Nav: Home

Enormous genetic variation may shield tumors from treatment

November 09, 2015

The most rigorous genetic sequencing ever carried out on a single tumor reveals far greater genetic diversity among cancer cells than anticipated. Researchers from the University of Chicago and the Beijing Institute of Genomics estimate that the tumor, about 3.5 centimeters in diameter, contained more than 100 million distinct mutations within the coding regions of its genes--thousands of times more than expected.

The finding, published Nov. 9, 2015, in the Proceedings of the National Academy of Sciences, suggests that even microscopic tumors are likely to contain extremely high genetic diversity. With so much variation, even small tumors are likely to contain cells that may be able to resist standard post-surgical cancer treatment such as chemotherapy and radiation.

"With 100 million mutations, each capable of altering a protein in some way, there is a high probability that a significant minority of tumor cells will survive, even after aggressive treatment," said study director Chung-I Wu, PhD, professor of ecology and evolution at the University of Chicago. "In a setting with so much diversity, those cells could multiply to form new tumors, which would be resistant to standard treatments."

The high level of genetic variation also adds fuel to a long-running debate in evolutionary biology: Is evolution, at the DNA level, driven by selective Darwinian forces--the survival of the fittest? Or is there a role for random, or neutral, non-Darwinian changes--the persistence of the luckiest?

For this study, the researchers closely examined an ordinary tumor removed from a human liver. This hepatocellular carcinoma was slightly smaller than a ping-pong ball and contained more than a billion cells.

Scientists at the Beijing Institute of Genomics rigorously sampled nearly 300 regions from one slice of the tumor and sequenced or genotyped each one looking for genetic changes. When they analyzed their data, using modern population genetic theory, they came up with estimates for the whole tumor of more than 100 million coding-region mutations. That is far more mutations than one would expect, "by orders of magnitude," Wu said.

Such rapid and extensive generation of enormous diversity, way beyond what a Darwinian process would permit, makes the selectionism vs. neutralism debate of the 1980s "suddenly medically relevant," according to Wu. Until now, no one had probed a tumor so thoroughly. The prevailing notion was that tumors had from a few hundred up to 20,000 genetic alterations that were not present in the patient's healthy cells.

"Our study is the non-Darwinian process writ small, down to the cellular level," Wu said. "In the Darwinian struggle, there are--from the tumor's point of view--few beneficial mutations, meaning changes that give tumor cells a growth advantage." Over time, such good mutations would be expected to drive out the deleterious ones. That limits diversity. "When there are no such limits on genetic variation, however, mutations can emerge and apparently thrive," he said.

"This could potentially change how we think about tumor growth and spread, but the direct clinical implications of this study may not be obvious on the surface," said co-author medical oncologist Daniel Catenacci, MD, assistant professor of medicine at the University of Chicago.

The bulk of the mutations were in very low frequencies; 99 percent were found in fewer than 100 cells. Cells carrying these rare mutations were often in clumps. They were "competing mostly with themselves," according to the authors.

But drug treatment could remove those constraints. "It 'looses up' the population," they wrote, enabling "effective competition to occur."

"The presence of so many random mutations could present a problem to specifically targeted therapies," Catenacci said. "It almost guarantees that some cells will be resistant. But it also suggests that aggressive treatment could push tumor cells into a more Darwinian mode."

The study focused on just one exhaustively sampled tumor, but it raises important questions. Previous studies have found that patient survival decreases as genetic diversity within tumors increases. More mutations make drug resistance more likely. "The possibility of high intra-tumor diversity even in small tumors suggests a need to reevaluate treatment strategies," the authors conclude.
-end-
The National Basic Research Program of China, Research Programs of Chinese Academy of Sciences, the National Science Foundation of China, and the National High-tech R&D Program of China funded this study. Additional authors were Xuemei Lu, Shaoping Ling, Zheng Hu, Zuyu Yang, Fang Yang, Yawei Li, Ke Chen, Lili Dong, Lihua Cao, Yong Tao, Lingtong Hao, Qiang Gong, Dafei Wu, Wenjie Li, and Wenming Zhao of the Chinese Academy of Sciences; Pei Lin and Qingjian Chen of the Sun Yat-Sen University, Guangzhou; Xiuyun Tian, Chunyi Hao, Peking University Cancer Hospital, Beijing; and Eric A. Hungate, Daniel V.T. Catenacci, Richard R. Hudson and Wen-Hsiung Li of the University of Chicago.

University of Chicago Medical Center

Related Cancer Cells Articles:

Cancer cells send signals boosting survival and drug resistance in other cancer cells
Researchers at University of California San Diego School of Medicine report that cancer cells appear to communicate to other cancer cells, activating an internal mechanism that boosts resistance to common chemotherapies and promotes tumor survival.
A protein that stem cells require could be a target in killing breast cancer cells
Researchers have identified a protein that must be present in order for mammary stem cells to perform their normal functions.
Single gene encourages growth of intestinal stem cells, supporting 'niche' cells -- and cancer
A gene previously identified as critical for tumor growth in many human cancers also maintains intestinal stem cells and encourages the growth of cells that support them, according to results of a study led by Johns Hopkins researchers.
Prostate cancer cells grow with malfunction of cholesterol control in cells
Advanced prostate cancer and high blood cholesterol have long been known to be connected, but it has been a chicken-or-egg problem.
Immune therapy scientists discover distinct cells that block cancer-fighting immune cells
Princess Margaret Cancer Centre scientists have discovered a distinct cell population in tumours that inhibits the body's immune response to fight cancer.
New system developed that can switch on immune cells to attack cancer cells
Researchers have developed an artificial structure that mimics the cell membrane, which can switch on immune cells to attack and destroy a designated target.
Hybrid immune cells in early-stage lung cancer spur anti-tumor T cells to action
Researchers have identified a unique subset of these cells that exhibit hybrid characteristics of two immune cell types -- neutrophils and antigen-presenting cells -- in samples from early-stage human lung cancers.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Sleep hormone helps breast cancer drug kill more cancer cells
Tiny bubbles filled with the sleep hormone melatonin can make breast cancer treatment more effective, which means people need a lower dose, giving them less severe side effects.
Breast cancer tumor-initiating cells use mTOR signaling to recruit suppressor cells to promote tumor
Baylor College of Medicine researchers report a new mechanism that helps cancer cells engage myeloid-derived suppressor cells.

Related Cancer Cells Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#529 Do You Really Want to Find Out Who's Your Daddy?
At least some of you by now have probably spit into a tube and mailed it off to find out who your closest relatives are, where you might be from, and what terrible diseases might await you. But what exactly did you find out? And what did you give away? In this live panel at Awesome Con we bring in science writer Tina Saey to talk about all her DNA testing, and bioethicist Debra Mathews, to determine whether Tina should have done it at all. Related links: What FamilyTreeDNA sharing genetic data with police means for you Crime solvers embraced...