A fascinating story came out of two papers published in Science Translational Medicine recently, (here and here) but didn’t get as much attention as they deserved IMHO because they don’t fit the “race for the cure” cancer research meme. Both groups used high-throughput genome sequencing to detect the “mutation signature” of a specific plant carcinogen, aristolochic acid (AA). This work joins a small list of other types of environmental exposures, e.g. sunlight and tobacco that have gene signatures that can be detected by DNA sequencing.
AA first came to prominence as a potent nephrotoxin and carcinogen through its inadvertent inclusion in an herbal remedy administered by a weight loss clinic in Belgium in the early 1990’s. Soon thereafter, Balkan endemic nephropathy, a condition associated with urothelial carcinoma of the upper urinary tract (UTUC) in rural populations along the River Danube, was found to be caused by accidental contamination of harvested wheat with the weed Aristolochia, which contains AA. — Genomics Traces Carcinogen Fingerprints, William Lee and Marc Ladanyi
Devra Davis in her book “The Secret History of the War on Cancer” tells the story of how US research enthralled by the pharmaceutical industry has almost systematically refused to look at the environmental causes of cancer. As a doctor specializing in bone marrow transplant, I must admit I always thought prevention was for weenies. We deal with diseases (leukemia, lymphoma, myeloma) that have generally not been considered preventable. Prevention anyway is difficult– our tools (mammograms, PSA tests) are clumsy and inaccurate. On the other hand, understanding how advanced cancers work and finding “the cure” is an easy-to-understand concept that has won the vast majority of research funding. And the “search for the cure” has dominated the narrative of science communication.
Many papers have used cancer genome sequencing in an effort to find specific mutations that drive cancer development. The “race for the cure” meme dictates that the reason we care is so that we can find drugs to block these specific cancer driver mutations.
Studying cancer genome sequences several years ago, I wrote that ” Our genomes…have not received the drug company memos.” I meant that our intense desire to use sequencing experiments to find a “magic bullet,” was preventing us from learning important lessons. Could we stop for a minute and listen to what the data were telling us? To my mind, data were telling us, in the words of Clifton Leaf, we must “com[e] to terms with the fact that cancer is a disease of progressive, unyielding, mind-boggling heterogeneity. There is no magic bullet for that.”
These new papers are interesting because rather than looking for specific mutations, they looked at the DNA in these tumors broadly as a kind of “radio antenna” to detect a general type of mutation. They found that UTUC tumors were filled with not one mutation, but a class of mutation, A>T transversions on the non-transcribed strand. The tumors that arose because of exposure to AA did not necessarily have one particular gene mutated, but they were filled with thousands of these specific types of mutations, providing a signature of exposure to this carcinogen.
But despite a growing list of new treatments, our progress remains incremental at best. Cancer is a heterogeneous set of diseases that are tremendously resistant to cures once they become advanced. It breaks my heart to see the suffering and death caused by cancer and to feel that we might be misdirecting our efforts and
And the latest data from genome sequencing, if we are willing to listen, is telling us a story of cancer as a disease of environmental exposures. And perhaps instead of looking for magic bullets, we should be looking at the processed foods and chemicals we surround ourselves with.
Addendum: A third paper just released surveys many cancer types and finds additional mutational signatures possibly related to carcinogens: Signatures of mutational processes in human cancer