Individuals with germline BRCA1/2 mutations face a significantly increased risk of breast cancer and other cancers. Advances in the understanding of genetic and epigenetic regulation are revealing novel pathways in tumorigenesis, pointing the way toward new biomarkers and therapeutic targets.

During the 2025 San Antonio Breast Cancer Symposium^®, Joan Brugge, PhD, will deliver the plenary lecture Genetic and Epigenetic Determinants of BRCA1/2 Tumorigenesis on Friday, December 12, from 8:30 to 9:00 a.m. CT in Hall 1 of the Henry B. Gonzalez Convention Center. Dr. Brugge, Louise Foote Pfeiffer Professor of Cell Biology and Director of the Ludwig Center at Harvard Medical School, will review findings that provide new insights into the role of chromosomal alterations in breast cancer development.

“We know from multiple studies that cancer is initiated in a single cell by a genetic alteration,” Dr. Brugge said. “We found that essentially every breast, in individuals with or without a germline BRCA1/2 mutation, contains small populations of cells that harbor some of the same genomic changes frequently observed in breast cancer. The most common changes are gain of chromosome 1q and deletion of the q arm of chromosome 16. We also see losses at chromosomes 22q, 7q, and 10q.”

These new insights suggest that the classic two-hit hypothesis of BRCA1/2-related cancer development may be incomplete, she said. The two-hit hypothesis posits that, in individuals with a germline mutation in one BRCA allele, loss of the other BRCA allele jumpstarts cancer development.

“Most of us believed the first step was the loss of the normal BRCA allele, leaving two defective copies,” Dr. Brugge explained. “Our data clearly show that other chromosomal gains and losses precede loss of the wild-type BRCA copy. Cells that have lost the wild-type BRCA1 or BRCA2 allele invariably demonstrate either chromosome 1q gain, 16q loss, or both. We believe these alterations prime cells to survive the complete loss of BRCA function.”

“Findings from other labs that I will discuss suggest that selection for chromosome 1q gain is essential for BRCA1/2-mutant tumors to progress,” Dr. Brugge said. “It increasingly appears that these chromosomal changes are the precursors of many, possibly all, BRCA1/2-driven, and even many non-BRCA1/2-driven, breast cancers.”

Only about 5 in every 1,000 breast cells harbor these chromosomal alterations, she said. Ongoing work in Dr. Brugge’s lab is focused on identifying surface markers for these aberrant cells, which may serve as targets for future therapeutic strategies.

These investigations also highlight the role of epigenetic changes in tumor development. In mouse models, sequencing of chromatin-accessible DNA has revealed distinct gene regions that are open or closed for transcription in mammary epithelial cells harboring heterozygous Brca1 mutations, profiles that partially mirror the gene expression programs of tumor cells.

“These regions of open chromatin are not actively producing RNA but are primed, making them more permissive to activation of oncogenic pathways,” Dr. Brugge said. “We are now searching for similar epigenetic changes in human breast tissues. Defining the cellular programs that accelerate tumorigenesis could yield promising prevention strategies — or at least approaches to delay cancer onset. While translating these findings to the clinic remains a challenge, for the first time we have a platform to build upon.”