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Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity

Metaplastic breast carcinoma (MBC) is rare and has a poor prognosis. Here we describe genetic analysis of a 41-yr-old female patient with MBC and neurofibromatosis type I (NF1). She initially presented with pT3N1a, grade 3 MBC, but lung metastases were discovered subsequently. To identify the molecu...

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Autores principales: Suarez-Kelly, Lorena P., Akagi, Keiko, Reeser, Julie W., Samorodnitsky, Eric, Reeder, Matthew, Smith, Amy, Roychowdhury, Sameek, Symer, David E., Carson, William E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880258/
https://www.ncbi.nlm.nih.gov/pubmed/29449315
http://dx.doi.org/10.1101/mcs.a002352
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author Suarez-Kelly, Lorena P.
Akagi, Keiko
Reeser, Julie W.
Samorodnitsky, Eric
Reeder, Matthew
Smith, Amy
Roychowdhury, Sameek
Symer, David E.
Carson, William E.
author_facet Suarez-Kelly, Lorena P.
Akagi, Keiko
Reeser, Julie W.
Samorodnitsky, Eric
Reeder, Matthew
Smith, Amy
Roychowdhury, Sameek
Symer, David E.
Carson, William E.
author_sort Suarez-Kelly, Lorena P.
collection PubMed
description Metaplastic breast carcinoma (MBC) is rare and has a poor prognosis. Here we describe genetic analysis of a 41-yr-old female patient with MBC and neurofibromatosis type I (NF1). She initially presented with pT3N1a, grade 3 MBC, but lung metastases were discovered subsequently. To identify the molecular cause of her NF1, we screened for germline mutations disrupting NF1 or SPRED1, revealing a heterozygous germline single-nucleotide variant (SNV) in exon 21 of NF1 at c.2709G>A, Chr 17: 29556342. By report, this variant disrupts pre-mRNA splicing of NF1 transcripts. No pathogenic mutations were identified in SPRED1. A potential association between MBC and NF1 was reported in eight previous cases, but none underwent detailed genomics analysis. To identify additional candidate germline variants potentially predisposing to MBC, we conducted targeted exome sequencing of 279 established cancer-causing genes in a control blood sample, disclosing four rare SNVs. Analysis of her breast tumor showed markedly altered variant allelic fractions (VAFs) for two (50%) of them, revealing somatic loss of heterozygosity (LOH) at germline SNVs. Of these, only the VAF of the pathogenic SNV in NF1 was increased in the tumor. Tumor sequencing demonstrated five somatic mutations altering TP53, BRCA1, and other genes potentially contributing to cancer formation. Because somatic LOH at certain germline SNVs can enhance their impacts, we conclude that increased allelic imbalance of the pathogenic SNV in NF1 likely contributed to tumorigenesis. Our results highlight a need to assess predisposing genetic factors and LOH that can cause rare, aggressive diseases such as MBC in NF1.
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spelling pubmed-58802582018-04-13 Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity Suarez-Kelly, Lorena P. Akagi, Keiko Reeser, Julie W. Samorodnitsky, Eric Reeder, Matthew Smith, Amy Roychowdhury, Sameek Symer, David E. Carson, William E. Cold Spring Harb Mol Case Stud Research Report Metaplastic breast carcinoma (MBC) is rare and has a poor prognosis. Here we describe genetic analysis of a 41-yr-old female patient with MBC and neurofibromatosis type I (NF1). She initially presented with pT3N1a, grade 3 MBC, but lung metastases were discovered subsequently. To identify the molecular cause of her NF1, we screened for germline mutations disrupting NF1 or SPRED1, revealing a heterozygous germline single-nucleotide variant (SNV) in exon 21 of NF1 at c.2709G>A, Chr 17: 29556342. By report, this variant disrupts pre-mRNA splicing of NF1 transcripts. No pathogenic mutations were identified in SPRED1. A potential association between MBC and NF1 was reported in eight previous cases, but none underwent detailed genomics analysis. To identify additional candidate germline variants potentially predisposing to MBC, we conducted targeted exome sequencing of 279 established cancer-causing genes in a control blood sample, disclosing four rare SNVs. Analysis of her breast tumor showed markedly altered variant allelic fractions (VAFs) for two (50%) of them, revealing somatic loss of heterozygosity (LOH) at germline SNVs. Of these, only the VAF of the pathogenic SNV in NF1 was increased in the tumor. Tumor sequencing demonstrated five somatic mutations altering TP53, BRCA1, and other genes potentially contributing to cancer formation. Because somatic LOH at certain germline SNVs can enhance their impacts, we conclude that increased allelic imbalance of the pathogenic SNV in NF1 likely contributed to tumorigenesis. Our results highlight a need to assess predisposing genetic factors and LOH that can cause rare, aggressive diseases such as MBC in NF1. Cold Spring Harbor Laboratory Press 2018-04 /pmc/articles/PMC5880258/ /pubmed/29449315 http://dx.doi.org/10.1101/mcs.a002352 Text en © 2018 Suarez-Kelly et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Suarez-Kelly, Lorena P.
Akagi, Keiko
Reeser, Julie W.
Samorodnitsky, Eric
Reeder, Matthew
Smith, Amy
Roychowdhury, Sameek
Symer, David E.
Carson, William E.
Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity
title Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity
title_full Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity
title_fullStr Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity
title_full_unstemmed Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity
title_short Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity
title_sort metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880258/
https://www.ncbi.nlm.nih.gov/pubmed/29449315
http://dx.doi.org/10.1101/mcs.a002352
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