Insights Into Genetic ‘Hotspots’ Could Produce New Cancer Treatment Strategies

Many cancers contain similar genetic “hotspots” — areas of DNA that are likely to be mutated. For example, more than 50% of cancers contain a mutation in a gene called TP53, often within a narrow DNA range.

Researchers know that hotspots can contribute to cancer development and growth. The TP53 gene, for example, makes a protein that plays a critical role in removing cells with genetic mistakes that could lead to cancer. When TP53 is mutated, precancerous cells have less of a defense to stop them from growing uncontrollably.

Researchers have wondered why certain hotspots keep occurring across many different cancers. Mutations in specific spots seem to provide growth and survival advantages to cancer cells. But scientists have not understood what determines why hotspots occur in one DNA stretch over another in the same gene — or in some tumor-suppressing genes over others.

“Different explanations have been out there about why you see these same hotspots come up across different tumor types,” says Memorial Sloan Kettering Cancer Center (MSK) computational biologist Benjamin Greenbaum. “That’s always a good opportunity for computational or mathematical modeling to see if you can put all these pieces together in a consistent way.”

Now research by Dr. Greenbaum and MSK colleagues reveals that TP53 mutations advantageous to cancer growth also can make a cell more noticeable to the immune system, leaving it open to attack. The study sheds light on the relationship between these two forces, and how tension between them can create hotspots.

The insights they gained have implications for possibly making cancer therapies — especially immunotherapies — work better.

The study, reported in Nature on May 11, 2022, was led by Dr. Greenbaum and David Hoyos in the Greenbaum Lab, in collaboration with immunologists Jedd Wolchok and Taha Merghoub, and Roberta Zappasodi and Isabell Schultze in the Wolchok-Merghoub Laboratory. The group also included physician-scientist Vinod Balachandran and Zachary Sethna, a physicist in the Balachandran Lab.

Cancer Cells Trade Off Between Growth and Invisibility

Their findings modify previous thinking about hotspots, which assumed that avoiding immune attack was an independent factor in enabling cancer cells to survive and grow.

“We thought many hotspots would not be particularly visible to the immune system, but with this work, we are learning that might not be the case,” Dr. Greenbaum says. “The cancer cells have to make trade-offs between growth and invisibility. Sometimes, a feature that provides a strong fitness advantage [for growth] is what makes it easier for the immune system to see. These two features can be coupled together.”

The researchers focused on TP53 because it has been so thoroughly studied: Its various mutations have been clearly delineated. First the team looked at how different mutations are distributed across the gene. Then they developed a mathematical model to determine how a cancer cell’s survival depends on these competing factors: mutations that promote growth and mutations that “hide” from immune detection.

One important conclusion from their analysis is that invisibility isn’t everything. While some hotspots persist by avoiding immune detection, other hotspots promote cancer growth so strongly that it compensates for being visible to the immune system. As cells turn cancerous and make new copies, they retain these hotspots because the growth advantage they provide is too important to discard.

“It’s like an accelerator pressed to the floor, driving growth so strongly that it overpowers any brake put forth by the immune system,” Dr. Merghoub says.

The researchers also wondered whether TP53 hotspots are present before cells turn cancerous. They analyzed dozens of publications identifying mutations in precancerous tissue and found the same hotspots — but with an intriguing twist: The ranking of their frequency was altered. The cells had more “pro-growth” hotpots and fewer “invisibility” hotspots. This suggests that in the early stages of cancer development, hotspots that confer a growth advantage take priority over those that avoid immune detection.

“It might be that in the early stage, the cancer cells haven’t derived much of an advantage by avoiding immune detection,” Dr. Greenbaum says. “The pressure from the immune system comes in a bit later.”

Earlier Intervention With Immunotherapy

The finding may hold promise for new ways to use immunotherapies. A hotspot that is easier to see might also be easier to target with immune-stimulating drugs — provided the drugs are given early enough. The researchers are looking further into their data to determine whether immune-based therapies in select patients might arrest cancer development at the earliest stage.

Dr. Greenbaum said these discoveries were possible because of the partnership between laboratory and clinical researchers, including the Program in Computational Immuno-Oncology that was recently formed to bridge MSK’s Computational Oncology Service, led by Sohrab Shah, and the Parker Institute for Cancer Immunotherapy at MSK, led by Dr. Wolchok.

“We have a unique program that really fosters collaboration between experts in computational oncology and immunotherapy,” Dr. Greenbaum says. “It’s a wonderful, productive relationship our lab has with Jedd and Taha’s, and that MSK has with other institutions. One of the senior authors, Marta Łuksza, is a longtime colleague at Mount Sinai, so it really is a product of a group effort.”

Drs. Merghoub, Zappasodi, Wolchok, and Balachandran also have faculty appointments at Weill Cornell Medicine, and Dr. Greenbaum has an appointment in the Weill Cornell Graduate School of Medical Sciences.