Insights into genetic ‘hotspots’ could produce new cancer treatment strategies

NEW YORK CITY, May 11, 2022 –  

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 critical for 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.”

The research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748; the Swim Across America, Ludwig Institute for Cancer Research, Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering, Cancer Research Institute, Parker Institute for Cancer Immunotherapy, NIH grant R01AI081848, U01CA224175, R01CA240924 and U01CA228963; a collaboration by Stand Up to Cancer, a program of the Entertainment Industry Foundation, the Society for Immunotherapy of Cancer, and the Lustgarten Foundation; the V Foundation for Cancer Research; Sephora; and the Pershing Square Sohn Foundation. The authors would like the acknowledge productive conversations with Uri Alon, Chang Chan, Neal Copeland, Pierre Hainaut, Nancy Jenkins, Scott Lowe, Drew Pardoll, Alexandra Synder, David Ting, and the Balachandran, Greenbaum, Savage, and Wolchok Laboratories.

Institutions collaborating with Memorial Sloan Kettering Cancer Center for this study include Weill Cornell Medical College; the National Cancer Institute; Technical University of Denmark; Adaptive Biotechnologies, Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ; and Icahn School of Medicine at Mount Sinai.

Dr. Greenbaum has received honoraria for speaking engagements from Merck, Bristol Myers Squibb, and Chugai Pharmaceuticals; has received research funding form Bristol Myers Squibb; and has been a compensated consultant for PMV Pharma, Darwin Health, and Rome Therapeutics, of which he is a co-founder.

Dr. Merghoub is a co-founder and holds equity in IMVAQ Therapeutics; is a consultant for Immunos Therapeutics, ImmunoGenesis, and Pfizer; has research support from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea; and has patents related to work oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4.

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About Memorial Sloan Kettering Cancer Center (MSK):

As the world’s oldest and largest private cancer center, Memorial Sloan Kettering Cancer Center has devoted more than 135 years to exceptional patient care, influential educational programs, and innovative research to discover more effective strategies to prevent, control, and, ultimately, cure cancer. MSK is home to more than 20,000 physicians, scientists, nurses, and staff united by a relentless dedication to conquering cancer. Today, we are one of 52 National Cancer Institute-designated Comprehensive Cancer Centers, with state-of-the-art science and technology supporting groundbreaking clinical studies, personalized treatment, and compassionate care for our patients. We also train the next generation of clinical and scientific leaders in oncology through our continually evolving educational programs here and around the world. Year after year, we are ranked among the top two cancer hospitals in the country, consistently recognized for our expertise in adult and pediatric oncology specialties. www.mskcc.org.