A Molecular Portrait of High-Grade Ductal Carcinoma <i>In Situ</i>

Abba, Martı́n C.; Gong, Ting; Lu, Yue; Lee, Jae-Ho; Zhong, Yi; Lacunza, Ezequiel; Butti, Matías; Takata, Yoko; Gaddis, Sally; Shen, Jianjun; Estécio, Marcos R.H.; Şahin, Ayşegül; Aldaz, C. Marcelo

doi:10.1158/0008-5472.can-15-0506

Cited by 123 publications

(152 citation statements)

References 57 publications

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“…Forty variants (87%) were located in exons and the remaining six (13%) at essential splice sites. Similar to previous studies of DCIS, 14,15 single-nucleotide substitutions were the most frequent mutation type detected (33/46, 71.7%), with the most frequent substitution being C4T:G4A (14/33, 42.4%) (Figure 1).…”

Section: Mutated Genes In Dcissupporting

confidence: 88%

“…The C4T:G4A alteration forms a major part of three of the five mutational signatures identified in breast cancer 35 and is thought to occur through the spontaneous deamination of 5-methyl-cytosine which accumulates with age 35,36 and overactivity of the APOBEC family of cytidine deaminases. 35,37 Although C4T:G4A alterations are also characteristic of formalin-related DNA damage 18 the proportion of C4T:G4A alterations is similar to that reported in fresh-frozen samples of invasive breast cancer (~40%) 4 and DCIS (~50%) 14,15 , so the C4T: G4A alterations detected are unlikely to represent formalin-fixation artefacts.…”

Section: Discussionsupporting

confidence: 70%

“…The panel was selected to represent frequently mutated breast fresh-frozen tumor specimens, but this study shows that interrogation of formalin-fixed paraffin embedded-derived DNA can now be applied to a variety of DCIS cases from hospital-based series, including cases archived for up to nine years at the time of DNA extraction. The rate of variants in DCIS samples was higher (5.6 mutations/Mb) than that previously reported for DCIS (1.61 mutations/Mb) 14 and invasive breast cancer (1.66 mutations/Mb) 4 and is likely to be due to the use of a panel focussed on genes known to be mutated in breast cancer. Although potential germline variants might have contributed to this (these were unable to be completely excluded as few cases had matched normal DNA available), the number of these germline variants is expected to be small, as stringent population filters based on large public databases were applied.…”

Section: Discussioncontrasting

confidence: 63%

“…Notably, unlike Abba et al, 14 we only saw one case that had no common driver (ie, wildtype for TP53, PIK3CA, ERBB2, and GATA3). Although this case (P124) had a relatively stable genome (5% affected by copy number), the copy number changes included a CCND1 amplification, CBFB loss, and CDH1 loss.…”

Section: Discussioncontrasting

confidence: 63%

“…To date, whole genome or whole exome sequencing has been performed in only 45 published DCIS cases in total, all using DNA from fresh frozen tissue. 4,14,15 Therefore, the cases used to date have been highly selected, derived from large mass forming tumors with adequate sufficient tissue to spare after diagnostic samples were taken.…”

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confidence: 99%

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Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

et al. 2017

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The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n = 20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P = 0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P = 0.005), including a significant positive association with amplification or gain of ERBB2 (Po 0.05). The association between TP53 mutation and ERBB2 amplification was confirmed in a wider DCIS cohort using p53 immunohistochemistry as a surrogate marker for TP53 mutations (P = 0.03). RUNX1 mutations and MAP2K4 copy number loss were novel findings in DCIS. Frequent copy number alterations included gains on 1q, 8q, 17q, and 20q and losses on 8p, 11q, 16q, and 17p. Patterns of genomic alterations observed in DCIS were similar to those previously reported for invasive breast cancers, with all DCIS having at least one bona fide breast cancer driver event. However, an increase in GATA3 mutations and fewer copy number changes were noted in DCIS compared with invasive carcinomas. The role of such alterations as prognostic and predictive biomarkers in DCIS is an avenue for further investigation.

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Section: Mutated Genes In Dcissupporting

confidence: 88%

Section: Discussionsupporting

confidence: 70%

Section: Discussioncontrasting

confidence: 63%

Section: Discussioncontrasting

confidence: 63%

mentioning

confidence: 99%

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Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

et al. 2017

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A PET‐Surrogate Signature for the Interrogation of the Metabolic Status of Breast Cancers

Confalonieri,

Matoskova,

Pennisi

et al. 2024

Advanced Science

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Metabolic alterations in cancers can be exploited for diagnostic, prognostic, and therapeutic purposes. This is exemplified by 18F‐fluorodeoxyglucose (FDG)‐positron emission tomography (FDG‐PET), an imaging tool that relies on enhanced glucose uptake by tumors for diagnosis and staging. By performing transcriptomic analysis of breast cancer (BC) samples from patients stratified by FDG‐PET, a 54‐gene signature (PETsign) is identified that recapitulates FDG uptake. PETsign is independently prognostic of clinical outcome in luminal BCs, the most common and heterogeneous BC molecular subtype, which requires improved stratification criteria to guide therapeutic decision‐making. The prognostic power of PETsign is stable across independent BC cohorts and disease stages including the earliest BC stage, arguing that PETsign is an ab initio metabolic signature. Transcriptomic and metabolomic analysis of BC cells reveals that PETsign predicts enhanced glycolytic dependence and reduced reliance on fatty acid oxidation. Moreover, coamplification of PETsign genes occurs frequently in BC arguing for their causal role in pathogenesis. CXCL8 and EGFR signaling pathways feature strongly in PETsign, and their activation in BC cells causes a shift toward a glycolytic phenotype. Thus, PETsign serves as a molecular surrogate for FDG‐PET that could inform clinical management strategies for BC patients.

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Integrative gene set enrichment analysis utilizing isoform‐specific expression

Wang

Xiao

et al. 2017

Genetic Epidemiology

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Gene Set Enrichment Analysis (GSEA) aims at identifying essential pathways, or more generally, sets of biologically related genes that are involved in complex human diseases. In the past, many studies have shown that GSEA is a very useful bioinformatics tool, which plays critical roles in the innovation of disease prevention and intervention strategies. Despite its tremendous success, it is striking that conclusions of GSEA drawn from isolated studies are often sparse, and different studies may lead to inconsistent and sometimes contradictory results. Further, in the wake of next generation sequencing technologies, it has been made possible to measure genome-wide isoform-specific expression levels, calling for innovations that can utilize the unprecedented resolution. Currently, enormous amounts of data have been created from various RNA-seq experiments. All these give rise to a pressing need for developing integrative methods that allow for explicit utilization of isoform-specific expression, to combine multiple enrichment studies, in order to enhance the power, reproducibility and interpretability of the analysis. We develop and evaluate integrative GSEA methods, based on two-stage procedures, which, for the first time, allow statistically efficient use of isoform-specific expression from multiple RNA-seq experiments. Through simulation and real data analysis, we show that our methods can greatly improve the performance in identifying essential gene sets compared to existing methods that can only use gene-level expression.

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A Molecular Portrait of High-Grade Ductal Carcinoma In Situ

Cited by 123 publications

References 57 publications

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

A PET‐Surrogate Signature for the Interrogation of the Metabolic Status of Breast Cancers

Integrative gene set enrichment analysis utilizing isoform‐specific expression

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