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Grantee: Richard White, MD, PhD
Institution: Memorial Sloan-Kettering Cancer Center in New York City
Area of Focus: Cancer Biology & Genetics
Grant Term: 09/01/19 to 08/31/23
“We recently experimented with zebrafish to learn more about acral melanoma—the type that only occurs on the palms, feet, and under nails. We discovered that whether cancer-causing genes—oncogenes—actually lead to cancer seems to also depend on the skin cell’s position in the body. It’s the location of the skin cell itself that dictates whether the oncogene causes cancer to develop. Our work leads to the interesting idea that instead of only treating the oncogene, we can develop drugs to treat the oncogene’s position.”
The Challenge: A rare type of skin cancer, called acral melanoma, occurs in the palms of the hands, soles of the feet, and under the nails. It’s the type of cancer that killed Jamaican reggae pioneer, singer, and songwriter Bob Marley. Scientists haven’t fully understood what distinguishes acral melanoma from the more common type, which typically occurs on the face, trunk, or back.
The Research: Recognizing that fins are the evolutionary precursors to hands and feet, American Cancer Society research grantee Richard White, MD, PhD, genetically-engineered zebrafish to look at gene programs, which are several hundred genes that work together in one cell to maintain its identity as a specific type of cell, including the cell’s position in the body.
In a study reported in Nature, White describes how his lab discovered how genes associated with a cell’s positional identity determine why cancers arise in specific areas.
First, White’s team sequenced DNA of human acral melanoma tumors and found a alterations in the CRKL gene (pronounced “crackle"). That was unusual because melanoma occurring in other parts of the body typically have mutations in the BRAF gene. His lab was the first to report CRKL as a driver of acral melanoma.
Then the researchers went to their zebrafish to learn more. They genetically engineered zebrafish to have either extra CRKL genes or mutated BRAF ones. After several months, many of the fish with CRKL genes had developed tumors (Melanoma cells were tagged with fluorescence so they could be easily seen.) on their fins rather than on their bodies.
That’s when the researchers wondered if CRKL proteins synergize with genes for positional identity in these areas. They looked at which genes were “turned on” in fins compared to genes “turned on” in the body and found that they were different.
They did further experiments using the gene-editing tool CRISPR to interrupt this limb positional identity gene program—and that interruption prevented the development of acral melanoma, even in fish with more CRKL genes!
Why Does It Matter? White’s discovery about how anatomic location influences whether a particular genetic mutation will lead to cancer or not. It also opens a new potential way for new melanoma treatments—drugs that block positional cues from genes instead of the genes themselves.
As White explained, “Not only can a DNA mutation behave differently depending on the type of cell it finds itself in, but different parts of the body are susceptible to different mutations because of their hardwired positional identity.”
Positional identity may help answer the question about why cancers occur in different locations for other skin cancers too, as well as for cancers in the bile ducts, brain, colon, and stomach.