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The genetic landscape of breast carcinomas with neuroendocrine differentiation.
- Source :
-
The Journal of pathology [J Pathol] 2017 Feb; Vol. 241 (3), pp. 405-419. Date of Electronic Publication: 2016 Dec 26. - Publication Year :
- 2017
-
Abstract
- Neuroendocrine breast carcinomas (NBCs) account for 2-5% of all invasive breast cancers, and are histologically similar to neuroendocrine tumours from other sites. They typically express oestrogen receptor (ER), and are HER2-negative and of luminal 'intrinsic' subtype. Here, we sought to define the mutational profile of NBCs, and to investigate whether NBCs and common forms of luminal (ER <superscript>+</superscript> /HER2 <superscript>-</superscript> ) breast carcinoma show distinct repertoires of somatic mutations. Eighteen ER <superscript>+</superscript> /HER2 <superscript>-</superscript> NBCs, defined as harbouring >50% of tumour cells expressing chromogranin A and/or synaptophysin, and matched normal tissues were microdissected and subjected to massively parallel sequencing targeting all exons of 254 genes most frequently mutated in breast carcinomas and/or related to DNA repair. Their mutational repertoire was compared with that of ER <superscript>+</superscript> /HER2 <superscript>-</superscript> breast carcinomas (n = 240), PAM50-defined luminal breast carcinomas (luminal A, n = 209; luminal B, n = 111) and invasive lobular carcinomas (n = 127) from The Cancer Genome Atlas. NBCs were found to harbour a median of 4.5 (range 1-11) somatic mutations, similar to that of luminal B breast carcinomas (median = 3, range 0-17) but significantly higher than that of luminal A breast carcinomas (median = 3, range 0-18, p = 0.02). The most frequently mutated genes were GATA3, FOXA1, TBX3, and ARID1A (3/18, 17%), and PIK3CA, AKT1, and CDH1 (2/18, 11%). NBCs less frequently harboured PIK3CA mutations than common forms of ER <superscript>+</superscript> /HER2 <superscript>-</superscript> , luminal A and invasive lobular carcinomas (p < 0.05), and showed a significantly higher frequency of somatic mutations affecting ARID1A (17% versus 2%, p < 0.05) and the transcription factor-encoding genes FOXA1 (17% versus 2%, p = 0.01) and TBX3 (17% versus 3%, p < 0.05) than common-type ER <superscript>+</superscript> /HER2 <superscript>-</superscript> breast carcinomas. No TP53 somatic mutations were detected in NBCs. As compared with common forms of luminal breast carcinomas, NBCs show a distinctive repertoire of somatic mutations featuring lower frequencies of TP53 and PIK3CA mutations, enrichment for FOXA1 and TBX3 mutations, and, akin to neuroendocrine tumours from other sites, ARID1A mutations. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.<br /> (Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Subjects :
- Biomarkers, Tumor metabolism
Breast Neoplasms metabolism
Carcinoma, Lobular metabolism
Class I Phosphatidylinositol 3-Kinases
Female
Humans
Mutation genetics
Phosphatidylinositol 3-Kinases genetics
Receptors, Estrogen metabolism
Biomarkers, Tumor genetics
Breast Neoplasms pathology
Carcinoma, Lobular pathology
Carcinoma, Neuroendocrine pathology
Gene Expression Regulation, Neoplastic
Subjects
Details
- Language :
- English
- ISSN :
- 1096-9896
- Volume :
- 241
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 27925203
- Full Text :
- https://doi.org/10.1002/path.4837