Appraisal of the technologies and review of the genomic landscape of ductal carcinoma in situ of the breast

Pang, Jia-Min; Gorringe, Kylie L.; Wong, Stephen Q.; Dobrovic, Alexander; Campbell, Ian; Fox, Stephen B.

doi:10.1186/s13058-015-0586-z

Cited by 7 publications

(4 citation statements)

References 87 publications

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“…Studies of conventional DCIS have demonstrated largely similar mutational and copy number profiles between the in situ and invasive components, albeit with increased numbers of copy number alterations in invasive cancer, and our results in metaplastic carcinomas are consistent with this [61][62][63][64][65]. As in conventional DCIS [62,63,65,66], we show that PIK3CA alterations are early events in metaplastic carcinoma, with mutations in this and other growthpromoting PI-3 kinase/Ras-Map kinase pathway genes being present in clonal frequencies of associated DCIS and paired invasive tumors.…”

Section: Discussionsupporting

confidence: 88%

Genomic profiling of metaplastic breast carcinomas reveals genetic heterogeneity and relationship to ductal carcinoma

Krings

Chen

2018

Modern Pathology

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Metaplastic breast carcinomas comprise a histologically heterogenous group of tumors. Although most are triple (estrogen/progesterone receptor, HER2) negative, these rare tumors are clinicopathologically distinct from other triple negative carcinomas and may be aggressive with worse chemotherapy responses. On the other hand, metaplastic carcinomas are histologically diverse, which is reflected in gene expression differences among subtypes. Whether metaplastic carcinomas are genetically distinct from other triple negative cancers and whether genetic differences underlie histologic subtypes remains poorly understood. We sequenced 408 cancer-related genes in 28 metaplastic carcinomas, including chondroid matrix-producing carcinomas (n = 10), spindle cell carcinomas (n = 5), and carcinomas with squamous (n = 5), mixed spindle/squamous (n = 5), and mixed metaplastic (n = 3) differentiation. Metaplastic carcinomas were highly enriched for PIK3CA/PIK3R1 (61%) and Ras-Map kinase (25%) pathway aberrations compared to other triple negative carcinomas (TCGA dataset 14%, p < 0.001 and 7%, p = 0.005, respectively) and harbored a high frequency of TP53 (64%) and TERT promoter (25%) mutations, but this varied among subtypes. Chondroid-matrix producing carcinomas lacked PI-3 kinase and Ras-Map kinase aberrations and TERT promoter mutations, compared to 100%, 39%, and 39% of non-matrix-producing tumors, respectively. TERT promoter mutations were enriched (47%) in spindle cell carcinomas and tumors with squamous or spindle/squamous differentiation. Spindle cell carcinomas lacked TP53 mutations, in contrast to other subtypes (78%, p = 0.003). Separate analysis of paired ductal carcinoma in situ and metaplastic carcinoma revealed shared clonality in all cases (n = 8). Activating PI-3 kinase and Ras pathway mutations were early events, and inactivating mutations in tumor suppressors including RB1, CDKN2A, and TP53 were associated with invasion in individual cases. Metaplastic components of two tumors showed genetic progression from separately sequenced paired invasive ductal carcinoma. The findings suggest that metaplastic carcinomas are genetically distinct from other triple negative breast cancers and highlight genetic heterogeneity that broadly correlates with histologic subtype. Heterologous elements progress from associated ductal carcinoma.

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Section: Discussionsupporting

confidence: 88%

Genomic profiling of metaplastic breast carcinomas reveals genetic heterogeneity and relationship to ductal carcinoma

Krings

Chen

2018

Modern Pathology

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“…[25][26][27][28][29]. We found that in HG DCIS copy number changes in our candidate genes were not differentially distributed in PD and MD lesions ( Table 2), indicating that in this subgroup our oligo-gene signature may not be useful.…”

Section: Positivementioning

confidence: 81%

Validation of an oligo-gene signature for the prognostic stratification of ductal carcinoma in situ (DCIS)

Geradts

Groth

et al. 2016

Breast Cancer Res Treat

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Current evidence suggests that the majority of DCIS lesions do not progress to invasive carcinoma, and overtreatment of DCIS is a significant problem. We previously reported an 8-gene signature that differentiated microdissected low-grade (LG) DCIS lesions with and without associated stromal invasion, based on differential DNA copy number changes detected by quantitative (q) PCR. The current study was undertaken to validate our candidate breast cancer invasion gene panel in a larger series of non-microdissected LG DCIS cases, and to investigate its potential utility in intermediate-grade (IG) and high-grade (HG) DCIS. Representative paraffin blocks were selected from 267 resected DCIS cases with 5-15 years of follow-up (139 pure DCIS ["PD"] and 128 mixed DCIS with associated invasion ["MD"]). These included 171 LG, 46 IG and 50 HG DCIS cases. Gene copy number changes were determined by qPCR, and their differential distribution in the PD and MD subgroups was evaluated. As an alternate platform, we employed immunohistochemistry (IHC). Novel IHC assays were developed for all eight candidate genes, and increased or reduced protein expression was manually scored. Separate multi-gene models were developed for qPCR and IHC to distinguish progressing and non-progressing DCIS lesions. By qPCR analysis, a panel of six genes, as well as CELSR1 alone (a potential invasion suppressor), differentiated PD and MD cases in LG and IG, but not in HG DCIS. By IHC, a panel of three genes, as well as GRAP2 alone (a potential invasion promoter), also distinguished PD and MD cases in LG and IG, but not in HG DCIS. The combination of CELSR1 (by qPCR) and GRAP2 (by IHC) had the best discriminatory power (p = 0.00004). Assays testing either or both of these genes have the potential to become important adjuncts for choosing appropriate treatment for LG/IG DCIS patients.

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“…Genomic DNA biomarkers report genome-level changes using a variety of methods, including genome sequencing, qPCR and digital PCR 148 to accurately report SNPs, CNVs, genomic rearrangements and rare genetic sequences that functionally underpin the pathophysiology of disease 149 . This approach is most frequently used in oncology.…”

Section: Evs and Dna Biomarkersmentioning

confidence: 99%

Extracellular vesicles and their nucleic acids for biomarker discovery

Momen-Heravi

Getting

Moschos

2018

Pharmacology & Therapeutics

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Extracellular vesicles (EVs) are a heterogenous population of vesicles originate from cells. EVs are found in different biofluids and carry different macromolecules, including proteins, lipids, and nucleic acids, providing a snap shot of the parental cells at the time of release. EVs have the ability to transfer molecular cargoes to other cells and can initiate different physiological and pathological processes. Mounting lines of evidence demonstrated that EVs' cargo and machinery is affected in disease states, positioning EVs as potential sources for the discovery of novel biomarkers. In this review, we demonstrate a conceptual overview of the EV field with particular focus on their nucleic acid cargoes. Current knowledge of EV subtypes, nucleic acid cargo and pathophysiological roles are outlined, with emphasis placed on advantages against competing analytes. We review the utility of EVs and their nucleic acid cargoes as biomarkers and critically assess the newly available advances in the field of EV biomarkers and high throughput technologies. Challenges to achieving the diagnostic potential of EVs, including sample handling, EV isolation, methodological considerations, and bioassay reproducibility are discussed. Future implementation of 'omics-based technologies and integration of systems biology approaches for the development of EV-based biomarkers and personalized medicine are also considered.

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Appraisal of the technologies and review of the genomic landscape of ductal carcinoma in situ of the breast

Cited by 7 publications

References 87 publications

Genomic profiling of metaplastic breast carcinomas reveals genetic heterogeneity and relationship to ductal carcinoma

Genomic profiling of metaplastic breast carcinomas reveals genetic heterogeneity and relationship to ductal carcinoma

Validation of an oligo-gene signature for the prognostic stratification of ductal carcinoma in situ (DCIS)

Extracellular vesicles and their nucleic acids for biomarker discovery

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