Update on genetic predisposition to colorectal cancer and polyposis

Laura Valle*, Richarda M. de Voer, Yael Goldberg, Wenche Sjursen, Asta Försti, Clara Ruiz-Ponte, Trinidad Caldés, Pilar Garré, Maren F. Olsen, Margareta Nordling, Sergi Castellvi-Bel, Kari Hemminki

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

106 Scopus citations


The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new hereditary CRC and polyposis syndromes, non-CRC hereditary cancer genes found mutated in CRC patients, strategies used to identify novel causal genes, and review of candidate genes that have been proposed to predispose to CRC and/or colonic polyposis. We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC. The implementation of next generation sequencing approaches for genetic testing has exposed the presence of pathogenic germline variants in genes associated with hereditary cancer syndromes not traditionally linked to CRC, which may have an impact on genetic testing, counseling and surveillance. The identification of new hereditary CRC and polyposis genes has not deemed an easy endeavor, even though known CRC-related genes explain a small proportion of the estimated familial risk. Whole-genome sequencing may offer a technology for increasing this proportion, particularly if applied on pedigree data allowing linkage type of analysis. The final section critically surveys the large number of candidate genes that have been recently proposed for CRC predisposition.

Original languageEnglish
Pages (from-to)10-26
Number of pages17
JournalMolecular Aspects of Medicine
StatePublished - Oct 2019
Externally publishedYes


FundersFunder number
Ag?ncia de Gesti?
Dutch Cancer Society
d'Ajuts Universitaris i de RecercaGCB13131592CAST, SLT002/16/00398
Ministerio de Ciencia, Innovación y Universidades
Fundación Olga Torres
European Cooperation in Science and TechnologyCA17118
Generalitat de CatalunyaSLT002/16/0037
Agència de Gestió d'Ajuts Universitaris i de Recerca2017SGR1282
Instituto de Salud Carlos IIICB16/12/00234
KWF KankerbestrijdingKUN2014-6666
European Regional Development FundSAF2016-80888-R, PI17/00509, PI16/01292, PI17/00878


    • Cancer-predisposing genes
    • Hereditary colorectal cancer
    • Identification of causal genes
    • Next generation sequencing
    • Polyposis


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