TP53 pathogenic variants in colorectal cancer patients in absence of Li-Fraumeni-associated phenotypes

Mariona Terradas1,2, Sami Belhadj1,2, Victor Moreno2,3,4,5, Pau M. Munoz-Torres1,2, Pilar Mur1,2,6, Isabel Quintana1,2, Matilde Navarro1,2,6, Joan Brunet7,2,6, Conxi Lázaro1,2,6, Marta Pineda1,2,6, Gabriel Capellá1,2,6, Laura Valle1,2,6

1Hereditary Cancer Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain. 2Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. 3Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. 4Centro de Investigación Biomédica en Red de Epidemiologia y Salud Pública (CIBERESP), Madrid, Spain. 5Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain. 6Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. 7Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain



TP53 analysis in colorectal cancer (CRC) patients, either familiar/early-onset or unselected, has revealed the presence of pathogenic variants in patients who do not fulfill the clinical criteria for Li-Fraumeni Syndrome (LFS)1-11. We aim at elucidating whether these findings are the result of detecting background population prevalence of TP53 mutations or of pleiotropism.


TP53 mutational screening was performed in 473 mismatch repair-proficient familial CRC cases. Our findings were analysed together with results from five previous additional studies that evaluated the prevalence of TP53 germline variants in familial/early-onset CRC1,2,3,4,5, four in unselected early-onset CRC3,6,7,8 and four in unselected CRC3,9,10,11 (Total CRC patients included: 6,085). Data from controls and LFS cases were obtained from GnomAD and the IARC TP53 database. Variants were classified according to the ACMG/AMP guidelines (InterVar, PathoMAN; automatic classification).


Taking our and previously published results, germline TP53 (likely) pathogenic variants were detected in 0.15-0.22% (InterVar) or in 0.06-0.08% (PathoMAN) of CRC patients, either familial, early-onset or unselected, compared to 0.07% (InterVar) or 0.01% (PathoMAN) of carriers identified among controls. None of the carriers in the CRC cohorts had clinical histories meeting the criteria currently considered for TP53 testing. 78% of the variants identified had been previously reported in individuals with LFS-related clinical histories, and location of missense changes did not differ from those identified in LFS. Dominant negative activity of missense variants might explain the differences in disease expresivity.


Our results indicate that is a CRC predisposing gene, independent of a LFS diagnosis.

Abstract references

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