ArticleBiomolecules2022
Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis.
Article in Biomolecules, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 20 citations in OpenAlex.
- ERN GENTURIS guidelines on constitutional mismatch repair deficiency diagnosis, genetic counselling, surveillance, quality of life, and clinical management.European journal of human genetics : EJHG · 2024Guideline
- The impact of international care networks on the clinical management of constitutional mismatch repair deficiency (CMMRD): a review of recent developments.Familial cancer · 2026Review
- Lynch Syndrome as a Spectrum of Four Distinct Genetic Disorders: Toward Genotype-Guided Precision Management in the NGS Era.Cancers · 2026Review
- Colorectal cancer in a 13-year-old with constitutional mismatch repair deficiency andJPGN reports · 2025Article
- Genetics, genomics and clinical features of adenomatous polyposis.Familial cancer · 2025Review
- PolED: a manually curated database of functional studies of POLE and POLD1 variants reported in humans.Database : the journal of biological databases and curation · 2025Article
- Case Report: Expansion of theFrontiers in oncology · 2025Article
- Report of the sixth meeting of the European Consortium 'Care for CMMRD' (CFamilial cancer · 2024Article
- MSH6-proficient crypt foci in MSH6 constitutional mismatch repair deficiency: reversion of a frameshifted coding microsatellite to its wild-type sequence.Familial cancer · 2024Article
- Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.NPJ precision oncology · 2024Article
- Lynch syndrome: influence of additional susceptibility variants on cancer risk.European journal of human genetics : EJHG · 2023Article
- Colorectal cancer in adolescent and young adults: epidemiology in Japan and narrative review.Journal of gastrointestinal oncology · 2023Review
- Using comprehensive genomic and functional analyses for resolving genotype-phenotype mismatches in children with suspected CMMRD in Lebanon: an IRRDC study.Human genetics · 2023Article
- Prospects of POLD1 in Human Cancers: A Review.Cancers · 2023Review
- PMS2-associated Lynch syndrome: Past, present and future.Frontiers in oncology · 2023Review
- Unraveling the impact of a germline heterozygousFrontiers in molecular biosciences · 2023Article
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
Colorectal cancer (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant MLH1 and MSH2 alleles, familial adenomatous polyposis (FAP), constitutional mismatch-repair deficiency (CMMRD), and polymerase proofreading-associated polyposis (PPAP). Yet, 60% of AYA-CRC cases remain unexplained. In two teenage siblings with multiple adenomas and CRC, we identified a maternally inherited heterozygous PMS2 exon 12 deletion, NM_000535.7:c.2007-786_2174+493del1447, and a paternally inherited POLD1 variant, NP_002682.2:p.Asp316Asn. Comprehensive molecular tumor analysis revealed ultra-mutation (>100 Mut/Mb) and a large contribution of COSMIC signature SBS20 in both siblings’ CRCs, confirming their predisposition to AYA-CRC results from a high propensity for somatic MMR deficiency (MMRd) compounded by a constitutional Pol δ proofreading defect. COSMIC signature SBS20 as well as SBS26 in the index patient’s CRC were associated with an early mutation burst, suggesting MMRd was an early event in tumorigenesis. The somatic second hits in PMS2 were through loss of heterozygosity (LOH) in both tumors, suggesting PPd-independent acquisition of MMRd. Taken together, these patients represent the first cases of cancer predisposition due to heterozygous variants in PMS2 and POLD1. Analysis of their CRCs supports that POLD1-mutated tumors acquire hypermutation only with concurrent MMRd.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.