p53 major hotspot variants are associated with poorer prognostic features in hereditary cancer patients


      TP53 pathogenic germline variation is associated with the multi-cancer predisposition Li–Fraumeni syndrome (LFS). Next-generation sequencing and multigene panel testing are highlighting variability in the clinical presentation of patients with TP53 positive results. We aimed to investigate if the p53 variants considered as major hotspots at both germline and somatic levels (p.Arg175His, p.Gly245Asp, p.Gly245Ser, p.Arg248Gln, p.Arg248Trp, p.Arg273Cys, p.Arg273His, and p.Arg282Trp) were associated with poorer prognostic features compared to other pathogenic missense variants in the DNA-binding domain. To do so, we assessed clinical features from 1025 carriers of germline TP53 pathogenic variants (749 probands and 276 relatives) from three independent datasets (IARC TP53 Database, Ambry Single Gene Testing, and Ambry Multigene Panel Testing). We observed that, compared to carriers of non-hotspot germline variants, individuals that carried a hotspot germline variant were more likely to present with a Classic LFS phenotype, earlier age of first breast cancer onset, and shorter time to diagnosis to any cancer. Further studies with larger datasets addressing differences in cancer phenotypes by genotype are thus needed to replicate our findings and consider variant effect and position, towards future personalized clinical management of pathogenic variant carriers.

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        • Zilfou J.T.
        • Lowe S.W.
        Tumor suppressive functions of p53.
        Cold Spring Harb Perspect Biol. 2009; 1a001883
        • Daly M.B.
        • et al.
        NCCN guidelines insights: genetic/familial high-risk assessment: breast and Ovarian, Version 2.2017.
        J Natl Compr Canc Netw. 2017; 15: 9-20
        • Fortuno C.
        • James P.A.
        • Spurdle A.B.
        Current review of TP53 pathogenic germline variants in breast cancer patients outside Li–Fraumeni syndrome.
        Hum Mutat. 2018; 39: 1764-1773
        • Bouaoun L.
        • et al.
        TP53 variations in human cancers: new lessons from the IARC TP53 database and genomics data.
        Hum Mutat. 2016; 37: 865-876
        • Ognjanovic S.
        • et al.
        Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database.
        Cancer. 2012; 118: 1387-1396
        • Olivier M.
        • et al.
        Li–Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype.
        Cancer Res. 2003; 63: 6643-6650
        • Monti P.
        • et al.
        Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.
        Mol Cancer Res. 2011; 9: 271-279
        • Bougeard G.
        • et al.
        Revisiting Li–Fraumeni Syndrome From TP53 Mutation Carriers.
        J Clin Oncol. 2015; 33: 2345-2352
        • Olivier M.
        • Hollstein M.
        • Hainaut P.
        TP53 mutations in human cancers: origins, consequences, and clinical use.
        Cold Spring Harb Perspect Biol. 2010; 2a001008
        • Freed-Pastor W.A.
        • Prives C.
        Mutant p53: one name, many proteins.
        Genes Dev. 2012; 26: 1268-1286
        • Brosh R.
        • Rotter V.
        When mutants gain new powers: news from the mutant p53 field.
        Nat Rev Cancer. 2009; 9: 701-713
        • Kotler E.
        • et al.
        A systematic p53 mutation library links differential functional impact to cancer mutation pattern and evolutionary conservation.
        Mol Cell. 2018; 71 (e8): 178-190
        • Achatz M.I.
        • Hainaut P.
        • Ashton-Prolla P.
        Highly prevalent TP53 mutation predisposing to many cancers in the Brazilian population: a case for newborn screening?.
        Lancet Oncol. 2009; 10: 920-925
        • Giacomelli A.O.
        • et al.
        Mutational processes shape the landscape of TP53 mutations in human cancer.
        Nat Genet. 2018; 50: 1381-1387
        • Xu J.
        • et al.
        Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity.
        Cell Death Dis. 2014; 5: e1108
        • Baugh E.H.
        • et al.
        Why are there hotspot mutations in the TP53 gene in human cancers?.
        Cell Death Differ. 2018; 25: 154-160
        • Ascierto P.A.
        • et al.
        The role of BRAF V600 mutation in melanoma.
        J Transl Med. 2012; 10: 85
        • Miller M.L.
        • et al.
        Pan-cancer analysis of mutation hotspots in protein domains.
        Cell Syst. 2015; 1: 197-209
        • Vijayan V.
        • Yiu S.M.
        • Zhang L.
        Improving somatic variant identification through integration of genome and exome data.
        BMC Genom. 2017; 18: 748
        • Weitzel J.N.
        • et al.
        Somatic TP53 variants frequently confound germ-line testing results.
        Genet Med. 2017;
        • Coffee B.
        • et al.
        Detection of somatic variants in peripheral blood lymphocytes using a next generation sequencing multigene pan cancer panel.
        Cancer Genet. 2017; 211: 5-8
        • Pesaran T.
        • et al.
        Beyond DNA: an integrated and functional approach for classifying germline variants in breast cancer genes.
        Int J Breast Cancer. 2016; 20162469523
        • Fortuno C.
        • et al.
        Improved, ACMG-Compliant, in silico prediction of pathogenicity for missense substitutions encoded by TP53 variants.
        Hum Mutat. 2018;
        • Chang M.T.
        • et al.
        Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.
        Nat Biotechnol. 2016; 34: 155-163
        • Chang M.T.
        • et al.
        Accelerating discovery of functional mutant alleles in cancer.
        Cancer Discov. 2018; 8: 174-183
        • Petitjean A.
        • et al.
        TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes.
        Oncogene. 2007; 26: 2157-2165
        • Eccles D.M.
        • et al.
        Genetic testing in a cohort of young patients with HER2-amplified breast cancer.
        Ann Oncol. 2016; 27: 467-473
        • Rana H.Q.
        • et al.
        Genotype-phenotype associations among panel-based TP53+ subjects.
        Genet Med. 2019; ([Epub ahead of print])