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The Capital Region of Denmark - a part of Copenhagen University Hospital
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New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

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  1. Mutation Load of Single, Large-Scale Deletions of mtDNA in Mitotic and Postmitotic Tissues

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  2. Estimating Effect Sizes and Expected Replication Probabilities from GWAS Summary Statistics

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  3. Establishing the pig as a large animal model for vaccine development against human cancer

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  4. Network-based analysis of the sphingolipid metabolism in hypertension

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  1. Medical and Nonmedical Information during Multidisciplinary Team Meetings in Cancer Care

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  2. Clinical impact of endoscopic ultrasound-guided through-the-needle microbiopsy in patients with pancreatic cysts

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  3. Hidden morbidities: drop in cancer diagnoses during the COVID-19 pandemic in Denmark

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A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.

Original languageEnglish
Article number566266
JournalFrontiers in genetics
Volume11
Pages (from-to)566266
ISSN1664-8021
DOIs
Publication statusPublished - 24 Sep 2020

    Research areas

  • RPS20, early onset colorectal cancer, familial cancer, gene panel analysis, hereditary colorectal cancer, oligogenic inheritance

ID: 61250403