Synapse - The genetic landscape of breast carcinomas with neuroendocrine differentiation

The genetic landscape of breast carcinomas with neuroendocrine differentiation Journal Article

Authors:	Marchiò, C.; Geyer, F. C.; Ng, C. K. Y.; Piscuoglio, S.; De Filippo, M. R.; Cupo, M.; Schultheis, A. M.; Lim, R. S.; Burke, K. A.; Guerini-Rocco, E.; Papotti, M.; Norton, L.; Sapino, A.; Weigelt, B.; Reis-Filho, J. S.
Article Title:	The genetic landscape of breast carcinomas with neuroendocrine differentiation
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+/HER2−) breast carcinoma show distinct repertoires of somatic mutations. Eighteen ER+/HER2− 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+/HER2− 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+/HER2−, 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+/HER2− 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. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Keywords:	breast carcinoma; synaptophysin; chromogranin a; massively parallel sequencing; somatic mutations; neuroendocrine differentiation; copy number alterations
Journal Title:	Journal of Pathology
Volume:	241
Issue:	3
ISSN:	0022-3417
Publisher:	Wiley Blackwell
Date Published:	2017-02-01
Start Page:	405
End Page:	419
Language:	English
DOI:	10.1002/path.4837
PROVIDER:	scopus
PUBMED:	27925203
PMCID:	PMC5481202
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85007282397&doi=10.1002%2fpath.4837&partnerID=40&md5=fcaa44a3bcc8b8b41a197292029fafaa
Notes:	Article -- Export Date: 2 February 2017 -- Source: Scopus