Comprehensive screening for mutations associated with colorectal cancer in unselected cases reveals penetrant and nonpenetrant mutations

Kraus, Cornelia; Rau, Tilman T.; Lux, P.; Erlenbach-Wünsch, Katharina; Löhr, Sabine; Krumbiegel, Mandy; Thiel, Christian T.; Stöhr, Robert; Agaimy, Abbas; Croner, Roland S.; Hohenberger, Werner; Hartmann, Arndt; Reis, André

doi:10.1002/ijc.29149

Cited by 22 publications

(19 citation statements)

References 42 publications

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“…This gives a mutation detection frequency of 8.8 % (8/91) for the class 5 variants only and a frequency of 17.6 % (16/91) when also class 4 variants are included. These results are in concordance with the results obtained in other studies of similar gene panels [6, 18]. Two pathogenic variants in PMS2 in patients I:26 and I:50 were missed in the initial analyses of the MMR genes performed in an external laboratory.…”

Section: Resultssupporting

confidence: 91%

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Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing

et al. 2016

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Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.Electronic supplementary materialThe online version of this article (doi:10.1007/s10689-016-9934-0) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 91%

“…The increased use of multigene panels have already shown a higher mutation detection rate compared with traditional testing based on clinical criteria [6, 18], as is also confirmed by this study. The reason for this is probably a large genetic heterogeneity and overlapping clinical presentation of the different CRC syndromes.…”

Section: Resultssupporting

confidence: 84%

Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing

et al. 2016

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“…Additionally, a major question in the development and progression of human cancer has been the contribution of germline alterations to cancer predisposition. Although estimates have been proposed in specific tumor types (14, 15), the comprehensive examination of cancer-predisposing alterations in apparently sporadic cancer patients has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Personalized genomic analyses for cancer mutation discovery and interpretation

et al. 2015

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Massively parallel sequencing approaches are beginning to be used clinically to characterize individual patient tumors and to select therapies based on the identified mutations. A major question in these analyses is the extent to which these methods identify clinically actionable alterations and whether the examination of the tumor tissue alone is sufficient or whether matched normal DNA should also be analyzed to accurately identify tumor-specific (somatic) alterations. To address these issues, we comprehensively evaluated 815 tumor-normal paired samples from patients of 15 tumor types. We identified genomic alterations using next-generation sequencing of whole exomes or 111 targeted genes that were validated with sensitivities >95% and >99%, respectively, and specificities >99.99%. These analyses revealed an average of 140 and 4.3 somatic mutations per exome and targeted analysis, respectively. More than 75% of cases had somatic alterations in genes associated with known therapies or current clinical trials. Analyses of matched normal DNA identified germline alterations in cancer-predisposing genes in 3% of patients with apparently sporadic cancers. In contrast, a tumor-only sequencing approach could not definitively identify germline changes in cancer-predisposing genes and led to additional false-positive findings comprising 31% and 65% of alterations identified in targeted and exome analyses, respectively, including in potentially actionable genes. These data suggest that matched tumor-normal sequencing analyses are essential for precise identification and interpretation of somatic and germline alterations and have important implications for the diagnostic and therapeutic management of cancer patients.

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“…Previously, patients without evidence of pathogenic APC variants were analyzed for mutations in the MUTYH gene . The recent advent of NGS techniques affords the opportunity to rapidly screen patients for a comprehensive panel of CRC susceptibility genes in a cost‐effective fashion . In this study, mutation screening of 46 unrelated probands was performed using a panel of 19 genes previously associated with CRC by NGS.…”

Section: Discussionmentioning

confidence: 99%

Clinical characterization and mutation spectrum in patients with familial adenomatous polyposis in China

Kang

Yang

et al. 2019

J of Gastro and Hepatol

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Background and Aim Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. Patients with FAP are screened for germline mutations of two genes, APC and MUTYH. However, limited data exist on the clinical characterization and genotypic spectrum of FAP in China. This study was aimed to determine APC and MUTYH mutational status in a small cohort of FAP probands in China and to characterize the genotype–phenotype correlation in mutated patients. Methods Mutation screening of 46 unrelated probands was performed using multigene panels by next‐generation sequencing. Clinical data of the index were used to assess genotype–phenotype correlations. Results Overall, 42 out of 46 (91.30%) unrelated probands found mutations, including 35 (76.09%) with APC mutations, 3 (6.52%) with MUTYH mutations, and 4 (8.70%) with both APC and MUTYH mutations. Ten APC genetic alterations variants were novel. The hereditary pattern of the family with both APC and MUTYH mutations was autosomal dominant inheritance. Upper gastrointestinal polyp was the most common extracolonic manifestations. The onset time for patients with both APC and MUTYH mutations was earlier than MUTYH mutation carriers and similar to APC mutation carriers. But the age of carcinogenesis for patients with both APC and MUTYH mutations was later than APC mutation carriers and similar to MUTYH mutation carriers. Conclusion In this study, we show the importance of using multigene panels that allow for a parallel comprehensive screening. We suggest that genetic testing of patients with suspected adenomatous polyposis syndromes should include APC and MUTYH gene mutation analyses simultaneously.

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Comprehensive screening for mutations associated with colorectal cancer in unselected cases reveals penetrant and nonpenetrant mutations

Cited by 22 publications

References 42 publications

Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing

Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing

Personalized genomic analyses for cancer mutation discovery and interpretation

Clinical characterization and mutation spectrum in patients with familial adenomatous polyposis in China

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