1732P - Descriptive analysis of families with TP53 mutations: Is there a genotype/phenotype correlation?

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Familial Cancer
Pathology/Molecular Biology
Presenter José Silva
Citation Annals of Oncology (2017) 28 (suppl_5): v595-v604. 10.1093/annonc/mdx391
Authors J.P. Silva1, B. Filipe2, A. Luís3, A. Clara3, S. Bento3, P. Machado2, P. Rodrigues3, J. Parreira3, F. Vaz3
  • 1Medical Oncology, Instituto Portuguès de Oncologia de Lisboa Francisco Gentil, E.P.E. (IPOLFG EPE), 1099-023 - Lisbon/PT
  • 2Molecular Pathobiology Investigation Unit, Instituto Portuguès de Oncologia de Lisboa Francisco Gentil, E.P.E. (IPOLFG EPE), 1099-023 - Lisbon/PT
  • 3Familiar Cancer Risk Clinic, Instituto Portuguès de Oncologia de Lisboa Francisco Gentil, E.P.E. (IPOLFG EPE), 1099-023 - Lisbon/PT

Abstract

Background

Li-Fraumeni syndrome (LFS) is a rare and serious hereditary cancer syndrome caused by germline mutations in the TP53 gene. Our objective is to review the molecular and clinical characteristics of our LFS families.

Methods

Retrospective descriptive analysis. Molecular germinal diagnosis was done either by Sanger or NG Sequencing (Trusight Cancer, Illumina); Large Genomic rearrangements were tested by MLPA (MRC Holland).

Results

Among 4952 non-related families registered in our multidisciplinary program, 395 are BRCA1/2 families and 36 haver other molecular diagnoses with 7/36 confirmed TP53 families. Twenty-nine pts were reviewed, including 2 male carriers, (36, 40 years) that haven’t developed cancers yet. Forty-one tumours were registered (median of 1,41 tumours/carrier, 0–4). Female/male was 2:1. Median age for the first tumour was 24 years (1-45) in the index cases and 35 (1,5-61) in relatives (p > 0,05). Breast cancer (BC) (34% of cancers/48% pts) and sarcomas (31% of cancers/44% pts) were the most common malignancies. For BC cases hormone receptor status was confirmed in 8/14 (positive in 6/8, simultaneous HER2 positivity in 2 cases). Median age of death was 40 (34-58). Most mutations were missense (5 - 2 dominant-negative affecting the DNA binding domain: c.743G>A, p.R248Q and c.725G>A, p.C242Y), none was recurrent and the only frequent mutation observed was c.743G>A, p.R248Q. One of the missense and the 2 frameshift mutations have never been described as germinal: c.481G>A, p.A161T; c.86del, p.N29Tfs*15 and c.990del, p.Q331Rfs*14 Chompret criteria were met in 6/7 (85%) of cases and didn't identitfy a breast cancer only family, with 3 consecutive generations affected.

Conclusions

Our data confirms the heterogeneity and complexity of malignancies and mutations in LSF. Breast cancer and sarcomas were the most frequent cancers and missense, non-recurrent mutations were mostly observed. In this study c.481G>A, p.A161T; c.86del, p.N29Tfs*15 and c.990del, p.Q331Rfs*14 are, for the first time, identified as germinal mutations. At this time no genotype-to-phenotype correlation could be confirmed. Chompret’s criteria had only 85% sensitivity for the identification of TP53 families.

Clinical trial identification

Legal entity responsible for the study

Instituto Português de Oncologia de Lisboa Francisco Gentil

Funding

None

Disclosure

J.P. Silva: Travel grants for oncology Congresses: Bristol Meyers-Squibb.

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All other authors have declared no conflicts of interest.

Disclosure

J.P. Silva: Travel grants for oncology Congresses: Bristol Meyers-Squibb.

All other authors have declared no conflicts of interest.