Reconsidered: breast cancer origins and risk factors

New research challenges the dogma that mutations arising during our lifetimes are the primary factors influencing whether we get cancer. They matter, but a wide variety of gene sequences we’re born with may play a more decisive role than realized.

“This study unearthed a new class of biomarkers to forecast tumor progression and an entirely new way of understanding breast cancer origins,” said Christina Curtis, PhD, the RZ Cao Professor and a professor of genetics and of biomedical data science. Curtis and postdoctoral scholar Kathleen Houlahan, PhD, described the research in May in Science.

Curtis has been interested in how cancers start since she was in high school, having lost family members to the disease. More recently, her parents were diagnosed with different cancers within one month of one another, when Curtis was juggling her work identifying the molecular basis of malignancy and metastasis with parenting her young children. Her father recovered. Her mother did not.

“The whole experience impressed on me a renewed need to intercept earlier,” Curtis said. “It’s not enough to optimize therapy once a tumor has already spread. We have the tools to do more earlier.”

Only a few high-profile cancer-associated mutations in genes like BRCA1 and BRCA2 are regularly used to predict cancer risk. These mutations have been associated with distinct subtypes of disease. The new findings suggest there are tens or maybe even hundreds of other gene variants that influence breast cancer development and progression.

The researchers looked at the relationship between oncogenes — normal genes that, when mutated, can free a cell from functioning normally — and an immune system intent on destroying developing cancers.

Their study zeroed in on small chunks of internal proteins that even healthy cells routinely display on their outer membranes — an outward display that reflects their inner style. Like fashion police, immune cells called T cells prowl the body and peruse these protein chunks (called epitopes), looking for any suspicious or overly flashy bling that might signal something amiss inside the cell.

Curtis and Houlahan wondered whether highly recognizable epitopes would be more likely to attract the attention of T cells than other, more modest, offerings (think golf-ball-sized, dangly turquoise earrings versus a simple stud).

If so, a cell that inherited an oncogene producing a particularly flashy epitope might be less able to pull off its amplification — a cancer-associated mutation in which a cell ends up with multiple copies of an oncogene — without alerting the immune system. In other words, one pair of oversized turquoise earrings can be excused; five pairs might cause a patrolling fashionista T cell to switch from tutting to terminating.

The researchers studied nearly 6,000 breast tumors and found that people who inherited an oncogene that produced an immunologically gaudy epitope — and displayed it prominently — were significantly less likely to develop breast cancer subtypes in which that oncogene is amplified. But if they did manage to escape the roving immune cells early in their development, they tended to be more aggressive and have a poorer prognosis than their more subdued peers.

“Our findings not only explain which subtype of breast cancer an individual is likely to develop,” Houlahan said, “but they also hint at how aggressive and prone to metastasizing that subtype will be.”

The researchers envision a future in which the inherited genome is used to better tailor treatments to individual patients, including factoring in the risk of developing an invasive breast cancer. Such information, which can be obtained from a routine blood sample, can also be combined with other molecular features.

“We’re examining other cancers through this new lens by integrating hereditary factors, immunity and acquired alterations to better forecast disease,” Curtis said.

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