Analysis of Mutation and Loss of Heterozygosity by Whole-Exome Sequencing Yields Insights into Pseudomyxoma Peritonei

Pengelly, Reuben J.; Rowaiye, Babatunde; Pickard, Karen; Moran, Brendan; Dayal, Sanjeev; Tapper, William; Mirnezami, Alex H.; Cecil, Tom; Mohamed, Faheez; Carr, Norman J.; Ennis, Sarah

doi:10.1016/j.jmoldx.2018.05.002

Cited by 22 publications

(31 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An RNF43 stop-gained mutation in a region of LOH in a LAMN has recently been described [10]. In 5 LAMNs, a mutation signature consistent with deamination of 5-methylcytosine was commonly detected [10].…”

Section: Introductionmentioning

confidence: 99%

“…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]. Compared to colorectal cancer, somatic mutations in the APC gene are observed at a much lower frequency, ranging between 0 and 33% [4,7,9,10]. An RNF43 stop-gained mutation in a region of LOH in a LAMN has recently been described [10].…”

Section: Introductionmentioning

confidence: 99%

“…Compared to colorectal cancer, somatic mutations in the APC gene are observed at a much lower frequency, ranging between 0 and 33% [4,7,9,10]. An RNF43 stop-gained mutation in a region of LOH in a LAMN has recently been described [10]. In 5 LAMNs, a mutation signature consistent with deamination of 5-methylcytosine was commonly detected [10].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Molecular studies of PMP and AMTs are limited, but somatic mutations have been identified in KRAS(60-100%) GNAS in (30-74%), SMAD4 (16%), and TP53 (5-14%) (3)(4)(5)(6)(7)(8)(9). Compared to colorectal cancer, somatic mutations in the APC gene are observed at a much lower frequency, ranging between 0-33% (4,7,9,10). An RNF43 stop-gained mutation in a region of LOH in a LAMN has recently been described (10).…”

Section: Introductionmentioning

confidence: 99%

“…Compared to colorectal cancer, somatic mutations in the APC gene are observed at a much lower frequency, ranging between 0-33% (4,7,9,10). An RNF43 stop-gained mutation in a region of LOH in a LAMN has recently been described (10). In 5 LAMNs, a mutation signature consistent with deamination of 5-methylcytosine was commonly detected (10).…”

Section: Introductionmentioning

confidence: 99%

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

Lung

Mitchell

Doyle

et al. 2019

Preprint

View full text Add to dashboard Cite

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.

show abstract

Targeted Genetic Sequencing Analysis of 223 Cases of Pseudomyxoma Peritonei Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Shows Survival Related to GNAS and KRAS Status

Gibson,

Pengelly,

Mirandari

et al. 2024

Cancer Medicine

View full text Add to dashboard Cite

Background and AimPseudomyxoma peritonei (PMP) is an unusual condition with unique behaviour caused by a mucinous neoplasm, usually arising from the appendix. The aim of this study was to evaluate the prevalence of genomic alterations in clinical specimens of PMP using a targeted assay and correlate the findings with clinical, pathological and outcome data. Sequencing data from 223 patients were analysed.ResultsThe median follow‐up interval was 48 months. The primary neoplasm was appendiceal in 216 patients, ovarian in 4, urachal in 2 and renal in one. We confirmed common mutations in GNAS and KRAS (42% each) with significant co‐occurrence of variants in these genes. TP53 mutations were found in 8%. Other mutations were rare but included novel mutations in BAP1 and ERBB4. Of 17 patients with acellular peritoneal mucin, 6 (35%) were positive for DNA mutations. The non‐appendiceal cases generally showed a similar mutational landscape to the appendiceal lesions with GNAS and KRAS commonly mutated, although one urachal lesion showed multi‐hit TP53 mutation without variants in either GNAS or KRAS. Survival was significantly associated with the grade of the primary neoplasm, the grade of the peritoneal disease, the completeness of cytoreduction score and with mutation in either GNAS, KRAS or both. The hazard ratio (HR) associated with mutation in GNAS and/or KRAS was 1.87 (p = 0.004).ConclusionsSurvival outcome was more closely associated with the grade of the peritoneal disease than with the grade of the primary neoplasm. Our findings support the developing concept that mutational analysis may provide prognostic information in patients with PMP.

show abstract

Analysis of Mutation and Loss of Heterozygosity by Whole-Exome Sequencing Yields Insights into Pseudomyxoma Peritonei

Cited by 22 publications

References 45 publications

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

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

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

Targeted Genetic Sequencing Analysis of 223 Cases of Pseudomyxoma Peritonei Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Shows Survival Related to GNAS and KRAS Status

Contact Info

Product

Resources

About