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Micropapillary variant of mucinous carcinoma of the breast shows genetic alterations intermediate between those of mucinous carcinoma and micropapillary carcinoma.

ABSTRACT: AIMS:Micropapillary variant of mucinous carcinoma of the breast (MPMC) is a rare histological form of oestrogen receptor (ER)-positive invasive carcinoma that is characterised by micropapillary clusters of tumour cells in lakes of extracellular mucin. The aims of this study were to determine the genetic alterations underpinning MPMCs, and to determine whether they overlap with those of mucinous carcinomas and/or invasive micropapillary carcinomas. METHODS AND RESULTS:DNA from five MPMCs was subjected to whole-exome sequencing. Somatic mutations, copy number alterations and mutational signatures were determined with state-of-the-art bioinformatics methods. No mutations in genes significantly mutated in breast cancer, including TP53, PIK3CA, GATA3, and MAP3K1, were detected. We identified copy number alterations that have been reported in invasive micropapillary carcinomas, such as recurrent gains in 1q, 6p, 8q, and 10q, and recurrent losses in 16q, 11q, and 13q, as well as a recurrent 8p12-8p11.2 amplification encompassing FGFR1. Like mucinous carcinomas, three of the five MPMCs analysed lacked PIK3CA mutations, 1q gains, and 16q losses, which are the hallmark genetic alterations of ER-positive breast cancers, whereas two MPMCs harboured 16q losses and/or a complex pattern of copy number alterations similar to those found in breast-invasive micropapillary carcinomas. CONCLUSIONS:MPMCs are heterogeneous at the genetic level; some tumours show a pattern of somatic genetic alterations similar to those of mucinous carcinomas, whereas others resemble invasive micropapillary carcinomas at the genetic level. These findings suggest that MPMCs may not constitute one histological subtype, but rather a convergent phenotype that can stem from mucinous carcinomas or invasive micropapillary carcinomas.

SUBMITTER: Pareja F

PROVIDER: S-EPMC6591080 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Micropapillary variant of mucinous carcinoma of the breast shows genetic alterations intermediate between those of mucinous carcinoma and micropapillary carcinoma.

Pareja Fresia F Selenica Pier P Brown David N DN Sebastiao Ana P M APM da Silva Edaise M EM Da Cruz Paula Arnaud A Del Angela A Fu Li L Weigelt Britta B Brogi Edi E Reis-Filho Jorge S JS Wen Hannah Y HY

Histopathology 20190613 1

<h4>Aims</h4>Micropapillary variant of mucinous carcinoma of the breast (MPMC) is a rare histological form of oestrogen receptor (ER)-positive invasive carcinoma that is characterised by micropapillary clusters of tumour cells in lakes of extracellular mucin. The aims of this study were to determine the genetic alterations underpinning MPMCs, and to determine whether they overlap with those of mucinous carcinomas and/or invasive micropapillary carcinomas.<h4>Methods and results</h4>DNA from five ...[more]

PMID: 30843622

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Project description:ObjectivePrevious studies have mostly discussed the clinical manifestations and prognosis of mucinous breast carcinoma with a micropapillary pattern. The purposes of this study were to investigate the sonographic features of pure mucinous breast carcinoma with micropapillary pattern (MUMPC) and to identify the role of ultrasound in the differential diagnosis between MUMPC and conventional pure mucinous breast carcinoma (cPMBC).Materials and methodsWe obtained written informed consent from all patients, and the Ethics Committee of West China Hospital approved this retrospective study. The study was conducted between May and August 2020. We enrolled 133 patients with 133 breast lesions confirmed as mucinous breast carcinoma (MBC) histopathologically between January 2014 and January 2020.We retrospectively assessed sonographic features (margin, shape, internal echogenicity, calcification, posterior acoustic feature, invasive growth, blood flow grade, and rate of missed diagnosis) and clinical characteristics (age, tumor size, tumor texture, initial symptom, and lymph node metastasis). Bivariable analyses were performed using SPSS version 19.0.ResultsThe 133 lesions included 11 MUMPCs, 65 cPMBCs, and 57 mixed MBCs (MMBCs). There were significant differences in margin, shape, calcification, posterior acoustic feature, invasive growth, rate of missed diagnosis, average tumor size, and lymph node metastasis among the three groups (p < 0.05). The subsequent pairwise comparisons showed that there were significant differences in lymph node metastasis, margin, and invasive growth between MUMPC and cPMBC (p < 0.05). In patients aged >45 years, there was a significant difference in tumor size among the three groups (p = 0.045), and paired comparison showed that the average tumor size in the cPMBC group was larger than that in the MMBC group (p = 0.014).ConclusionMUMPC showed a non-circumscribed margin and invasive growth more frequently than cPMBC did. Lymphatic metastasis was more likely to occur in MUMPC than cPMBC. Ultrasound is helpful to distinguish MUMPC from cPMBC.

Project description:INTRODUCTION:Pure invasive micropapillary carcinoma (IMPC) is a special type of breast carcinoma characterised by clusters of cells presenting polarity abnormalities. The biological alterations underlying this pattern remain unknown. METHODS:Pangenomic analysis (n=39), TP53 (n=43) and PIK3CA (n=41) sequencing in a series of IMPCs were performed. A subset of cases was also analysed with whole-exome sequencing (n=4) and RNA sequencing (n=6). Copy number variation profiles were compared with those of oestrogen receptors and grade-matched invasive ductal carcinomas (IDCs) of no special type. RESULTS:Unsupervised analysis of genomic data distinguished two IMPC subsets: one (Sawtooth/8/16) exhibited a significant increase in 16p gains (71%), and the other (Firestorm/Amplifier) was characterised by a high frequency of 8q (35%), 17q (20% to 46%) and 20q (23% to 30%) amplifications and 17p loss (74%). TP53 mutations (10%) were more frequently identified in the amplifier subset, and PIK3CA mutations (4%) were detected in both subsets. Compared to IDC, IMPC exhibited specific loss of the 6q16-q22 region (45%), which is associated with downregulation of FOXO3 and SEC63 gene expression. SEC63 and FOXO3 missense mutations were identified in one case each (2%). Whole-exome sequencing combined with RNA sequencing of IMPC allowed us to identify somatic mutations in genes involved in polarity, DNAH9 and FMN2 (8% and 2%, respectively) or ciliogenesis, BBS12 and BBS9 (2% each) or genes coding for endoplasmic reticulum protein, HSP90B1 and SPTLC3 (2% each) and cytoskeleton, UBR4 and PTPN21 (2% each), regardless of the genomic subset. The intracellular biological function of the mutated genes identified by gene ontology analysis suggests a driving role in the clinicopathological characteristics of IMPC. CONCLUSION:In our comprehensive molecular analysis of IMPC, we identified numerous genomic alterations without any recurrent fusion genes. Recurrent somatic mutations of genes participating in cellular polarity and shape suggest that they, together with other biological alterations (such as epigenetic modifications and stromal alterations), could contribute to the morphological pattern of IMPC. Though none of the individual abnormalities demonstrated specificity for IMPC, whether their combination in IMPC may have a cumulative effect that drives the abnormal polarity of IMPC needs to be examined further with in vitro experiments.

Dataset Information

Micropapillary variant of mucinous carcinoma of the breast shows genetic alterations intermediate between those of mucinous carcinoma and micropapillary carcinoma.

Publications

Micropapillary variant of mucinous carcinoma of the breast shows genetic alterations intermediate between those of mucinous carcinoma and micropapillary carcinoma.

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