In situ functional cell phenotyping reveals microdomain networks in colorectal cancer recurrence

Cell Reports Methods, Journal Year: 2021, Volume and Issue: 1(5), P. 100072 - 100072

Published: Sept. 1, 2021

Tumors are dynamic ecosystems comprising localized niches (microdomains), possessing distinct compositions and spatial configurations of cancer non-cancer cell populations. Microdomain-specific network signaling coevolves with a continuum states functional plasticity associated disease progression therapeutic responses. We present LEAPH, an unsupervised machine learning algorithm for identifying phenotypes, which applies recursive steps probabilistic clustering regularization to derive phenotypes (FPs) along continuum. Combining LEAPH pointwise mutual information biology analyses enables the discovery outcome-associated microdomains visualized as heterogeneous FPs. Utilization immunofluorescence-based (51 biomarkers) image dataset colorectal carcinoma primary tumors (n = 213) revealed microdomain-specific dysregulation supporting stem maintenance immunosuppression that selectively recurrence phenotype. explainable artificial intelligence platform providing insights into pathophysiological mechanisms novel drug targets inform personalized strategies.

Language: Английский

---

Accurate genome-wide germline profiling from decade-old archival tissue DNA reveals the contribution of common variants to precancer disease outcome

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: April 5, 2022

Abstract Background Inherited variants have been shown to contribute cancer risk, disease progression, and response treatment. Such studies are, however, arduous conduct, requiring large sample sizes, cohorts or families, more importantly, a long follow-up measure relevant outcome such as onset progression. Unless collected for dedicated study, germline DNA from blood saliva are typically not available retrospectively, in contrast surgical tissue specimens which systematically archived. Results We evaluated the feasibility of using extracted low amounts fixed-formalin paraffin-embedded (FFPE) tumor obtain accurate genetic profiles. Using matching archival 10 individuals, we benchmarked low-coverage whole-genome sequencing (lc-WGS) combined with genotype imputation measured genome-wide concordance genotypes, polygenic risk scores (PRS), HLA haplotypes. Concordance between was high (r 2 >0.94) common single nucleotide polymorphisms (SNPs) across 22 disease-related PRS (mean r=0.93). haplotypes imputed were 96.7% (Class I genes) 82.5% II concordant deep targeted DNA. validated methodology, estimated breast 36 patients diagnosed ductal carcinoma situ (11.7 years median time) including who subsequent event (BSCE). significantly associated BCSE (HR=2.5, 95%CI: 1.4–4.5) top decile modeled 24% chance at years, hence suggesting addition could improve prognostic models currently inadequate. Conclusions The abundance broad availability oncology clinics, paired effectiveness profiling lc-WGS imputation, represents an alternative cost resource-effective design long-term progression studies.

Language: Английский

---

Integrated Molecular Characterization of Intraductal Papillary Mucinous Neoplasms: An NCI Cancer Moonshot Precancer Atlas Pilot Project

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Oct. 18, 2022

Abstract Intraductal papillary mucinous neoplasms (IPMNs) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low grade (LG) high (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN have been analyzed using multi-region sequencing for somatic mutations, there is no integrated assessment molecular events, including copy number alterations (CNAs) and transcriptomics changes, that accompany progression. We performed laser capture microdissection on surgically resected varying grades histological dysplasia obtained 24 patients (total 74 independent lesions), followed by whole exome transcriptome sequencing. Overall, HG displayed a significantly greater aneuploidy score than LG lesions, with chromosome 1q amplification, particular, being associated cases harbored cooccurring PDAC. Furthermore, the combined single nucleotide variants (SNVs) CNAs identified both linear branched evolutionary trajectories, underscoring heterogeneity At level, upregulation MYC-regulated targets downregulation transcripts MHC class I antigen presentation machinery was common feature HG. Taken together, this work emphasizes role amplification as putative biomarker high-risk IPMNs, underscores importance immune evasion even non-invasive supports previously underappreciated CNA-driven branching evolution an avenue Our study provides important context risk stratification cancer interception opportunities IPMNs. Significance Integrated analysis genomic transcriptomic intraductal (IPMNs), which bona fide precursors cancer, identifies features low-risk might enable patient strategies.

Language: Английский

---

Active Surveillance for Atypical Ductal Hyperplasia and Ductal Carcinoma In Situ

Journal of Breast Imaging, Journal Year: 2023, Volume and Issue: 5(4), P. 396 - 415

Published: May 18, 2023

Abstract Atypical ductal hyperplasia (ADH) and carcinoma in situ (DCIS) are relatively common breast lesions on the same spectrum of disease. hyperblasia is a nonmalignant, high-risk lesion, DCIS noninvasive malignancy. While benefit screening mammography early cancer detection, it also leads to increased biopsy diagnosis lesions. Previously, treatment guidelines for both entities included surgical excision because risk upgrade invasive after surgery progression DCIS. However, this universal management approach not optimal all patients most upgraded surgery. Furthermore, some do progress clinically significant cancer. Overtreatment considered burden clinicians strain health care system. Extensive research has identified many potential histologic, clinical, imaging factors that may predict ADH thereby help select which should undergo be appropriate active surveillance (AS) with imaging. Additionally, multiple clinical trials currently underway evaluate whether AS feasible group patients. Recent advances MRI, artificial intelligence, molecular markers have an important role play stratifying delineating best guidelines. This review article discusses available evidence regarding feasibility limitations DCIS, as well recent patient stratification.

Language: Английский

---

Clinical proteomics reveals vulnerabilities in non-invasive breast ductal carcinoma and drives personalized treatment strategies

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

---