated. Biomarkers, including genetic mutation profiles, may aid treatment selection and decision making. In order to investigate this, we have applied whole-exome sequencing to five patients diagnosed with low grade appendiceal mucinous neoplasms, utilising paired tumour and germline samples. Multiple bioinformatic approaches were applied to these data and assess both somatic mutation profiles and loss of heterozygosity events. Mutation profiles of the tumours were consistent with deamination of methylcytosine being the prevailing mechanism. We identify pathogenic mutations in both KRAS and GNAS in all samples, as well as further mutations in genes implicated in PMP, namely FGFR2, APC, SMAD2 and FAT4. No TP53 somatic mutations were identified, matching expectations for low-grade tumours. Four of five samples exhibited clonal loss of heterozygosity; these regions were further examined and found to contain genes harbouring pathogenic somatic mutations in some samples. RNF43 was hereby implicated in the pathogenesis of PMP of appendiceal origin, having previously been demonstrated to increase sensitivity to Wnt signalling and have involvement in similar mucinous tumours. In conclusion, we have investigated the mutation profile of pseudomyxoma peritonei of appendiceal origin, and provided the first report of RNF43 involvement in its progression.

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Accepted/In Press date: 11 May 2018
e-pub ahead of print date: 22 June 2018
Published date: 1 September 2018

Identifiers

Local EPrints ID: 420926
URI: https://eprints.soton.ac.uk/id/eprint/420926
ISSN: 1525-1578
PURE UUID: 475f5ae7-f021-4072-b6c2-db61f98e491e
ORCID for Reuben Pengelly: ORCID iD orcid.org/0000-0001-7022-645X
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

Catalogue record

Date deposited: 18 May 2018 16:30
Last modified: 17 Apr 2019 00:36

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