Biology subjects

Bihie, M.

Publications and source records attributed to Bihie, M..

3 recordsLinked to original sources

bioRxiv2026

Tissue-Specific Prevalence and Clonal Architecture of BRCA1/2 LOH-Inducing Chromosomal Aneuploidy

Germline pathogenic variants in BRCA1 and BRCA2 confer disproportionately elevated cancer risks in breast and ovarian tissues, yet the basis for this tissue specificity remains incompletely understood. Here, we integrate bulk-tumor aneuploidy analysis across 340,824 cancer cases from three independent cohorts (TCGA, ICGC PCAWG, and FoundationCore) with single-cell whole-genome sequencing from two independent studies to investigate whether tissue-specific patterns of chromosomal deletion contribute to this phenomenon. We find that breast and ovarian cancers are consistently enriched for deletions of chromosome arms 17q and 13q--harboring the BRCA1 and BRCA2 genes, respectively--relative to other solid tumor types, and that mutational timing analysis independently places these deletions among the earliest somatic events in these cancers. Phylogenetic reconstruction of single-cell data reveals that in pre-malignant breast tissue from germline BRCA1/2 carriers, chr17q and chr13q deletions appear as localized subclonal events within small clades against a largely diploid background. In established malignancies, these same deletions are found within dominant clonal lineages accompanied by widespread genomic instability--consistent with clonal sweeps originating from early deletion events. These findings suggest that breast and ovarian cellular environments confer a selective advantage for chr17q and chr13q deletions, providing a mechanism that may contribute to the tissue-specific cancer risk observed in gBRCA1/2 carriers.

cancer biology↗

bioRxiv2025

Widespread Epistasis between Cancer Driver Mutations and Allele-Specific Copy Number Variations

Cancer driver mutations alone are often insufficient to fully explain tumorigenesis. We demonstrate that these mutations cooperate with somatic copy number variations (CNVs) in a tissue-specific pattern of genomic epistasis. Analyzing 93,462 tumors, we identified 54 gene-cancer type pairs with significant co-occurrence of somatic mutations and CNVs. Our new Binoculars algorithm, which resolved phased DNA/RNA reads, revealed frequent preferential amplification in oncogenic mutation alleles, including AKT1 p.E17K, BRAF p.V600E, KRAS p.G12C/D/V, NRAS p.Q61K, and a fraction of gain-of-function TP53 p.R175H. Conversely, deletions selectively targeted the reference alleles, leading to loss of heterozygosity of IDH1 p.R132H and tumor suppressor mutations, including CDKN2A and TP53 truncations. Lung cancer patients carrying co-occurrences of somatic mutation-CNVs in TP53 and KRAS showed poorer survival than those carrying the same gene mutations. These findings reveal epistasis of cancer mutations and CNVs at an allelic resolution, suggesting specific genomic events to enhance patient stratification and therapeutic targeting.

genomics↗

bioRxiv2024

Deletions Rate-Limit Breast and Ovarian Cancer Initiation

Optimizing prevention and early detection of cancer requires understanding the number, types and timing of driver mutations. To quantify this, we exploited the elevated cancer incidence and mutation rates in germline BRCA1 and BRCA2 (gBRCA1/2) carriers. Using novel statistical models, we identify genomic deletions as the likely rate-limiting mutational processes, with 1-3 deletions required to initiate breast and ovarian tumors. gBRCA1/2-driven hereditary and sporadic tumors undergo convergent evolution to develop a similar set of driver deletions, and deletions explain the elevated cancer risk of gBRCA1/2-carriers. Orthogonal mutation timing analysis identifies deletions of chromosome 17 and 13q as early, recurrent events. Single-cell analyses confirmed deletion rate differences in gBRCA1/2 vs. non-carrier tumors as well as cells engineered to harbor gBRCA1/2. The centrality of deletion-associated chromosomal instability to tumorigenesis shapes interpretation of the somatic evolution of non-malignant tissue and guides strategies for precision prevention and early detection.

cancer biology↗