Clinical proteomics reveals vulnerabilities in non-invasive breast ductal carcinoma and drives personalized treatment strategies DOI Open Access
Georgia Mitsa, Livia Florianova, Josiane Lafleur

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 12, 2023

Abstract Ductal carcinoma in situ (DCIS) is the most common type (80%) of noninvasive breast lesions. The lack validated prognostic markers, limited patient numbers and variable tissue quality significantly impact diagnosis, risk stratification, enrolment, results clinical studies. We performed label-free quantitative proteomics on 50 formalin-fixed, paraffin embedded biopsies, validating 22 putative biomarkers from independent genetic Our comprehensive proteomic phenotyping reveals more than 380 differentially expressed proteins metabolic vulnerabilities, that can inform new therapeutic strategies for DCIS IDC. Due to readily druggable nature metabolites, this study high interest research pharmaceutical industry. To further evaluate our findings, promote translation study, we developed a highly multiplexed targeted assay 90 associated with cancer metabolism, RNA regulation signature pathways, such as Pi3K/AKT/mTOR EGFR/RAS/RAF.

Language: Английский

Towards targeting the breast cancer immune microenvironment DOI
Michael A. Harris, Peter Savas, Balaji Virassamy

et al.

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(8), P. 554 - 577

Published: July 5, 2024

Language: Английский

Citations

64
Advances and challenges in cancer immunoprevention and immune interception DOI Creative Commons
Sasha E. Stanton, Philip E. Castle, Olivera J. Finn

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(3), P. e007815 - e007815

Published: March 1, 2024

Invasive cancers typically evade immune surveillance through profound local and systemic immunosuppression, preventing their elimination or control. Targeting interventions to prevent intercept premalignant lesions, before significant dysregulation has occurred, may be a more successful strategy. The field of cancer interception prevention is nascent, the scientific community been slow embrace this potentially most rational approach reducing global burden cancer. This change due recent promising advances in immunoprevention including use vaccines for viral cancers, cancer-associated antigen setting precancers, development cancer-preventative high-risk individuals who are healthy but carry heritable genetic mutations. Furthermore, there increasing recognition importance by national organizations. National Cancer Institute (NCI) recently released Plan, which includes among top priorities institute. NCI's Division Prevention introducing new funding opportunities scientists with an interest prevention: Prevention-Interception Targeted Agent Discovery Program Immunoprevention Network. Moreover, Human Tumor Atlas Network spearheading precancer atlas better understand biology pre-invasive changes, tissue microenvironment underlying genetics that drive carcinogenesis. These data will inform novel immunoprevention/immuno-interception strategies. International foundations have also started recognizing American Association Research, Research UK Society Immunotherapy each implementing programming focused on area. review present advances, opportunities, challenges emerging interception.

Language: Английский

Citations

10
An Update on the General Features of Breast Cancer in Male Patients—A Literature Review DOI Creative Commons
S Ionescu, Alin Codruț Nicolescu, M Marincaş

et al.

Diagnostics, Journal Year: 2022, Volume and Issue: 12(7), P. 1554 - 1554

Published: June 26, 2022

Male breast cancers are uncommon, as men account for less than 1 percent of all carcinomas. Among the predisposing risk factors male cancer, following appear to be significant: (a) breast/chest radiation exposure, (b) estrogen use, diseases associated with hyper-estrogenism, such cirrhosis or Klinefelter syndrome, and (c) family health history. Furthermore, there clear familial tendencies, a higher incidence among who have large number female relatives cancer (d) major inheritance susceptibility. Moreover, in families BRCA mutations, is an increased although appears greater inherited BRCA2 mutations BRCA1 mutations. Due diagnostic delays, more likely present at advanced stage. A core biopsy fine needle aspiration must performed confirm suspicious findings. Infiltrating ductal most prevalent form while invasive lobular carcinoma extremely uncommon. almost always positive hormone receptors. worse prognosis stage diagnosis cancer. Randomized controlled trials which recruit both patients should developed order gain consistent data on optimal clinical approach.

Language: Английский

Citations

14
Integrated Molecular Characterization of Intraductal Papillary Mucinous Neoplasms: An NCI Cancer Moonshot Precancer Atlas Pilot Project DOI Creative Commons
Alexander Semaan, Vincent Bernard, Justin Wong

et al.

Cancer Research Communications, Journal Year: 2023, Volume and Issue: 3(10), P. 2062 - 2073

Published: Sept. 18, 2023

Intraductal papillary mucinous neoplasms (IPMN) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low-grade (LG) high-grade (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN have been analyzed using multiregion sequencing for somatic mutations, there is no integrated assessment molecular events, including copy-number alterations (CNA) and transcriptional changes that accompany progression. We performed laser capture microdissection on surgically resected varying grades histologic dysplasia obtained 23 patients, followed by whole-exome whole-transcriptome sequencing. Overall, HG displayed a significantly greater aneuploidy score than LG lesions, with chromosome 1q amplification being associated cases harbored co-occurring PDAC. Furthermore, the combined single-nucleotide variants (SNV) CNAs identified both linear branched evolutionary trajectories, underscoring heterogeneity At transcriptome level, upregulation MYC-regulated targets downregulation transcripts MHC class I antigen presentation machinery as well pathways related glycosylation were common feature HG. In addition, established PDAC subtypes (basal-like classical) readily apparent within IPMNs. Taken together, this work emphasizes role putative biomarker high-risk IPMNs, underscores importance immune evasion even noninvasive reinforces heterogenous, comprised SNV CNA-driven events.

Language: Английский

Citations

6
Molecular signatures of in situ to invasive progression for basal-like breast cancers: An integrated mouse model and human DCIS study DOI Creative Commons

Aatish Thennavan,

Susana García‐Recio, Siyao Liu

et al.

npj Breast Cancer, Journal Year: 2022, Volume and Issue: 8(1)

Published: July 18, 2022

Abstract Ductal carcinoma in situ (DCIS) of the breast is a non-obligate precursor Invasive Carcinoma (IDC) and thus identification features that may predict DCIS progression would be potential clinical value. Experimental mouse models can used to address this challenge by studying DCIS-to-IDC biology. Here we utilize single cell RNA sequencing (scRNAseq) on C3Tag genetically engineered model forms DCIS-like lesions for which many progress into end-stage basal-like molecular subtype IDC. We also perform bulk RNAseq analysis 10 human synchronous DCIS-IDC pairs comprised estrogen receptor (ER) positive ER-negative subsets 2 additional public data sets comparison our model. By identifying malignant cells using inferred DNA copy number changes from murine scRNAseq data, show existence cancer within pre-DCIS, DCIS, IDC-like tumor specimens. These were further classified proliferative, hypoxic, inflammatory subpopulations, change frequency versus The was associated with increase Cancer-Associated Fibroblasts decrease activated T Importantly, translate genomic findings where find common only suggesting there are intrinsic unique features. This study identifies several microenvironmental provide signatures identify progression-prone context cancers.

Language: Английский

Citations

8
Clinical Implications of APOBEC3-Mediated Mutagenesis in Breast Cancer DOI
Pieter A. Roelofs, John W.M. Martens, Reuben S. Harris

et al.

Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 29(9), P. 1658 - 1669

Published: Dec. 8, 2022

Abstract Over recent years, members of the APOBEC3 family cytosine deaminases have been implicated in increased cancer genome mutagenesis, thereby contributing to intratumor and intertumor genomic heterogeneity therapy resistance in, among others, breast cancer. Understanding available methods for clinical detection these enzymes, conditions required their (dysregulated) expression, impact they have, implications may offer is crucial understanding current APOBEC3-mediated mutagenesis Here, we provide a comprehensive review developments responsible summarize pathways that control explore ramifications opportunities pose. We propose can function as helpful predictive biomarker several standard-of-care treatment plans be novel target treatment.

Language: Английский

Citations

8
Identification of molecularly unique tumor-associated mesenchymal stromal cells in breast cancer patients DOI Creative Commons

Jonathan A. R. Gordon,

Mark Evans,

Prachi N. Ghule

et al.

PLoS ONE, Journal Year: 2023, Volume and Issue: 18(3), P. e0282473 - e0282473

Published: March 20, 2023

The tumor microenvironment is a complex mixture of cell types that bi-directionally interact and influence initiation, progression, recurrence, patient survival. Mesenchymal stromal cells (MSCs) the engage in crosstalk with cancer to mediate epigenetic control gene expression. We identified CD90+ MSCs residing patients invasive breast exhibit unique expression signature. Single-cell transcriptional analysis these tumor-associated stroma distinct subpopulation characterized by increased genes functionally related extracellular matrix signaling. Blocking TGFβ pathway reveals directly contribute proliferation. Our findings provide novel insight into communication between are consistent an epithelial mesenchymal transition acquisition competency for compromised proliferation, mobility, motility, phenotype.

Language: Английский

Citations

4
Accurate genome-wide genotyping from archival tissue to explore the contribution of common genetic variants to pre-cancer outcomes DOI Creative Commons
Daniela Nachmanson, Meghana S. Pagadala,

J. S. Steward

et al.

Journal of Translational Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: Dec. 27, 2022

The contribution of common genetic variants to pre-cancer progression is understudied due long follow-up time, rarity poor outcomes and lack available germline DNA collection. Alternatively, from diagnostic archival tissue available, but its somatic nature, limited quantity suboptimal quality would require an accurate cost-effective genome-wide genotyping methodology.Blood 10 individuals were used benchmark the accuracy Single Nucleotide Polymorphisms (SNP) genotypes, Polygenic Risk Scores (PRS) or HLA haplotypes using low-coverage whole-genome sequencing (lc-WGS) genotype imputation. Tissue-derived PRS further evaluated for 36 breast cancer patients (11.7 years median time) diagnosed with DCIS model risk Breast Cancer Subsequent Events (BCSE).Tissue-derived profiling resulted in genotypes at SNPs (blood correlation r2 > 0.94) across 22 disease-related polygenic scores (PRS, mean r = 0.93). Imputed Class I II 96.7% 82.5% concordant clinical-grade blood haplotypes, respectively. In patients, tissue-derived was significantly associated BCSE (HR 2, 95% CI 1.2-3.8). top bottom decile had estimated 28% 5% chance years, respectively.Archival lc-WGS imputation, represents a cost resource-effective alternative retrospective design long-term disease studies. Initial results suggest that contribute progression.

Language: Английский

Citations

3
Tumor microenvironmental determinants of high-risk DCIS progression DOI Creative Commons
Alexander D. Borowsky, Alexa Glencer, Kirithiga Ramalingam

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: May 9, 2024

Abstract Ductal carcinomain situ(DCIS) constitutes an array of morphologically recognized intraductal neoplasms in the mammary ductal tree defined by increased risk for subsequent invasive carcinomas at or near site biopsy detection. However, only 15-45% untreated DCIS cases progress to cancer, so understanding mechanisms that prevent progression is key avoid overtreatment and provides a basis alternative therapies prevention. This study was designed characterize tumor microenvironment molecular profile high-risk grew large size but remained as DCIS. All patients had lesions >5cm with least one additional feature: young age (<45 years), high nuclear grade, hormone receptor negativity, HER2 positivity, presence comedonecrosis, palpable mass. The immune characterized using multiplex immunofluorescence identify cells their spatial relationships within ducts stroma. Gene copy number analysis whole exome DNA sequencing identified mutational burden driver mutations, quantitative whole-transcriptome/gene expression analyses were performed. There no association between percent genome variants (CNAs) recurrence events (DCIS invasive). Mutations, especially missense breast cancer genesPIK3CAandTP53were common this cohort (47% evaluated lesions). Tumor infiltrating lymphocyte (TIL) density higher TP53 mutations (p=0.0079) compared wildtype lesions, not withPIK3CAmutations (p=0.44). Immune infiltrates negatively associated status positively expression. High levels CD3+CD8- T good outcomes respect any cancer), whereas CD3+Foxp3+ Treg poor outcomes. Spatial proximity demonstrated close well recurrences. Interestingly, we found myoepithelial continuity (distance surrounding involved ducts) significantly lower normal tissue (p=0.0002) atypical hyperplasia (p=0.011). set enrichment several pathways low score better outcomes, suggesting gaps layer may allow access/interactions cells. Our demonstrates DCIS, particular cells, are important determinants disease.

Language: Английский

Citations

0
Clinical proteomics reveals vulnerabilities in non-invasive breast ductal carcinoma and drives personalized treatment strategies DOI Creative Commons
Georgia Mitsa, Livia Florianova,

Josiane Lafleur

et al.

Cancer Research Communications, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 26, 2024

Abstract Ductal carcinoma in situ (DCIS) is the most common type (80%) of non-invasive breast lesions women. The lack validated prognostic markers, limited patient numbers, and variable tissue quality have a significant impact on diagnosis, risk stratification, enrolment, results clinical studies. Here, we performed label-free quantitative proteomics 50 formalin-fixed, paraffin embedded biopsies, validating 22 putative biomarkers from independent genetic Our comprehensive proteomic phenotyping reveals more than 380 differentially expressed proteins metabolic vulnerabilities, that can inform new therapeutic strategies for DCIS invasive ductal (IDC). Due to readily druggable nature enzymes or metabolism inhibitors, this study high interest research pharmaceutical industry. To further evaluate our findings, promote translation study, developed highly multiplexed targeted assay 90 associated with cancer metabolism, RNA regulation signature pathways, such as PI3K/AKT/mTOR EGFR/RAS/RAF.

Language: Английский

Citations

0