Breast cancer is a heterogeneous disease, comprising multiple entities associated with distinctive histological and biological features, clinical presentations and behaviours and responses to ...therapy. Microarray-based technologies have unravelled the molecular underpinning of several characteristics of breast cancer, including metastatic propensity and histological grade, and have led to the identification of prognostic and predictive gene expression signatures. Furthermore, a molecular taxonomy of breast cancer based on transcriptomic analysis has been proposed. However, microarray studies have primarily focused on invasive ductal carcinomas of no special type. Owing to the relative rarity of special types of breast cancer, information about the biology and clinical behaviour of breast cancers conveyed by histological type has not been taken into account. Histological special types of breast cancer account for up to 25% of all invasive breast cancers. Recent studies have provided direct evidence of the existence of genotypic–phenotypic correlations. For instance, secretory carcinomas of the breast consistently harbour the t(12;15) translocation that leads to the formation of the
ETV6–
NTRK3 fusion gene, adenoid cystic carcinomas consistently display the t(6;9)
MYB–
NFIB translocation and lobular carcinomas consistently show inactivation of the
CDH1 gene through multiple molecular mechanisms. Furthermore, histopathological and molecular analysis of tumours from conditional mouse models has provided direct evidence for the causative role of specific genes in the genesis of specific histological special types of breast cancer. Here we review the associations between the molecular taxonomy of breast cancer and histological special types, discuss the possible origins of the heterogeneity of breast cancer and propose an approach for the identification of novel therapeutic targets based on the study of histological special types of breast cancer.
Triple-negative breast cancer is viewed clinically as an aggressive subgroup of breast cancer. In fact, most triple-negative breast cancers are poor-prognosis tumors with a complex genomic landscape. ...However, triple-negative disease is vastly heterogeneous, encompassing multiple entities with marked genetic, transcriptional, histologic, and clinical differences, with neoplasms in this group ranging from low to high grade. Among the less common low-grade triple-negative lesions, two large subgroups, both with a rather indolent behavior, can be distinguished: a low-grade triple-negative breast neoplasia family, which includes nonobligate precursors of triple-negative breast cancer, and, despite being low-grade, harbors the complex genomic landscape of usual triple-negative breast cancer, and the salivary gland-like tumors of the breast, lacking all the cardinal molecular features of conventional triple-negative breast cancer and underpinned by specific fusion genes or hotspot mutations, which may be of diagnostic and possibly therapeutic utility. Progression to high-grade triple-negative breast cancer likely occurs in both subgroups but at different rates. In this review, we describe the heterogeneity of triple-negative disease, focusing on the histologic and molecular features of the low-grade lesions. Recognition that triple-negative breast cancer is an operational term and that triple-negative disease is heterogeneous and includes low-grade forms driven by distinct sets of genetic alterations is germane to the successful implementation of precision medicine.
Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we ...investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic.
Lopez‐Garcia M A, Geyer F C, Lacroix‐Triki M, Marchió C & Reis‐Filho J S (2010) Histopathology 57, 171–192 Breast cancer precursors revisited: molecular features and progression pathways
Increasingly ...more coherent data on the molecular characteristics of benign breast lesions and breast cancer precursors have led to the delineation of new multistep pathways of breast cancer progression through genotypic–phenotypic correlations. It has become apparent that oestrogen receptor (ER)‐positive and ‐negative breast lesions are fundamentally distinct diseases. Within the ER‐positive group, histological grade is strongly associated with the number and complexity of genetic abnormalities in breast cancer cells. Genomic analyses of high‐grade ER‐positive breast cancers have revealed that a substantial proportion of these tumours harbour the characteristic genetic aberrations found in low‐grade ER‐positive disease, suggesting that at least a subgroup of high‐grade ER‐positive breast cancers may originate from low‐grade lesions. The ER‐negative group is more complex and heterogeneous, comprising distinct molecular entities, including basal‐like, HER2 and molecular apocrine lesions. Importantly, the type and pattern of genetic aberrations found in ER‐negative cancers differ from those of ER‐positive disease. Here, we review the available molecular data on breast cancer risk indicator and precursor lesions, the putative mechanisms of progression from in situ to invasive disease, and propose a revised model of breast cancer evolution based on the molecular characteristics of distinct subtypes of in situ and invasive breast cancers.
The Genomic Landscape of Mucinous Breast Cancer Pareja, Fresia; Lee, Ju Youn; Brown, David N ...
JNCI : Journal of the National Cancer Institute,
07/2019, Letnik:
111, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Abstract
Mucinous carcinoma of the breast (MCB) is a rare histologic form of estrogen receptor (ER)-positive/HER2-negative breast cancer (BC) characterized by tumor cells floating in lakes of mucin. ...We assessed the genomic landscape of 32 MCBs by whole-exome sequencing and/or RNA-sequencing. GATA3 (23.8%), KMT2C (19.0%), and MAP3K1 (14.3%) were the most frequently mutated genes in pure MCBs. In addition, two recurrent but not pathognomonic fusion genes, OAZ1-CSNK1G2 and RFC4-LPP, were detected in 3/31 (9.7%) and 2/31 (6.5%) samples, respectively. Compared with ER-positive/HER2-negative common forms of BC, MCBs displayed lower PIK3CA and TP53 mutation rates and fewer concurrent 1q gains and 16q losses. Clonal decomposition analysis of the mucinous and ductal components independently microdissected from five mixed MCBs revealed that they are clonally related and evolve following clonal selection or parallel evolution. Our findings indicate that MCB represents a genetically distinct ER-positive/HER2-negative form of BC.
In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline ...and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.
Aberrant β-catenin expression as determined by assessment of its subcellular localization constitutes a surrogate marker of Wnt signalling pathway activation and has been reported in a subset of ...breast cancers. The association of β-catenin/Wnt pathway activation with clinical outcome and the mechanisms leading to its activation in breast cancers still remain a matter of controversy. The aims of this study were to address the distribution of β-catenin expression in invasive breast cancers, the correlations between β-catenin expression and clinicopathological features and survival of breast cancer patients, and to determine whether aberrant β-catenin expression is driven by CTNNB1 (β-catenin encoding gene) activating mutations. Immunohistochemistry was performed on a tissue microarray containing 245 invasive breast carcinomas from uniformly treated patients, using two anti-β-catenin monoclonal antibodies. Selected samples were subjected to CTNNB1 exon 3 mutation analysis by direct gene sequencing. A good correlation between the two β-catenin antibodies was observed (Spearman's r >0.62, P<0.001). Respectively, 31 and 11% of the cases displayed lack/reduction of β-catenin membranous expression and nuclear accumulation. Complete lack of β-catenin expression was significantly associated with invasive lobular carcinoma histological type. Subgroup analysis of non-lobular cancers or non-lobular grade 3 carcinomas revealed that lack/reduction of β-catenin membranous expression and/or nuclear accumulation were significantly associated with oestrogen receptor negativity, absence of HER2 gene amplification and overexpression, lack/reduction of E-cadherin expression and tumours of triple-negative and basal-like phenotype. Univariate survival analysis revealed a significant association between β-catenin nuclear expression and shorter metastasis-free and overall survival in the whole cohort; however, β-catenin nuclear expression was not an independent predictor of outcome in multivariate analysis. No CTNNB1 mutations were identified in the 28 selected breast carcinomas analysed. In conclusion, β-catenin/Wnt pathway activation is preferentially found in triple-negative/basal-like breast carcinomas, is associated with poor clinical outcome and is unlikely to be driven by CTNNB1 mutations in breast cancer.
Breast cancers in
BRCA1 mutation carriers frequently have a distinctive basal-like phenotype. It has been suggested that this results from an origin in basal breast epithelial stem cells. Here, we ...demonstrate that deleting
Brca1 in mouse mammary epithelial luminal progenitors produces tumors that phenocopy human
BRCA1 breast cancers. They also resemble the majority of sporadic basal-like breast tumors. However, directing
Brca1 deficiency to basal cells generates tumors that express molecular markers of basal breast cancers but do not histologically resemble either human
BRCA1 or the majority of sporadic basal-like breast tumors. These findings support a derivation of the majority of human
BRCA1-associated and sporadic basal-like tumors from luminal progenitors rather than from basal stem cells. They also demonstrate that when target cells for transformation have the potential for phenotypic plasticity, tumor phenotypes may not directly reflect histogenesis. This has important implications for cancer prevention strategies.
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BRCA1 breast cancers have been suggested to develop in basal mammary stem cells ► Targeted
Brca1 loss in stem cells did not generate human
BRCA1-like tumors ►
Brca1 loss in luminal progenitors produced tumors identical to human cancers ► Luminal progenitors are probably the true origin of human
BRCA1 breast cancers
PTEN (phosphatase and tensin homolog) loss of function is the most common genetic aberration in endometrioid endometrial carcinomas. In addition to its well-described role in cell signaling, PTEN is ...involved in the maintenance of genomic stability. Loss of PTEN function causes defects in repair of DNA double-strand breaks by homologous recombination and, therefore, sensitizes cells to inhibition of the poly(adenosine diphosphate ribose) polymerase (PARP). Here, we determined the PTEN status of eight endometrioid endometrial carcinoma cell lines and correlated it with in vitro sensitivity to the PARP inhibitor KU0058948. PTEN-deficient cells showed a significantly greater sensitivity to KU0058948 than the two endometrioid endometrial carcinoma cell lines with wild-type PTEN. The cell lines lacking PTEN expression were unable to elicit a homologous recombination damage response as assayed by RAD51 focus function (a marker of competent homologous recombination DNA repair) upon irradiation and treatment with PARP inhibitors. PTEN silencing in PTEN wild-type Hec-1b cells resulted in reduced RAD51 foci formation after DNA damage and increased sensitivity to PARP inhibition. PTEN reexpression in PTEN-null cell lines resulted in enhanced RAD51 foci formation and in relative resistance to KU0058948. Given that up to 80% of endometrioid endometrial cancers lack PTEN expression, our results suggest that PARP inhibitors may be therapeutically useful for a subset of endometrioid endometrial cancers.
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