A novel diagnostic method targeting genomic instability in intracystic tumors of the breast

Oikawa, Masayuki; Yano, Hiroshi; Matsumoto, Megumi; Otsubo, Ryota; Shibata, Kenichiro; Hayashi, Tomayoshi; Abe, Kuniko; Kinoshita, N.; Yoshiura, Koh-ichiro; Nagayasu, Takeshi

doi:10.1007/s12282-013-0516-9

Cited by 5 publications

(7 citation statements)

References 25 publications

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“…Direct lineage models provide an alternative explanation for the evolution of the DCIS and IDC subpopulations, through a single initiating cell (N 1 ) in normal breast tissue (Figure B, C). Direct lineage models are supported by numerous genomic studies, using aCGH and NGS to profile synchronous DCIS–IDC. These studies report a high correlation in copy number profiles of in situ and invasive subpopulations in synchronous DCIS patients , and many concordant point mutations .…”

Section: Direct Genomic Lineagesmentioning

confidence: 99%

“…Concordant mutations between DCIS and IDC are often referred to as ‘truncal’ mutations by evolutionary biologists, because they can be traced back to the last common ancestor in the tumour. However, many genomic studies also report discordant mutations and CNAs arising at later stages of evolution, specific to either in situ or invasive subpopulations . These data suggest that some DCIS cancers may evolve through an evolutionary bottleneck and select minor clones with invasive phenotypes, while others may evolve through migration of multiple dominant clones.…”

Section: Direct Genomic Lineagesmentioning

confidence: 99%

“…Other genomic studies did not perform evolutionary analyses, but instead reported concordance of mutations and CNAs in patients with synchronous DCIS–IDC. Studies using aCGH to profile microdissected DCIS and IDC regions often showed that while most CNAs are concordant, there are also many invasive‐specific amplifications of oncogenes and deletions of tumour suppressors . Similarly, sequencing and genotyping analysis of synchronous DCIS–IDC regions have reported patients with invasive‐specific mutations consistent with an evolutionary bottleneck .…”

Section: Clonal Evolutionmentioning

confidence: 99%

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Genome evolution in ductal carcinoma in situ: invasion of the clones

Casasent

Edgerton

Navin

2016

The Journal of Pathology

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Ductal Carcinoma In Situ (DCIS) is the most frequently diagnosed early stage breast cancer. Only a subset of patients progress to invasive ductal carcinoma (IDC), and this presents a formidable clinical challenge for determining which patients to treat aggressively and which patients to monitor without therapeutic intervention. Understanding the molecular and genomic basis of invasion has been difficult to study in DCIS cancers due to several technical obstacles, including low tumour cellularity, lack of fresh-frozen tissues, and intratumour heterogeneity. In this review we discuss the role of intratumour heterogeneity in the progression of DCIS to IDC in the context of three evolutionary models: independent lineages, evolutionary bottlenecks, and multiclonal invasion. We examine the evidence in support of these models and their relevance to the diagnosis and treatment of patients with DCIS. We also discuss how emerging technologies, such as single cell sequencing, STAR-FISH and imaging mass spectrometry are likely to provide new insights into the evolution of this enigmatic disease.

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Section: Direct Genomic Lineagesmentioning

confidence: 99%

Section: Direct Genomic Lineagesmentioning

confidence: 99%

Section: Clonal Evolutionmentioning

confidence: 99%

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Genome evolution in ductal carcinoma in situ: invasion of the clones

Casasent

Edgerton

Navin

2016

The Journal of Pathology

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“…This model is supported by indirect evidence from extremely high levels of concordance between CNAs and mutations between DCIS and IDC (as high as 97%); in contrast, an evolutionary bottleneck model would likely have multiple divergent branches between its transition from DCIS to IDC, which would be expected to have lower levels of concordance. 26,27 Extrinsic causes of DCIS progression to IDC involve the microenvironment, which consists of the cellular components (eg, fibroblasts, endothelial cells, immune cells, adipocytes) and noncellular components [eg, extracellular matrix (ECM), growth factors, cytokines, pH] that influence the cancer cells. 28,29 The microenvironment has been causally implicated in multiple aspects of cancer biology, including progression, metastasis, and drug resistance.…”

Section: Models Of Dcis Progressionmentioning

confidence: 99%

Ductal Carcinoma in Situ Biomarkers in a Precision Medicine Era

Shee¹,

Muller

Marotti

et al. 2019

The American Journal of Pathology

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“…Thus, small FFPE PML specimens pose significant challenges in the generation of high throughput sequencing libraries and preclude the investigation of genetic biomarkers. To overcome these limitations, previous studies have been performed in fresh PML from areas adjacent to invasive disease instead of on pure PML, ignoring the vast majority of PML that are less likely to progress [10][11][12][13][14][15]. Profiling of pure PML in the absence of invasive disease is required to avoid such biases and thus necessitates methodology to work with archival FFPE specimens.…”

Section: Introductionmentioning

confidence: 99%

Mutational profiling of micro-dissected pre-malignant lesions from archived specimens

Nachmanson

Steward²,

Yao

et al. 2020

Preprint

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Background: Systematic cancer screening has led to the increased detection of pre-malignant lesions (PMLs). The absence of reliable prognostic markers can lead to inadequate treatment resulting in unnecessary stress or avoidable progression. Importantly, most mutational profiling studies have relied on PML synchronous to invasive cancer, or performed in patients without outcome information, hence limiting their utility for biomarker discovery. The limitations in comprehensive mutational profiling of PMLs are in large part due to the significant technical and methodological challenges: most PML specimens are small, fixed in formalin and paraffin embedded (FFPE) and lack matching normal DNA. Methods:Using test DNA from a highly degraded FFPE specimen, multiple targeted sequencing approaches were evaluated, varying DNA input amount (3-200 ng), library preparation strategy (BE: Blunt-End, SS: Single-Strand, AT: A-Tailing) and target size (whole exome vs cancer gene panel). Variants in high-input DNA from FFPE and mirrored frozen specimens were used for PML-specific variant calling training and testing, respectively. The resulting approach was applied to profile and compare multiple regions micro-dissected (mean area 5 mm 2 ) from 3 breast ductal carcinoma in situ (DCIS). Results:Using low-input FFPE DNA, BE and SS libraries resulted in 4.9 and 3.7 increase over AT libraries in the fraction of whole exome covered at 20x (BE:87%, SS:63%, AT:17%).Compared to high-confidence somatic mutations from frozen specimens, PML-specific variant filtering increased recall (BE:79%, SS:74%, AT:62%) and precision (BE:87%, SS:88%, AT:80%) to levels expected from sampling variation. Copy number alterations were consistent across all tested approaches and only impacted by the design of the capture probe-set. Applied to DNA extracted from 9 micro-dissected regions (8 PML, 1 normal epithelium), the approach achieved comparable performance, identified candidate driver events (gains of ERBB2 or FGFR1, loss of TP53) and illustrated the adequacy of the data to identify candidate driver mutations and measure intra-lesion genetic heterogeneity. Conclusion:The approach presented enables mutational profiling from archived microdissected PML regions, supporting the identification of pre-malignant drivers, and the characterization of PML molecular heterogeneity and evolution, all critical milestones the development of biology-informed prognostic markers and precision chemo-prevention strategies.

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A novel diagnostic method targeting genomic instability in intracystic tumors of the breast

Abstract: Background: Even after needle biopsy, intracystic tumors of the breast are challenging

Cited by 5 publications

References 25 publications

Genome evolution in ductal carcinoma in situ: invasion of the clones

Genome evolution in ductal carcinoma in situ: invasion of the clones

Ductal Carcinoma in Situ Biomarkers in a Precision Medicine Era

Mutational profiling of micro-dissected pre-malignant lesions from archived specimens

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