At a glance:
The findings suggest the dominant “two-hit” hypothesis of cancer development may not tell the full story behind how cancer arises.
Study identifies cellular changes that prime cancer-related genes for action and render cells vulnerable to tumor growth.
The findings can inform new treatments that block the priming effect to prevent breast cancer formation.
People inherit two copies of each gene — one from each parent — an evolutionary fail-safe to ensure survival even when one of them doesn’t function.
For cancer-suppressor genes like BRCA1, researchers have long hypothesized that a single healthy copy could still guard against tumor development. Yet women with one harmful BRCA1 mutation are far more likely to develop breast cancer — a risk traditionally explained by a second mutation that arises later in life, damages the healthy copy of the gene, and triggers disease.
But does this two-hit model tell the whole story?
Likely not, according to the findings of a new study led by scientists at Harvard Medical School.
The research, published Nov. 11 in Nature Genetics, shows that even in the absence of a second mutational hit, a single faulty copy of BRCA1 renders breast cells more vulnerable to cancer and is sufficient to ignite tumor growth.
Authorship, funding, disclosures
Additional authors included Alyssa Cordes, Michael U J Oliphant, Mayura Thomas, Laura M. Selfors, Francesca Silvestri, Nomeda Girnius, Gianmarco Rinaldi, Jason J. Zoeller, Hana Shapiro, Christina Tsiobikas, Kushali P. Gupta, all of Harvard Medical School; S. Aidan Quinn, and Cigall Kadoch, Dana-Farber Cancer Institute and Broad Institute; Shailja Pathania, University of Massachusetts; Aviv Regev, Broad Institute and Genentech; and Senthil K. Muthuswamy, Center for Cancer Research at the National Cancer Institute.
This work was supported in part by a Gray Foundation gift, a Susan G. Komen Postdoctoral Fellowship, a Croucher Postdoctoral Fellowship, a Goldberg Family Research Fund gift, a Komen Scholar Award SAC180002, and a National Cancer Institute grant R35 CA242428.
Regev is a co-founder of and equity holder in Celsius Therapeutics, an equity holder in Immunitas. She was a Scientific Advisory Board member of Thermo Fisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics, and Asimov until July 31, 2020. Regev has been an employee of Genentech since August 2020 and has equity in Roche.