"One thing we've learned about cancers is that each has its own unique recipe for malignancy. Some use the same ingredients and some a have a wide palate of ingredients."
This is the analogy Paul Khavari, MD, PhD, professor and chair of dermatology at Stanford, used to describe the mutated genes that turn our own cells against us. The abnormal proteins derived from these genes disrupt the cellular machinery that keeps cell growth under control and monitors the DNA for mistakes. Fast-multiplying, unmonitored cells acquire more mutations in their DNA and the cycle continues.
By the time the cancer is detected, the DNA can be so riddled with mutations and rearrangements that even the power of next generation sequencing to read the DNA of the chromosomes might not be enough to identify the key ingredients - the mutated genes that drive the cancer.
The two T-cell cancers Khavari studies, mycosis fungoides and Sezary syndrome, come from particularly eclectic genetic cookbooks lacking a single obvious cancer-causing mutation. This makes identifying drugs that would fight these cancers extremely difficult.
By turning to clinical and biological data, Khavari's team selected about 500 genes for deeper investigation. An identical point mutation in a single gene seen in only 5 percent of the examined tumor led them to identify a cell-survival mechanism that had not previously been implicated in any cancer.
In a paper published today in Nature Genetics the researchers reported that almost 40 percent of patients had a genetic abnormality in at least one gene involved in this mechanism. In our press release on the paper, I wrote about how these mutations turn the cells cancerous:
Khavari... likens skin T cells to patrolling sentries, rotating on and off duty. At the end of their shift, the cell-survival mechanism shuts down, and, with no signal, the T cells leave or die. The mutations Khavari's team found prevent the pathway from turning off, causing T cells to pile up in the skin or circulate through the blood stream. "More and more sentries keep showing up for duty," said Khavari. "It's out of control."
With the mutated genes identified, Khavari plans to introduce them into mice models. By studying their biological effects he hopes to suss out the mutations that are the cancers' critical ingredients.
To read more about a stem cell treatment for these cancers being developed at Stanford, check out this article in the most recent Stanford Medicine magazine.
Kim Smuga-Otto is a student in UC Santa Cruz's science communication program and a writing intern in the medical school's Office of Communication and Public Affairs.
Previously: Smoking gun or hit-and-run? How oncogenes make good cells go bad, When a rash just isn't a rash: A patient's battle with mycosis fungoides and Linking cancer gene expression with survival rates, Stanford researchers bring "big data" into the clinic
Photo by April Griffus