Journal article
Multimodal genome-wide survey of progressing and non-progressing breast ductal carcinoma in-situ
Breast cancer research : BCR, Vol.26(1), pp.1-15
12/04/2024
DOI: 10.1186/s13058-024-01927-1
PMCID: PMC11616160
PMID: 39633428
Abstract
Background
Ductal carcinoma in-situ (DCIS) is a pre-invasive form of invasive breast cancer (IBC). Due to improved breast cancer screening, it now accounts for ~ 25% of all breast cancers. While the treatment success rates are over 90%, this comes at the cost of considerable morbidity, considering that the majority of DCIS never become invasive and our understanding of the molecular changes occurring in DCIS that predispose to invasive disease is limited. The aim of this study is to characterize molecular changes that occur in DCIS, with the goal of improving DCIS risk stratification.
Methods
We identified and obtained a total of 197 breast tissue samples from 5 institutions (93 DCIS progressors, 93 DCIS non-progressors, and 11 adjacent normal breast tissues) that had at least 10-year follow-up. We isolated DNA and RNA from archival tissue blocks and characterized genome-wide mRNA expression, DNA methylation, DNA copy number variation, and RNA splicing variation.
Results
We obtained all four genomic data sets in 122 of the 197 samples. Our intrinsic expression subtype-stratified analyses identified multiple molecular differences both between DCIS subtypes and between DCIS and IBC. While there was heterogeneity in molecular signatures and outcomes within intrinsic subtypes, several gene sets that differed significantly between progressing and non-progressing DCIS were identified by Gene Set Enrichment Analysis.
Conclusion
DCIS is a molecularly highly heterogenous disease with variable outcomes, and the molecular events determining DCIS disease progression remain poorly defined. Our genome-wide multi-omic survey documents DCIS-associated alterations and reveals molecular heterogeneity within the intrinsic DCIS subtypes. Further studies investigating intrinsic subtype-stratified characteristics and molecular signatures are needed to determine if these may be exploitable for risk assessment and mitigation of DCIS progression. The highly significant associations of specific gene sets with IBC progression revealed by our Gene Set Enrichment Analysis may lend themselves to the development of a prognostic molecular score, to be validated on independent DCIS cohorts.
Details
- Title: Subtitle
- Multimodal genome-wide survey of progressing and non-progressing breast ductal carcinoma in-situ
- Creators
- Marija Debeljak - Johns Hopkins UniversitySoonweng Cho - Johns Hopkins MedicineBradley M. Downs - Johns Hopkins UniversityMichael Considine - Johns Hopkins MedicineBrittany Avin-McKelvey - Johns Hopkins MedicineYongchun Wang - Johns Hopkins MedicinePhillip N. PerezWilliam E. Grizzle - University of Alabama at BirminghamKatherine A. Hoadley - University of North Carolina at Chapel HillCharles F. Lynch - University of IowaBrenda Y. Hernandez - University of Hawaii SystemPaul J. van Diest - University Medical Center UtrechtWendy CozenAnn S. Hamilton - University of Southern CaliforniaDebra Hawes - Children's Hospital of Los AngelesEdward Gabrielson - Johns Hopkins MedicineAshley Cimino-Mathews - Johns Hopkins MedicineLiliana D. Florea - Johns Hopkins UniversityLeslie Cope - Johns Hopkins MedicineChristopher B. Umbricht - Johns Hopkins Medicine
- Resource Type
- Journal article
- Publication Details
- Breast cancer research : BCR, Vol.26(1), pp.1-15
- Publisher
- BioMed Central
- DOI
- 10.1186/s13058-024-01927-1
- PMID
- 39633428
- PMCID
- PMC11616160
- ISSN
- 1465-5411
- eISSN
- 1465-542X
- Grant note
- National Cancer Institute
We thank Dr. Jean Wright for helpful discussions. We acknowledge Freda Salk, D. Oelschlager, and D. Trusty for technical assistance.
- Language
- English
- Date published
- 12/04/2024
- Academic Unit
- Epidemiology
- Record Identifier
- 9984757064102771
Metrics
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