Abstract
Background: The majority of low- and moderate-risk [odds ratios (OR) ≤ 3] susceptibility genes for peri- and post-menopausal breast cancer (≥50 years of age), particularly those with minor allele frequency (MAF) of <30%, have not yet been identified and/or validated. We used a hypothesis-driven integrative approach to identify breast cancer susceptibility genes by analyzing pedigree and multi-omics (genomics, transcriptomics, mutation landscape) data. Methods: We conducted pedigree analysis in 31 families with DNA repair disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD), Cockayne syndrome (CS), XP/TTD and XP/CS. These disorders can be caused by mutations in genes involved in the nucleotide excision repair (NER) pathway such as XPA-XPG, ERCC6 and ERCC8. We estimated the frequency of hereditary breast cancer, defined as the presence of at least two cases of premenopausal breast cancer (diagnosed <50 years of age) or one case of premenopausal breast cancer and one case of ovarian cancer in one side of the family, in our study. Furthermore, we conducted individual analysis of four genome-wide association studies (GWAS) datasets (totaling 2961 cases and 4335 controls), individual and meta-analysis of two gene expression microarray datasets (98 cases and 163 controls), and targeted analysis of The Cancer Genome Atlas (TCGA) (522 breast cancers). All analyses involved invasive ductal breast carcinoma in women diagnosed at ≥50 years of age. Results: In an XP family with causative mutations in XPA, there were four cases of premenopausal breast cancer (including heterozygote mutation carriers), one case of ovarian cancer, and one case of prostate cancer. Comprehensive sequencing failed to identify a BRCA1 or BRCA2 mutation in this family. Overall, 7 of 31 (22.6%) families with DNA repair disorders had a family history that was compatible with hereditary breast cancer. Hence, we selected a panel of NER genes as candidates for association studies with breast cancer. Our candidate-gene association analysis of GWAS datasets suggested an increased risk of breast cancer with ERCC6 (main effect:1.29 ≤ OR ≤ 2.91, 0.005 ≤ p ≤ 0.04, 11.8 ≤ MAF ≤ 29.7%) and implicated its interaction with ERCC8 (joint effect:3.03 ≤ OR ≤ 5.31, 0.01 ≤ pinteraction ≤ 0.03). Our transcriptomics analysis identified significant upregulation of ERCC6 (p=7.95 × 10–6) and ERCC8 (p=4.67 × 10–6) in breast cancer. Our analysis of TCGA breast tumor data showed similar mutation frequency of ERCC6 (1.8%) and ERCC8 (0.3%) as known breast cancer susceptibility genes such as BLM (1.9%) and LSP1 (0.3%). Conclusion: Our integrative analyses suggest that ERCC6 may be a previously unreported low- to moderate-risk breast cancer susceptibility gene, which may also interact with ERCC8. ERCC6 and ERCC8 code for the main components of the transcription-coupled (TC) repair sub-pathway of the NER. TC-NER protects against genotoxic agents, such as free radicals and reactive oxygen species. Our results provide a deeper biologic insight and leads for prevention of common breast cancer.
Citation Format: Roxana Moslehi, Amiran Dzutsev. Pedigree and multi-omics analyses implicate nucleotide excision repair genes, XPA, ERCC6, and ERCC8, in susceptibility to breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B012.
Need a simple solution for managing your BibTeX entries? Explore CiteDrive!
- Web-based, modern reference management
- Collaborate and share with fellow researchers
- Integration with Overleaf
- Comprehensive BibTeX/BibLaTeX support
- Save articles and websites directly from your browser
- Search for new articles from a database of tens of millions of references
Try out CiteDrive More from our Archive
-
DOI: 10.1158/1940-6207.capr-23-0359 2024
Acceptability of Personalized Lung Cancer Screening Program Among Primary Care Providers
Paul J. Resong, Jiangong Niu, Gabrielle F. Duhon, Lewis E. Foxhall, Sanjay Shete, Robert J. Volk, Iakovos Toumazis
-
DOI: 10.1146/annurev-cancerbio-061421-014236 2024
Next-Generation Therapies for Multiple Myeloma
Erin W. Meermeier, P. Leif Bergsagel, Marta Chesi
-
DOI: 10.1146/annurev-cancerbio-062822-110356 2024
Therapeutic Discovery for Chromatin Complexes: Where Do We Stand?
Dominic D.G. Owens, Matthew E.R. Maitland, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy
-
DOI: 10.1146/annurev-cancerbio-062722-012209 2024
Small-Molecule Approaches to Target Transcription Factors
Huarui Cui, Morgan Stilgenbauer, Angela N. Koehler
-
DOI: 10.1200/jco.23.01796 2024
Improved Cardiomyopathy Risk Prediction Using Global Longitudinal Strain and N-Terminal-Pro-B-Type Natriuretic Peptide in Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy
Matthew J. Ehrhardt, Qi Liu, Daniel A. Mulrooney, Isaac B. Rhea, Stephanie B. Dixon, John T. Lucas, Yadav Sapkota, Kyla Shelton, Kirsten K. Ness, Deo Kumar Srivastava, Aaron McDonald, Leslie L. Robison, Melissa M. Hudson, Yutaka Yasui, Gregory T. Armstrong
-
DOI: 10.1200/po.23.00257 2024
Use of Neoadjuvant Vandetanib in Aggressive Pediatric Medullary Thyroid Carcinoma
Ronik Kothari, Sara Kreimer, Helen Nadel, Hilary Seeley, Gary Hartman, Kara D. Meister
-
DOI: 10.1200/po.23.00296 2024
Validity and Efficiency of Progression-Free Survival-2 as a Surrogate End Point for Overall Survival in Advanced Cancer Randomized Trials
Rachel Woodford, Deborah Zhou, Peey-Sei Kok, Sally J. Lord, Michael Friedlander, Ian Marschner, R. John Simes, Chee Khoon Lee
-
DOI: 10.1200/po.23.00333 2024
Somatic Versus Germline: A Case Series of Three Children With <i>ATM</i>-Mutated Medulloblastoma
Lydia T. Tam, Bonnie Cole, Shannon M. Stasi, Vera A. Paulson, Jason N. Wright, Corrine Hoeppner, Susan Holtzclaw, Erin E. Crotty, Richard G. Ellenbogen, Amy Lee, Ralph P. Ermoian, Christina M. Lockwood, Sarah E.S. Leary, Rebecca Ronsley
-
DOI: 10.1200/po.23.00117 2024
Precision Medicine for Childhood Cancer: Current Limitations and Future Perspectives
Martin G. McCabe, Birgit Geoerger, Louis Chesler, Darren Hargrave, D. Williams Parsons, Cornelis M. van Tilburg, Gudrun Schleiermacher, John A. Hickman, Sally L. George
-
DOI: 10.1200/po.23.00196 2024
Modifiable Risk Factors and Risk of Colorectal and Endometrial Cancers in Lynch Syndrome: A Systematic Review and Meta-Analysis
Robert F. Power, Damien E. Doherty, Imelda Parker, David J. Gallagher, Maeve A. Lowery, Karen A. Cadoo