PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression

BACKGROUND: Lobular carcinoma in situ (LCIS) is a non-invasive breast lesion that is typically found incidentally on biopsy and is often associated with invasive lobular carcinoma (ILC). LCIS is considered by some to be a risk factor for future breast cancer rather than a true precursor lesion. The...

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Autores principales: Shah, Vandna, Nowinski, Salpie, Levi, Dina, Shinomiya, Irek, Kebaier Ep Chaabouni, Narda, Gillett, Cheryl, Grigoriadis, Anita, Graham, Trevor A., Roylance, Rebecca, Simpson, Michael A., Pinder, Sarah E., Sawyer, Elinor J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240238/
https://www.ncbi.nlm.nih.gov/pubmed/28095868
http://dx.doi.org/10.1186/s13058-016-0789-y
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author Shah, Vandna
Nowinski, Salpie
Levi, Dina
Shinomiya, Irek
Kebaier Ep Chaabouni, Narda
Gillett, Cheryl
Grigoriadis, Anita
Graham, Trevor A.
Roylance, Rebecca
Simpson, Michael A.
Pinder, Sarah E.
Sawyer, Elinor J.
author_facet Shah, Vandna
Nowinski, Salpie
Levi, Dina
Shinomiya, Irek
Kebaier Ep Chaabouni, Narda
Gillett, Cheryl
Grigoriadis, Anita
Graham, Trevor A.
Roylance, Rebecca
Simpson, Michael A.
Pinder, Sarah E.
Sawyer, Elinor J.
author_sort Shah, Vandna
collection PubMed
description BACKGROUND: Lobular carcinoma in situ (LCIS) is a non-invasive breast lesion that is typically found incidentally on biopsy and is often associated with invasive lobular carcinoma (ILC). LCIS is considered by some to be a risk factor for future breast cancer rather than a true precursor lesion. The aim of this study was to identify genetic changes that could be used as biomarkers of progression of LCIS to invasive disease using cases of pure LCIS and comparing their genetic profiles to LCIS which presented contemporaneously with associated ILC, on the hypothesis that the latter represents LCIS that has already progressed. METHODS: Somatic copy number aberrations (SCNAs) were assessed by SNP array in three subgroups: pure LCIS, LCIS associated with ILC and the paired ILC. In addition exome sequencing was performed on seven fresh frozen samples of LCIS associated with ILC, to identify recurrent somatic mutations. RESULTS: The copy number profiles of pure LCIS and LCIS associated with ILC were almost identical. However, four SCNAs were more frequent in ILC than LCIS associated with ILC, including gain/amplification of CCND1. CCND1 protein over-expression assessed by immunohistochemical analysis in a second set of samples from 32 patients with pure LCIS and long-term follow up, was associated with invasive recurrence (P = 0.02, Fisher’s exact test). Exome sequencing revealed that PIK3CA mutations were as frequent as CDH1 mutations in LCIS, but were not a useful biomarker of LCIS progression as they were as frequent in pure LCIS as in LCIS associated with ILC. We also observed heterogeneity of PIK3CA mutations and evidence of sub-clonal populations in LCIS irrespective of whether they were associated with ILC. CONCLUSIONS: Our data shows that pure LCIS and LCIS co-existing with ILC have very similar SCNA profiles, supporting the hypothesis that LCIS is a true precursor lesion. We have provided evidence that over-expression of CCND1 may identify a subgroup of patients with pure LCIS who are more likely to develop invasive disease, in contrast to PIK3CA mutations, which occur too early in lobular tumorigenesis to be informative. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-016-0789-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-52402382017-01-19 PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression Shah, Vandna Nowinski, Salpie Levi, Dina Shinomiya, Irek Kebaier Ep Chaabouni, Narda Gillett, Cheryl Grigoriadis, Anita Graham, Trevor A. Roylance, Rebecca Simpson, Michael A. Pinder, Sarah E. Sawyer, Elinor J. Breast Cancer Res Research Article BACKGROUND: Lobular carcinoma in situ (LCIS) is a non-invasive breast lesion that is typically found incidentally on biopsy and is often associated with invasive lobular carcinoma (ILC). LCIS is considered by some to be a risk factor for future breast cancer rather than a true precursor lesion. The aim of this study was to identify genetic changes that could be used as biomarkers of progression of LCIS to invasive disease using cases of pure LCIS and comparing their genetic profiles to LCIS which presented contemporaneously with associated ILC, on the hypothesis that the latter represents LCIS that has already progressed. METHODS: Somatic copy number aberrations (SCNAs) were assessed by SNP array in three subgroups: pure LCIS, LCIS associated with ILC and the paired ILC. In addition exome sequencing was performed on seven fresh frozen samples of LCIS associated with ILC, to identify recurrent somatic mutations. RESULTS: The copy number profiles of pure LCIS and LCIS associated with ILC were almost identical. However, four SCNAs were more frequent in ILC than LCIS associated with ILC, including gain/amplification of CCND1. CCND1 protein over-expression assessed by immunohistochemical analysis in a second set of samples from 32 patients with pure LCIS and long-term follow up, was associated with invasive recurrence (P = 0.02, Fisher’s exact test). Exome sequencing revealed that PIK3CA mutations were as frequent as CDH1 mutations in LCIS, but were not a useful biomarker of LCIS progression as they were as frequent in pure LCIS as in LCIS associated with ILC. We also observed heterogeneity of PIK3CA mutations and evidence of sub-clonal populations in LCIS irrespective of whether they were associated with ILC. CONCLUSIONS: Our data shows that pure LCIS and LCIS co-existing with ILC have very similar SCNA profiles, supporting the hypothesis that LCIS is a true precursor lesion. We have provided evidence that over-expression of CCND1 may identify a subgroup of patients with pure LCIS who are more likely to develop invasive disease, in contrast to PIK3CA mutations, which occur too early in lobular tumorigenesis to be informative. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-016-0789-y) contains supplementary material, which is available to authorized users. BioMed Central 2017-01-17 2017 /pmc/articles/PMC5240238/ /pubmed/28095868 http://dx.doi.org/10.1186/s13058-016-0789-y Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Shah, Vandna
Nowinski, Salpie
Levi, Dina
Shinomiya, Irek
Kebaier Ep Chaabouni, Narda
Gillett, Cheryl
Grigoriadis, Anita
Graham, Trevor A.
Roylance, Rebecca
Simpson, Michael A.
Pinder, Sarah E.
Sawyer, Elinor J.
PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression
title PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression
title_full PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression
title_fullStr PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression
title_full_unstemmed PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression
title_short PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression
title_sort pik3ca mutations are common in lobular carcinoma in situ, but are not a biomarker of progression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240238/
https://www.ncbi.nlm.nih.gov/pubmed/28095868
http://dx.doi.org/10.1186/s13058-016-0789-y
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