title: Mucinous and neuroendocrine breast carcinomas are transcriptionally distinct from invasive ductal carcinomas of no special type.
abstract: Mucinous carcinoma is considered a distinct pathological entity. However, mucinous tumours can be divided into a least two groups: mucinous A (or paucicellular) and mucinous B (or hypercellular). Mucinous B cancers display histological features that significantly overlap with those of neuroendocrine carcinomas. We investigate using genome-wide oligonucleotide microarrays whether mucinous A, mucinous B and neuroendocrine carcinomas are entities distinct from histological grade- and molecular subtype-matched invasive ductal carcinomas of no special type. Mucinous A and B and five neuroendocrine carcinomas were of luminal A subtype, whereas one neuroendocrine tumour was of luminal B phenotype. When analysed in conjunction with grade- and molecular subtype-matched invasive ductal carcinomas, hierarchical clustering analysis showed that the majority of mucinous and neuroendocrine cancers formed a separate cluster. Significance analysis of microarrays identified 3155 genes differentially expressed between mucinous/ neuroendocrine carcinomas and grade- and molecular subtype-matched invasive ductal carcinomas (false discovery rate <0.85%), and revealed that genes associated with connective tissue/extracellular matrix were downregulated in mucinous/neuroendocrine cancers compared to invasive ductal carcinomas. When subjected to hierarchical clustering analysis separately, mucinous A cancers formed a discrete subgroup, whereas no separation was observed between mucinous B and neuroendocrine cancers. In fact, significance of microarray analysis showed no transcriptomic differences between mucinous B and neuroendocrine cancers, whereas mucinous A cancers displayed 89 up- and 26 downregulated genes when compared with mucinous B (false discovery rate <1.15%) and 368 up- and 48 downregulated genes when compared to neuroendocrine carcinomas (false discovery rate <1.0%). Our results provide circumstantial evidence to suggest that mucinous and neuroendocrine carcinomas are transcriptionally distinct from histological grade- and molecular subtype-matched invasive ductal carcinomas, and that luminal A breast cancers are a heterogeneous group of tumours. These findings support the contention that mucinous B and neuroendocrine carcinomas are part of a spectrum of lesions, whereas mucinous A is a discrete entity.
authors.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. Britta.Weigelt@cancer.org.uk
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Horlings
authors.forename: Bas
authors.initials: B
authors.lastname: Kreike
authors.forename: Hans
authors.initials: H
authors.lastname: Halfwerk
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000378:metabolism; D002864:Chromogranins / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D020411:Oligonucleotide Array Sequence Analysis; D013194:Staining and Labeling; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019002:CD56 Antigen; D002864:Chromogranins; D016708:Synaptophysin