PHILADELPHIA (December 20, 2022)—Joining a list of over 100 previous orators, Robert Uzzo, MD, MBA, FACS, president and CEO of Fox Chase Cancer Center, delivered the Rhoads Oration for the Philadelphia Academy of Surgery this month at The College of Physicians of Philadelphia.
The Rhoads Oration has been part of the Philadelphia Academy of Surgery since its inception in 1881. It was named in honor of Jonathan E. Rhoads, whom the Academy described as “one of the most illustrious and faithful fellows of the Academy.” The oration is presented annually by a speaker who is a fellow of the Academy and appointed by its president.
Uzzo’s oration, “Renal Cell Carcinoma: In the Beginning,” discussed the origins of kidney cancer, as well as environmental and tissue-specific responses that may affect its development.
“One of the questions I really struggle with is when patients ask, ‘What caused my kidney cancer?’ The unfortunate answer is that we simply don’t know,” said Uzzo. “We can talk about the genetic events, what happens after the disease starts, all the pathways downstream, and how to best treat, but fundamentally we don’t know what caused it.”
During the lecture, Uzzo reviewed the most common hypotheses on the origins of cancers, including environmental influences, hereditary influences, and stochastic (random) genetic mutations. He noted that cancer develops as a result of mutational events that may be affected by any and all of these forces and elaborated on three major mutation triggers.
“I want to take you through my arguments for whether kidney cancer is primarily hereditary, caused by environmental factors, or a result of random replicative errors that the defense mechanisms of our bodies are unfortunately unable to identify and correct,” said Uzzo.
“The environmental risks of kidney cancer include obesity, smoking, diabetes, chronic kidney disease, and hypertension. There are not many among us who don’t have at least one of those things, and yet most of us will never get kidney cancer,” said Uzzo.
“The epidemiologic evidence for environmental causes of kidney cancer are probably more correlative than causative. By and large the data do not support that a significant environmental exposure is the primary cause of kidney cancer.”
Uzzo likened the risks to the concepts of “alpha” and “beta” in finance. “We all have some inherent risks due to genomic instability—our beta risks—that may be modestly modified by environmental influences—our alpha risk.”
In his discussion of hereditary causes of kidney cancer, Uzzo noted that the scientific community now knows more about the molecular biology of solid kidney tumors, including primary genomic drivers, than just about any other type of solid tumor. However, they also know that truly inherited forms of kidney cancer constitute only about 5% to 8% of kidney cancers, likely because true germline founder mutations can only occur during a very small time window.
“The most plausible and unfortunate answer is that most kidney cancers are likely caused by replicative errors that occur as a function of an ever-changing genomic landscape during cellular turnover. Our genome is constantly evolving, some for the better and some for the worse. The same biological mechanisms that lead to great molecular diversity in this world also expose us to disease.”
Uzzo cited the study, “Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal,” published in the journal Cell, which showed how cell mutations in kidney cancer patients likely occurred decades prior to presentation. “Many of these mutations in kidney cells are meaningless, while others evolve over many years to malignant clones,” he said.
“In the end, it seems to be that we may be able to shift our risks up or down, but really most cancers may be inherent and replicative in nature and occur very early in life. While the environment and hereditary factors certainly alter the cancer curve to some degree, replicative errors are the most likely cause,” said Uzzo.
“I’ve come to understand cancer as an evolutionary battle of the competing clones that exist within and one individual’s cancer. It is cellular competition and survival of the fittest cells. Sometimes, the fittest cell is a highly malignant clone.”
