Abstract
BackgroundBreast 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.MethodsTo 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.ResultsWe 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/p14ARF, and RUNX1).ConclusionsOur 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.
Highlights
Breast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome
Because patients with breast cancer (BC) harboring germline TP53 Pathogenic variant (PV) typically present with very early age of onset, routine TP53 testing has been suggested for women who develop BC before the age of 30 years, independent of family history, and TP53 detection rates within cohorts of patients with early-onset BC have been reported to be between 4% and 8% [8, 13, 14]
Two recent studies focused on cohorts of women meeting hereditary breast and ovarian cancer (HBOC) criteria clearly illustrate that a large percentage of germline TP53 mutation carriers may still be missed by current criteria; the two studies reported TP53 PVs in 13 patients overall, half of whom did not clinically meet either classic Li-Fraumeni syndrome (LFS) or Chompret criteria, nor did they present with very early-onset disease [15, 16]
Summary
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. Different diagnostic criteria with varying stringency in terms of tumor abundance, age of onset, and spectrum of malignancies are in use, including classic LFS criteria, Birch’s and Eeles’ Li-Fraumeni-like syndrome (LFL) criteria, and several versions of the Chompret criteria [1, 4,5,6,7,8,9]. Two recent studies focused on cohorts of women meeting hereditary breast and ovarian cancer (HBOC) criteria clearly illustrate that a large percentage of germline TP53 mutation carriers may still be missed by current criteria; the two studies reported TP53 PVs in 13 patients overall, half of whom did not clinically meet either classic LFS or Chompret criteria, nor did they present with very early-onset disease [15, 16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
