Universität zu Köln

Marchio, Caterina ORCID: 0000-0003-2024-6131, Geyer, Felipe C., Ng, Charlotte K. Y., Piscuoglio, Salvatore ORCID: 0000-0003-2686-2939, De Filippo, Maria R., Cupo, Marco, Schultheis, Anne M., Lim, Raymond S., Burke, Kathleen A., Guerini-Rocco, Elena, Papotti, Mauro, Norton, Larry, Sapino, Anna ORCID: 0000-0003-3542-9571, Weigelt, Britta and Reis-Filho, Jorge S. (2017). The genetic landscape of breast carcinomas with neuroendocrine differentiation. J. Pathol., 241 (3). S. 405 - 420. HOBOKEN: WILEY. ISSN 1096-9896

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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 (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Marchio, Caterina UNSPECIFIED orcid.org/0000-0003-2024-6131 UNSPECIFIED Geyer, Felipe C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ng, Charlotte K. Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Piscuoglio, Salvatore UNSPECIFIED orcid.org/0000-0003-2686-2939 UNSPECIFIED De Filippo, Maria R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cupo, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Schultheis, Anne M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lim, Raymond S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Burke, Kathleen A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Guerini-Rocco, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Papotti, Mauro UNSPECIFIED UNSPECIFIED UNSPECIFIED Norton, Larry UNSPECIFIED UNSPECIFIED UNSPECIFIED Sapino, Anna UNSPECIFIED orcid.org/0000-0003-3542-9571 UNSPECIFIED Weigelt, Britta UNSPECIFIED UNSPECIFIED UNSPECIFIED Reis-Filho, Jorge S. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-241165
DOI:	10.1002/path.4837
Journal or Publication Title:	J. Pathol.
Volume:	241
Number:	3
Page Range:	S. 405 - 420
Date:	2017
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1096-9896
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INVASIVE DUCTAL CARCINOMAS; SOMATIC MUTATION; CANCER GENES; COPY NUMBER; EXPRESSION; DNA; TUMORS; GRADE; RECOMMENDATIONS; HETEROGENEITY Multiple languages Oncology; Pathology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24116