bims-ovdlit 2024-11-03 papers

Issue of 2024–11–03
three papers selected by
Lara Paracchini, Humanitas Research

bioRxiv. 2024 Oct 21. pii: 2024.10.17.618945. [Epub ahead of print]

Deletions Rate-Limit Breast and Ovarian Cancer Initiation.

Kathleen E Houlahan, Mahad Bihie, Julián Grandvallet Contreras, Daniel J Fulop, Gonzalo Lopez, Hsin-Hsiung Huang, Peter Van Loo, Christina Curtis, Paul C Boutros, Kuan-Lin Huang.

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.

DOI: https://doi.org/10.1101/2024.10.17.618945

Nature. 2024 Oct;634(8036): 1062-1063

Thirty years since the race to the BRCA1 gene.

Alan Ashworth.

Keywords: Cancer; Genetics; History

DOI: https://doi.org/10.1038/d41586-024-03358-6

Nat Rev Cancer. 2024 Oct 28.

The present and future of the Cancer Dependency Map.

Rand Arafeh, Tsukasa Shibue, Joshua M Dempster, William C Hahn, Francisca Vazquez.

Despite tremendous progress in the past decade, the complex and heterogeneous nature of cancer complicates efforts to identify new therapies and therapeutic combinations that achieve durable responses in most patients. Further advances in cancer therapy will rely, in part, on the development of targeted therapeutics matched with the genetic and molecular characteristics of cancer. The Cancer Dependency Map (DepMap) is a large-scale data repository and research platform, aiming to systematically reveal the landscape of cancer vulnerabilities in thousands of genetically and molecularly annotated cancer models. DepMap is used routinely by cancer researchers and translational scientists and has facilitated the identification of several novel and selective therapeutic strategies for multiple cancer types that are being tested in the clinic. However, it is also clear that the current version of DepMap is not yet comprehensive. In this Perspective, we review (1) the impact and current uses of DepMap, (2) the opportunities to enhance DepMap to overcome its current limitations, and (3) the ongoing efforts to further improve and expand DepMap.

DOI: https://doi.org/10.1038/s41568-024-00763-x