Multimodal genome-wide survey of progressing and non-progressing breast ductal carcinoma in-situ

Marija Debeljak; Soonweng Cho; Bradley M Downs; Michael Considine; Brittany Avin-McKelvey; Yongchun Wang; Phillip N Perez; William E Grizzle; Katherine A Hoadley; Charles F Lynch; Brenda Y Hernandez; Paul J van Diest; Wendy Cozen; Ann S Hamilton; Debra Hawes; Edward Gabrielson; Ashley Cimino-Mathews; Liliana D Florea; Leslie Cope; Christopher B Umbricht

doi:10.1186/s13058-024-01927-1

Multimodal genome-wide survey of progressing and non-progressing breast ductal carcinoma in-situ

Breast Cancer Res. 2024 Dec 4;26(1):178. doi: 10.1186/s13058-024-01927-1.

Authors

Marija Debeljak¹, Soonweng Cho¹, Bradley M Downs², Michael Considine³, Brittany Avin-McKelvey¹, Yongchun Wang¹, Phillip N Perez¹, William E Grizzle⁴, Katherine A Hoadley⁵, Charles F Lynch⁶, Brenda Y Hernandez⁷, Paul J van Diest⁸, Wendy Cozen⁹, Ann S Hamilton¹⁰, Debra Hawes¹¹, Edward Gabrielson¹², Ashley Cimino-Mathews¹², Liliana D Florea¹³, Leslie Cope^{3

14}, Christopher B Umbricht^{15

16

17

18}

Affiliations

¹ Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD, USA.
³ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
⁵ Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA, USA.
⁷ Population Sciences in the Pacific-Program, University of Hawaii Cancer Research Center, Honolulu, HI, USA.
⁸ Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁹ Department of Medicine, School of Medicine, Susan and Henry Samueli College of Health Sciences, University of California at Irvine, Irvine, CA, USA.
¹⁰ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹¹ Department of Pathology and Laboratory Medicine, Keck School of Medicine, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA.
¹² Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Department of Biostatistics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁶ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁷ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁸ The Johns Hopkins University School of Medicine, Ross Building, Room 743, 720 Rutland Ave, Baltimore, MD, 21205, USA. [email protected].

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.

Keywords: Alternative splicing; DCIS progression; DNA copy number variation; Gene set enrichment analysis; Genome-wide survey; Methylome; Transcriptome.

MeSH terms

Adult
Aged
Biomarkers, Tumor / genetics
Breast Neoplasms* / genetics
Breast Neoplasms* / pathology
Carcinoma, Intraductal, Noninfiltrating* / genetics
Carcinoma, Intraductal, Noninfiltrating* / pathology
DNA Copy Number Variations
DNA Methylation
Disease Progression*
Female
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic
Genome-Wide Association Study
Humans
Middle Aged

Substances

Biomarkers, Tumor

Abstract

MeSH terms

Substances

Grants and funding