Objective Germline TP53 pathogenic (P) variants cause Li-Fraumeni syndrome (LFS), an aggressive multitumor-predisposing condition. Due to the implementation of multigene panel testing, TP53 variants have been detected in individuals without LFS suspicion, for example, patients with colorectal cancer (CRC). We aimed to decipher whether these findings are the result of detecting the background population prevalence or the aetiological basis of CRC.
Design We analysed TP53 in 473 familial/early-onset CRC cases and evaluated the results together with five additional studies performed in patients with CRC (total n=6200). Control population and LFS data were obtained from Genome Aggregation Database (gnomAD V.2.1.1) and the International Agency for Research on Cancer (IARC) TP53 database, respectively. All variants were reclassified according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), following the ClinGen TP53 Expert Panel specifications.
Results P or likely pathogenic (LP) variants were identified in 0.05% of controls (n=27/59 095) and 0.26% of patients with CRC (n=16/6200) (p<0.0001) (OR=5.7, 95% CI 2.8 to 10.9), none of whom fulfilled the clinical criteria established for TP53 testing. This association was still detected when patients with CRC diagnosed at more advanced ages (>50 and>60 years) were excluded from the analysis to minimise the inclusion of variants caused by clonal haematopoiesis. Loss-of-function and missense variants were strongly associated with CRC as compared with controls (OR=25.44, 95% CI 6.10 to 149.03, for loss of function and splice-site alleles, and OR=3.58, 95% CI 1.46 to 7.98, for missense P or LP variants).
Conclusion TP53 P variants should not be unequivocally associated with LFS. Prospective follow-up of carriers of germline TP53 P variants in the absence of LFS phenotypes will define how surveillance and clinical management of these individuals should be performed.
- cancer genetics
- cancer susceptibility
- cancer syndromes
- gene mutation
- genetic testing
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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MT, PM and SB contributed equally.
Contributors LV conceived, designed and supervised the study. MT, PM, SB and IQ performed the experiments. SB and PMM-T performed the bioinformatic analysis. MT, PM and VM carried out the statistical analyses. MT, PM, SB and LV performed the bibliographic search and analyzed the data. MT, PM, ERW, GJB, MP and DGRE performed and/or reviewed the evidences for TP53 variant classification. MN, JB, MP, CL and GC provided samples and the patient’s clinical and genetic information. LV, MT and PM wrote the manuscript, with relevant input from ERW and DGRE. All authors critically revised the article for important intellectual content.
Funding This study was funded by the Spanish Ministry of Science and Innovation, cofunded by FEDER funds: a way to build Europe (SAF2016-80888-R (LV), SAF2015-68016-R (GC and MP), FPI fellowship (IQ)); Instituto de Salud Carlos III, cofunded by FEDER funds: a way to build Europe (CIBERONC CB16/12/00234, FIS PI19/00553 (CL), Sara Borrell Postdoctoral contract (PM)); the Government of Catalonia (Health Department PERIS SLT002/16/0037, SLT002/16/00164, AGAUR 2017SGR1282, CERCA Programme); Fundación Olga Torres; and Scientific Foundation Asociación Española Contra el Cáncer (MT). DGRE and ERW are supported by the National Institute for Health Research BRC Manchester (1215–20007).
Competing interests None declared.
Patient and public involvement Patients and the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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