Evaluation of TP53 Pro72Arg and MDM2 SNP285–SNP309 polymorphisms in an Italian cohort of LFS suggestive patients lacking identifiable TP53 germline mutations

Abstract

Li-Fraumeni syndrome (LFS) is a rare genetic cancer predisposition disease, partly determined by the presence of a TP53 germline mutation; lacking thereof, in presence of a typical LFS phenotype, defines a wide group of 'LFS Suggestive' patients. Alternative LFS susceptibility genes have been investigated without promising results, thus suggesting other genetic determinants involvement in cancer predisposition. Hence, this study explores the single and combined effects of cancer risk, age of onset and cancer type of three single nucleotide polymorphisms (SNPs)-TP53 Pro72Arg, MDM2 SNP285 and SNP309-already described as modifiers on TP53 mutation carriers but not properly investigated in LFS Suggestive patients. This case-control study examines 34 Italian LFS Suggestive lacking of germline TP53 mutations and 95 tumour-free subjects. A significant prevalence of homozygous MDM2 SNP309 G in the LFS Suggestive group (p < 0.0005) confirms its contribute to cancer susceptibility, also highlighted in LFS TP53 positive families. Conversely its anticipating role on tumour onset has not been confirmed, as in our results it was associated with the SNP309 T allele. A strong combined outcome with a 'dosage' effect has also been reported for TP53 P72 and MDM2 SNP309 G allele on cancer susceptibility (p < 0.0005). Whereas the MDM2 SNP285 C allele neutralizing effect on MDM2 SNP309 G variant is not evident in our population. Although it needs further evaluations, obtained results strengthen the role of MDM2 SNP309 as a genetic factor in hereditary predisposition to cancer, so improving LFS Suggestive patients management.

Whole exome sequencing identified a novel POT1 variant as a candidate pathogenic allele underlying a Li–Fraumeni-like family

“…LFS/LFL TP53 (3), CHEK2 (8), POT1 (10, 11), BRCA2 (12), IDH1 (13), ATRX (14), MDM2 (15) Sarcoma ABCB5 (16), APC (17), AR (18), ATM (19), ATRX (17), ATR (19), BAG1 (20), BRCA1 (19), BRCA2 (19), BRIP1 (19), BUB1B (21), C16orf96 (16), CD86 (22), CD99 (23), CDKAIC (21), CDKN2A (17), CHEK2 (19), CMMRD (23), COL7A1 (19), CREBBP (21), CTLA-4 (24), DICER1 (19), EGR2 (23), ERCC2 (19), EWS (23), EXT1 (21), EXT2 (21), FAH (17), FANCC (19), FANCI (19), FANCL (19), FANCM (25), Fanconi Anemia genes mutations (23), FAS (26), FGF2 (25), FGFR3 (25), FH (21), GATA1 (27), GH1 (25), GJB2 (19), GNRH2 (25), GRM4 (28), GSTM1 (29), GSTT1 (29), H19 (21), HRAS (21), IDH1 (13), IGF1 (25), IGF2 (21), IGFALS (18), ITGA3 (30), KCNQ1OT1…”