Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity
Abstract 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 b...
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doaj-e22f263cf37d4328b380d9088edc90002021-03-02T05:59:46ZengBMCBreast Cancer Research1465-542X2018-08-0120111610.1186/s13058-018-1011-1Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredityJudith Penkert0Gunnar Schmidt1Winfried Hofmann2Stephanie Schubert3Maximilian Schieck4Bernd Auber5Tim Ripperger6Karl Hackmann7Marc Sturm8Holger Prokisch9Ursula Hille-Betz10Dorothea Mark11Thomas Illig12Brigitte Schlegelberger13Doris Steinemann14Department of Human Genetics, Hannover Medical SchoolDepartment of Human Genetics, Hannover Medical SchoolDepartment of Human Genetics, Hannover Medical SchoolDepartment of Human Genetics, Hannover Medical SchoolDepartment of Human Genetics, Hannover Medical SchoolDepartment of Human Genetics, Hannover Medical SchoolDepartment of Human Genetics, Hannover Medical SchoolInstitute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU DresdenInstitute of Medical Genetics and Applied Genomics, University of TübingenInstitute of Human Genetics, Helmholtz Zentrum MünchenDepartment of Gynecology and Obstetrics, Hannover Medical SchoolDepartment of Internal Medicine, Hematology/Oncology, University Hospital FrankfurtDepartment of Human Genetics, Hannover Medical SchoolDepartment of Human Genetics, Hannover Medical SchoolDepartment of Human Genetics, Hannover Medical SchoolAbstract 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/p14ARF, 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.http://link.springer.com/article/10.1186/s13058-018-1011-1Breast cancerHBOCLi-Fraumeni syndromeLi-Fraumeni-like syndromeTP53Fanconi pathway |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Judith Penkert Gunnar Schmidt Winfried Hofmann Stephanie Schubert Maximilian Schieck Bernd Auber Tim Ripperger Karl Hackmann Marc Sturm Holger Prokisch Ursula Hille-Betz Dorothea Mark Thomas Illig Brigitte Schlegelberger Doris Steinemann |
spellingShingle |
Judith Penkert Gunnar Schmidt Winfried Hofmann Stephanie Schubert Maximilian Schieck Bernd Auber Tim Ripperger Karl Hackmann Marc Sturm Holger Prokisch Ursula Hille-Betz Dorothea Mark Thomas Illig Brigitte Schlegelberger Doris Steinemann Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity Breast Cancer Research Breast cancer HBOC Li-Fraumeni syndrome Li-Fraumeni-like syndrome TP53 Fanconi pathway |
author_facet |
Judith Penkert Gunnar Schmidt Winfried Hofmann Stephanie Schubert Maximilian Schieck Bernd Auber Tim Ripperger Karl Hackmann Marc Sturm Holger Prokisch Ursula Hille-Betz Dorothea Mark Thomas Illig Brigitte Schlegelberger Doris Steinemann |
author_sort |
Judith Penkert |
title |
Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity |
title_short |
Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity |
title_full |
Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity |
title_fullStr |
Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity |
title_full_unstemmed |
Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity |
title_sort |
breast cancer patients suggestive of li-fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2018-08-01 |
description |
Abstract 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/p14ARF, 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. |
topic |
Breast cancer HBOC Li-Fraumeni syndrome Li-Fraumeni-like syndrome TP53 Fanconi pathway |
url |
http://link.springer.com/article/10.1186/s13058-018-1011-1 |
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