BRCA

In one line: BRCA1 and BRCA2 are not "cancer genes" but the body's DNA-repair caretakers — and their story runs from Mary-Claire King proving breast cancer can be inherited, through a four-year race to clone them, to a company that patented the genes themselves, to the Supreme Court ruling that you cannot own a piece of nature.

---

The genes

BRCA1 sits on chromosome 17 (band 17q21.31); BRCA2 sits on chromosome 13 (band 13q13.1). The names are short for BReast CAncer 1 and 2, but the label misleads: in a healthy body these are tumor suppressors — caretakers whose job is to repair broken DNA and keep a cell from turning cancerous. Everyone carries them. The danger isn't having a BRCA gene; it's inheriting a copy that doesn't work.

The hunt — and the race

For most of the twentieth century, breast cancer was widely treated as bad luck — environment, not heredity. In 1990, geneticist Mary-Claire King (then at Berkeley) ended that argument: by tracing large families and using linkage analysis, she mapped early-onset familial breast cancer to a region of chromosome 17q21 and named the locus BRCA1. Crucially, she had found where the gene lived — not yet the gene itself.

Locating a gene's neighborhood is not the same as holding the gene, and what followed was a four-year international race to clone it. In 1994, a team led by Mark Skolnick at a young company, Myriad Genetics (with academic collaborators), crossed the line first, reporting the actual sequence of BRCA1 in Science (Miki et al.). One gene didn't explain every family, though: a year later, in 1995, a British team led by Michael Stratton at the Institute of Cancer Research identified the second gene, BRCA2, on chromosome 13 (Wooster et al., Nature) — and published its sequence in the open.

The mechanism

Why is a broken repair gene so dangerous? Every day, the double helix of your DNA suffers double-strand breaks. BRCA1 and BRCA2 run the cell's most precise repair pathway, homologous recombination: BRCA2 loads the recombinase RAD51 onto the resected broken ends, which then copies the matching, undamaged sister strand to mend the break exactly — error-free. Lose that crew, and the cell must fall back on sloppier repair, and mutations accumulate.

This is also why the risk runs in families (the Knudson two-hit model). You inherit two copies of each gene. A carrier is born with one copy already faulty; the second, working copy still does the job — until a single breast or ovary cell happens to lose that second copy too. With no working repair left, that cell's genome destabilizes, and a tumor can grow.

The patent — and the courtroom

Here the science collided with the law. Myriad didn't just patent its test — it held patents on the isolated genes themselves. With BRCA2, the move was sharper: Stratton's team had already published the sequence openly, and Myriad raced to file its own patent on it anyway (while the UK's Cancer Research Campaign secured the UK patent and kept access open in Europe).

Those patents made Myriad the only place in the United States you could be tested for a BRCA mutation. The BRACAnalysis test ran around $3,000, and because no other lab was permitted to look, there was no way to get a second opinion on the sequence of your own DNA. The ACLU and the Public Patent Foundation sued. In June 2013, in Association for Molecular Pathology v. Myriad Genetics, the Supreme Court ruled 9–0 that a naturally occurring, isolated DNA sequence is a product of nature and cannot be patented (synthetic cDNA, being man-made, can be). Within hours, rival labs announced their own BRCA tests, and prices fell.

The stakes — and the testing era

Today a BRCA test is routine, and it carries real weight. The largest prospective study (Kuchenbaecker et al., JAMA 2017) put a BRCA1 carrier's cumulative breast-cancer risk to age 80 at about 72% (BRCA2 ~69%), with ovarian-cancer risk near 44% (BRCA1) and 17% (BRCA2). In May 2013, the actress Angelina Jolie revealed in a New York Times op-ed that she carried a BRCA1 mutation and had chosen a preventive double mastectomy — triggering the measurable, lasting "Angelina Jolie effect" of increased testing and awareness. Knowing early turns a hidden risk into a set of choices: enhanced screening, risk-reducing surgery, time.

The frontier

The most elegant twist is therapeutic. A BRCA-mutant cancer cell has already lost one DNA-repair route, so it leans heavily on a backup enzyme, PARP. Block PARP with a drug and a healthy cell shrugs (its BRCA crew still works), but the BRCA-mutant cancer cell — now with no repair route left — dies. This synthetic lethality turns the tumor's own defect into its weakness. The first PARP inhibitor, olaparib (Lynparza), was FDA-approved in December 2014 for BRCA-mutated advanced ovarian cancer. The very flaw that causes the cancer is now how we attack it.

Sources

Full claim-by-claim evidence is in references.md. Primary anchors:

• Hall, King et al. (1990) — Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689. (BRCA1 located)
• Miki et al. (1994) — A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71. (BRCA1 cloned, Myriad/Skolnick)
• Wooster et al. (1995) — Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792. (BRCA2, ICR/Stratton)
• Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013) — the unanimous gene-patent ruling.
• Kuchenbaecker et al. (2017) — Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317, 2402–2416.
• FDA / AstraZeneca (Dec 2014) — olaparib (Lynparza) approval; synthetic lethality (Farmer et al., Bryant et al., Nature 2005).

Accuracy note: The episode carefully separates two contributions that are often blurred: Mary-Claire King (1990) located and named BRCA1 by linkage; she did not clone it — Myriad/Skolnick (1994) won the race to sequence it. On the patent, the holding is precise: naturally occurring isolated DNA is not patentable, but cDNA is. Risk figures are stated qualitatively in narration ("up to ~70%"); exact cohort estimates (72%/69% breast; 44%/17% ovarian) are recorded here and in references.md.