Journal Article

Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity

Ripperger, Tim, Mark, Dorothea, Schlegelberger, Brigitte, Schieck, Maximilian, Hofmann, Winfried, Illig, Thomas, Schubert, Stephanie, Auber, Bernd, Hackmann, Karl, Sturm, Marc, Schmidt, Gunnar, Penkert, Judith, Prokisch, Holger, Steinemann, Doris, Hille-Betz, Ursula

2018

Overview

Background Breast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-like phenotype do not harbor detectable causative germline TP53 variants. Yet, no systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilling Li-Fraumeni(-like) clinical diagnostic criteria. Methods To specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germline variants. Results We identified 13 pathogenic or likely pathogenic germline variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in established hereditary breast cancer susceptibility genes (i.e., PALB2, CHEK2, ATM ). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibility to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A /p14 ARF , and RUNX1 ). Conclusions Our study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoallelic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-like) syndrome lacking TP53 variants in coding regions.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Biomedical and Life Sciences / Biomedicine / Brain cancer / BRCA1 protein / BRCA2 protein / Breast cancer / Breast Neoplasms - genetics / Cancer patients / Cancer Research / Cohort Studies / Copy number / Diagnosis / DNA Copy Number Variations / DNA Mutational Analysis - methods / Fanconi pathway / Female / Gene mutation / Genetic aspects / Genetic Predisposition to Disease / Genetic Testing - methods / Germ-Line Mutation - genetics / HBOC / Health aspects / High-Throughput Nucleotide Sequencing / Humans / Hybridization / Li-Fraumeni syndrome / Li-Fraumeni Syndrome - genetics / Li-Fraumeni-like syndrome / Mutation / Oligonucleotide Array Sequence Analysis / Oncology / p53 Protein / Phenotypes / Polymorphism, Single Nucleotide / RecQ protein / Research Article / Runx1 protein / Surgical Oncology / TP53 / Tumor Suppressor Protein p53 - genetics / Womens health / Young Adult