TY - JOUR
T1 - TP53, a gene for colorectal cancer predisposition in the absence of Li-Fraumeni-associated phenotypes
AU - Terradas, Mariona
AU - Mur, Pilar
AU - Belhadji, Sami
AU - Woodward, Emma
AU - Burghel, George
AU - Munoz-Torres, Pau M.
AU - Quintana, Isabel
AU - Navarro, Matilde
AU - Brunet, Joan
AU - Lázaro, Conxi
AU - Pineda, Marta
AU - Moreno, Victor
AU - Capellá, Gabriel
AU - Evans, D Gareth
AU - Valle, Laura
PY - 2020/8/24
Y1 - 2020/8/24
N2 - Objective. Germline TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), an aggressive multi-tumor-predisposing condition. Due to the implementation of multi-gene panel testing, TP53 variants have been detected in individuals without LFS suspicion, e.g. colorectal cancer (CRC) patients. We aim to decipher whether these findings are the result of detecting the background population prevalence or the etiologic basis of CRC.
Design. We analyzed TP53 in 473 familial/early-onset CRC cases and evaluated the results together with five additional studies performed in CRC patients (total n=6,200). Control population and LFS data were obtained from gnomAD and the IARC TP53 database, respectively. All variants were reclassified according to the ACMG/AMP guidelines, following the ClinGen TP53 Expert Panel specifications.
Results. Pathogenic or likely pathogenic variants were identified in 0.05% of controls (n=27/59,095) and 0.26% of CRC patients (n=16/6,200) (p<0.0001) [OR=5.7; 95%CI: 2.8-10.9], none of whom fulfilled the clinical criteria established for TP53 testing. The exclusion of carrier CRC patients diagnosed at more advances ages, performed to minimize the inclusion of variants caused by clonal hematopoiesis, did not prevent from detecting an association. Loss-of-function and missense variants were strongly associated with CRC as compared with controls (OR=25.44, 95% CI: 6.10-149.03 (p=8.34e-07) for loss of function and splice-site alleles; and OR=3.58, 95% CI: 1.46-7.98 (p=0.0029) for missense pathogenic variants). Conclusion. TP53 pathogenic variants should not be unequivocally associated with LFS. Prospective follow-up of carriers of germline TP53 pathogenic variants in absence of LFS phenotypes will define how surveillance and clinical management of these individuals should be performed.
AB - Objective. Germline TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), an aggressive multi-tumor-predisposing condition. Due to the implementation of multi-gene panel testing, TP53 variants have been detected in individuals without LFS suspicion, e.g. colorectal cancer (CRC) patients. We aim to decipher whether these findings are the result of detecting the background population prevalence or the etiologic basis of CRC.
Design. We analyzed TP53 in 473 familial/early-onset CRC cases and evaluated the results together with five additional studies performed in CRC patients (total n=6,200). Control population and LFS data were obtained from gnomAD and the IARC TP53 database, respectively. All variants were reclassified according to the ACMG/AMP guidelines, following the ClinGen TP53 Expert Panel specifications.
Results. Pathogenic or likely pathogenic variants were identified in 0.05% of controls (n=27/59,095) and 0.26% of CRC patients (n=16/6,200) (p<0.0001) [OR=5.7; 95%CI: 2.8-10.9], none of whom fulfilled the clinical criteria established for TP53 testing. The exclusion of carrier CRC patients diagnosed at more advances ages, performed to minimize the inclusion of variants caused by clonal hematopoiesis, did not prevent from detecting an association. Loss-of-function and missense variants were strongly associated with CRC as compared with controls (OR=25.44, 95% CI: 6.10-149.03 (p=8.34e-07) for loss of function and splice-site alleles; and OR=3.58, 95% CI: 1.46-7.98 (p=0.0029) for missense pathogenic variants). Conclusion. TP53 pathogenic variants should not be unequivocally associated with LFS. Prospective follow-up of carriers of germline TP53 pathogenic variants in absence of LFS phenotypes will define how surveillance and clinical management of these individuals should be performed.
M3 - Article
SN - 0017-5749
JO - Gut
JF - Gut
ER -