RESUMEN
PURPOSE OF REVIEW: Germline pathogenic TP53 mutation may predispose to multiple cancers but penetrance and cancer patterns remain incompletely documented. We have analyzed international agency for research on cancer TP53 database to reevaluate age and variant-dependent tumor patterns. RECENT FINDINGS: Genome-wide studies suggest that germline variants are more frequent than estimated prevalence of Li-Fraumeni syndrome (LFS), suggesting that many carriers of potentially pathogenic mutations may not develop the syndrome. Carriers of a germline TP53 mutation who are detected in a clinical context have a penetrance of 80% at age 70. Penetrance varies according to age, sex and mutation type. Temporal tumor patterns show distinct phases, with childhood phase (0-15 years, 22% of all cancers) characterized by adrenal cortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma and medulloblastoma; early adulthood phase (16-50 years, 51%) including breast cancer, osteosarcoma, soft tissue sarcomas, leukemia, astrocytoma and glioblastoma, colorectal and lung cancer; late adulthood phase (51-80 years, 27%) including pancreatic and prostate cancer. SUMMARY: Germline pathogenic variants in TP53 gene have different consequences according to cell, tissue, context and age. The occurrence of frequent variants in patients with no criteria suggestive of LFS calls for attention in predicting individual risk and highlights the need of additional predictors for assigning carriers to appropriate surveillance programs.
Asunto(s)
Genes p53 , Mutación de Línea Germinal , Síndrome de Li-Fraumeni/genética , Proteína p53 Supresora de Tumor/genética , Animales , HumanosRESUMEN
Aberrant DNA methylation pattern is a well-known epigenetic marker of cancer cells. Recently, aberrant methylation was also reported in the peripheral blood of cancer patients and it could potentially serve as a biomarker for cancer risk. We investigated the methylation pattern of LINE-1 and other repetitive DNA elements in peripheral blood of cutaneous melanoma patients in order to search for an association with clinical characteristics. The patient cohort was composed by 69 unrelated melanoma patients, 28 of whom were hereditary cases (with or without CDKN2A mutations) and 41 were isolated (sporadic) melanoma cases. Methylation of LINE-1 was evaluated by pyrosequencing, whereas additional repetitive DNA sequences were assessed using Illumina 450K methylation microarray. Melanoma patients exhibited a higher, albeit heterogeneous, LINE-1 methylation level compared with controls. Hereditary melanoma patients carrying CDKN2A mutations showed a hypermethylated pattern of both LINE-1 and repetitive DNA elements compared with other patients. In particular, the methylation level at one specific CpG of LINE-1 was found to be correlated with the occurrence of metastasis. Our data suggest that LINE-1 hypermethylation in peripheral blood of melanoma patients is a potential epigenetic biomarker for metastasis occurrence.