February 5, 2020, Wellcome Trust Sanger Institute
Summary: Causes of cancer are being catalogued by a huge international study revealing the genetic fingerprints of DNA-damaging processes that drive cancer development. This detailed list of genetic fingerprints will provide clues how each cancer developed. This will help scientists search for previously unknown causes of cancer, leading to better information for prevention strategies, and help signpost new directions for cancer diagnosis and treatments.
By Rich Haridy April 15, 2019
New research reveals specific DNA signatures of 41 different carcinogenic agents can be identified in tumors
We have known for well over a century that exposure to certain environmental agents can result in DNA mutations that ultimately cause cancer. However, it has been tricky to explicitly link specific tumors to individual culprits, such as UV light or tobacco smoke. Now a team of UK scientists has for the first time developed a way to identify specific mutational signatures in tumors that can be linked to certain carcinogens.
“Mutational signatures are the fingerprints that carcinogens leave behind on our DNA, and just like fingerprints, each one is unique,” says Serena Nik-Zainal, a researcher from the University of Cambridge working on the project. “They allow us to treat tumors as a crime scene and, like forensic scientists, allow us to identify the culprit – and their accomplices – responsible for the tumor.”
To create this catalog of mutational signatures, the researchers began by exposing induced pluripotent stem cells to a variety of environmental carcinogens. Using whole genome sequencing the researchers were able to identify specific mutational fingerprints from 41 carcinogenic agents, such as chemicals found in tobacco smoke, diesel fumes or certain foods.
The study was also able to measure how damaging each specific carcinogen could actually be, unsurprisingly confirming some well-known explicit cancerous connections, including UV with melanoma and smoking with lung cancer. Other carcinogenic agents analyzed presented smaller effect sizes, and the researchers urge caution in using this study to affirm conclusive relationships between some cancers and specific environmental exposures.
Of course, the research isn’t geared at finding a single conclusive cause for all individual cancers. Many of the carcinogenic agents examined presented such weak mutagenic signatures that it is suggested it would be difficult to conclusively claim the agent as the sole cause of a given tumor. Further work is inevitably needed to better catalog these mutagenic signatures found in tumors, as the legal implications of this research could be incredibly significant for those working in industries where exposure to certain carcinogenic agents is common.
The work is undeniably an impressive breakthrough in helping scientists more clearly understand the specific origins of individual cancers. Homing in on exactly what has contributed to the generation of a given tumor will help health care providers offer better advice for avoiding exposure to those carcinogenic agents in the future.
“Our reference library will allow doctors in future to identify those culprits responsible for causing cancer,” says Nik-Zainal. “Such information could be invaluable in helping inform measures to reduce people’s exposure to potentially dangerous carcinogens.”
Scientists in Cambridge and London have developed a catalogue of DNA mutation ‘fingerprints’ that could help doctors pinpoint the environmental culprit responsible for a patient’s tumour — including showing some of the fingerprints left in lung tumours by specific chemicals found in tobacco smoke.
Our DNA, the human genome, comprises of a string of molecules known as nucleotides. These are represented by the letters A, C, G and T. Sometimes, changes occur in the ‘spelling’ of our DNA — an A becomes a G, for example. These changes, known as mutations, can be caused by a number of factors, some environmental, such as exposure to tobacco smoke or to ultraviolet light.
As cells divide and multiply, they make copies of their DNA, so any spelling mistakes will be reproduced. Over time, the number of errors accumulates leading to uncontrolled cell growth — the development of tumours.
Previously, scientists have had only a limited number of tools for working out the cause of an individual’s tumour. As it is now possible to study the entire human genome very rapidly, scientists have been able to find all the mutations in a patient’s cancer, and see patterns — or ‘mutational signatures’ — in these tumours.
Now, in a study published in the journal Cell, a team of researchers from the University of Cambridge and King’s College London have developed a comprehensive catalogue of the mutational signatures caused by 41 environmental agents linked to cancer. In future they hope to expand it further, using similar experimental techniques, to produce an encyclopaedia of mutation patterns caused by environmental agents.
“Mutational signatures are the fingerprints that carcinogens leave behind on our DNA, and just like fingerprints, each one is unique,” explains Dr Serena Nik-Zainal from the Department of Medical Genetics and MRC Cancer Unit at the University of Cambridge, who led the Cambridge Team. “They allow us to treat tumours as a crime scene and, like forensic scientists, allow us to identify the culprit — and their accomplices — responsible for the tumour.”
The researchers exposed induced pluripotent stem cells — skin cells that have been reprogrammed to return to their original, ‘master’ state — to 79 known or suspected environmental carcinogens. The team then used whole genome sequencing to look at the patterns of changes caused by the agents and found that 41 of the suspects left a characteristic fingerprint on the stem cells’ DNA.
“We’ve used this technique to create the most comprehensive catalogue to date of the patterns of DNA damage produced by environmental agents across the whole human genome,” explains Professor David Phillips, who led the King’s College London team. “It should allow us to examine a patient’s tumour and identify some of the carcinogens they have been exposed to that may have caused the cancer.”
Some of the environmental agents studied are known carcinogens, such as polycyclic hydrocarbons and sunlight. For the first time, the researchers also studied some of the individual chemicals found in tobacco smoke and identified which ones cause signatures similar to those found in smokers’ lung cancer.
They also identified the fingerprints left behind by common chemotherapy drugs, some dietary chemicals and some present in diesel exhaust fumes. This study shows how human DNA is vulnerable to many agents in our surroundings.
Dr Nik-Zainal illustrates potential uses of the catalogue by referring to the case of Balkan endemic nephropathy (BEN), which is linked to dietary exposure to a plant chemical called aristolochic acid. The mutational signature of this chemical was verified in this study to be virtually identical to the signature found in the tumours of BEN patients. So, although this connection was first made prior to the current study, Dr Nik-Zainal says it is an example of how one might use their catalogue in future.
“Our reference library will allow doctors in future to identify those culprits responsible for causing cancer,” adds Dr Nik-Zainal. “Such information could be invaluable in helping inform measures to reduce people’s exposure to potentially dangerous carcinogens.”
The research was funded by a Wellcome Strategic Award, with additional support from Cancer Research UK and the Medical Research Council.
Jill E. Kucab, Xueqing Zou, Sandro Morganella, Madeleine Joel, A. Scott Nanda, Eszter Nagy, Celine Gomez, Andrea Degasperi, Rebecca Harris, Stephen P. Jackson, Volker M. Arlt, David H. Phillips, Serena Nik-Zainal. A Compendium of Mutational Signatures of Environmental Agents. Cell, 2019; DOI: 10.1016/j.cell.2019.03.001
University of Cambridge. “‘Fingerprint database’ could help scientists to identify new cancer culprits.” ScienceDaily. ScienceDaily, 15 April 2019. <www.sciencedaily.com/releases/2019/04/190415105048.htm>.
Illustration of cancer cells (stock image).Credit: © peterschreiber.media / Adobe Stock
Causes of cancer are being catalogued by a huge international study revealing the genetic fingerprints of DNA-damaging processes that drive cancer development. Researchers from the Wellcome Sanger Institute, Duke-NUS Medical School Singapore, University of California San Diego School of Medicine, the Broad Institute of MIT and Harvard and their collaborators around the world have achieved the most detailed list of these genetic fingerprints to date, providing clues as to how each cancer developed.
These fingerprints will allow scientists to search for previously unknown chemicals, biological pathways and environmental agents responsible for causing cancer.
The research, published in Nature today (5th February) as part of a global Pan-Cancer Project, will help understand the causes of cancer, informing prevention strategies, and help signpost new directions for cancer diagnosis and treatments.
Also published today in Nature and related journals, are 22 further studies from the Pan-Cancer Project. The collaboration involving more than 1,300 scientists and clinicians from 37 countries, analysed more than 2,600 genomes of 38 different tumour types. The project represents an unprecedented international exploration of cancer genomes, which significantly improves our fundamental understanding of cancer and zeros-in on mechanisms of cancer development.
In the UK, someone is diagnosed with cancer every two minutes, with 363,000 new cancer cases every year. The disease causes around 165,000 deaths in the UK annually.
Cancer is caused by genetic changes — mutations — in the DNA of a cell, allowing the cell to divide uncontrollably. Many known causes of cancer, such as UV light and tobacco smoking, leave a specific fingerprint of damage in the DNA, known as a mutational signature. These fingerprints can help understand how cancers develop, and potentially, how they can be prevented. However, past studies have not been large enough to identify all potential mutational signatures.
The fingerprint study identified new mutational signatures that had not been seen before, from single letter ‘typo’ mutations, to slightly larger insertions and deletions of genetic code. The result is the largest database of reference mutational signatures ever. Only about half of all the mutational signatures have known causes, however this resource can now be used to help find more of these causes and better understand cancer development.
Professor Steven Rozen, a senior author from Duke-NUS Medical School, Singapore, said: “Some types of these DNA fingerprints, or mutational signatures, reflect how the cancer could respond to drugs. Further research into this could help to diagnose some cancers and what drugs they might respond to.”
Professor Gad Getz, a senior author from the Broad Institute of MIT and Harvard, and Massachusetts General Hospital, said, “The availability of a large number of whole genomes enabled us to apply more advanced analytical methods to discover and refine mutational signatures and expand our study into additional types of mutations. Our new collection of signatures provides a more complete picture of biological and chemical processes that damage or repair DNA and will enable researchers to decipher the mutational processes that affect the genomes of newly sequenced cancers.”
Another study in the Pan-Cancer Project, published in Nature today, discovered that larger, more complex genetic changes that rearrange the DNA could also act as mutational signatures, and point towards causes of cancer. Researchers from the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and their collaborators found 16 of these signatures that spanned from rearrangements of single genes to entire chromosomes.
The global Pan-Cancer Project is the largest and most comprehensive study of whole cancer genomes yet. The collaboration has created a huge resource of primary cancer genomes, available to researchers worldwide to advance cancer research.
- Ludmil B. Alexandrov, Jaegil Kim, Nicholas J. Haradhvala, Mi Ni Huang, Alvin Wei Tian Ng, Yang Wu, Arnoud Boot, Kyle R. Covington, Dmitry A. Gordenin, Erik N. Bergstrom, S. M. Ashiqul Islam, Nuria Lopez-Bigas, Leszek J. Klimczak, John R. McPherson, Sandro Morganella, Radhakrishnan Sabarinathan, David A. Wheeler, Ville Mustonen, Gad Getz, Steven G. Rozen, Michael R. Stratton. The repertoire of mutational signatures in human cancer. Nature, 2020; 578 (7793): 94 DOI: 10.1038/s41586-020-1943-3
- Yilong Li, Nicola D. Roberts, Jeremiah A. Wala, Ofer Shapira, Steven E. Schumacher, Kiran Kumar, Ekta Khurana, Sebastian Waszak, Jan O. Korbel, James E. Haber, Marcin Imielinski, Joachim Weischenfeldt, Rameen Beroukhim, Peter J. Campbell. Patterns of somatic structural variation in human cancer genomes. Nature, 2020; 578 (7793): 112 DOI: 10.1038/s41586-019-1913-9
- The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature, 2020 DOI: 10.1038/s41586-020-1969-6
Wellcome Trust Sanger Institute. “Cancer-causing culprits will be caught by their DNA fingerprints: Study within Pan-Cancer Project will help research into cancer prevention, diagnosis and treatments.” ScienceDaily. ScienceDaily, 5 February 2020. <www.sciencedaily.com/releases/2020/02/200205132330.htm>
Scientists have identified a molecular ‘switch’ that controls the immune machinery responsible for chronic inflammation in the body. The finding could lead to new ways to halt or even reverse many age-related conditions, from from Alzheimer’s and Parkinson’s to diabetes and cancer.
Chronic inflammation, which results when old age, stress or environmental toxins keep the body’s immune system in overdrive, can contribute to a variety of devastating diseases, from Alzheimer’s and Parkinson’s to diabetes and cancer.
Now, scientists at the University of California, Berkeley, have identified a molecular “switch” that controls the immune machinery responsible for chronic inflammation in the body. The finding, which appears online Feb. 6 in the journal Cell Metabolism, could lead to new ways to halt or even reverse many of these age-related conditions.
“My lab is very interested in understanding the reversibility of aging,” said senior author Danica Chen, associate professor of metabolic biology, nutritional sciences and toxicology at UC Berkeley. “In the past, we showed that aged stem cells can be rejuvenated. Now, we are asking: to what extent can aging be reversed? And we are doing that by looking at physiological conditions, like inflammation and insulin resistance, that have been associated with aging-related degeneration and diseases.”
In the study, Chen and her team show that a bulky collection of immune proteins called the NLRP3 inflammasome — responsible for sensing potential threats to the body and launching an inflammation response — can be essentially switched off by removing a small bit of molecular matter in a process called deacetylation.
Overactivation of the NLRP3 inflammasome has been linked to a variety of chronic conditions, including multiple sclerosis, cancer, diabetes and dementia. Chen’s results suggest that drugs targeted toward deacetylating, or switching off, this NLRP3 inflammasome might help prevent or treat these conditions and possibly age-related degeneration in general.
“This acetylation can serve as a switch,” Chen said. “So, when it is acetylated, this inflammasome is on. When it is deacetylated, the inflammasome is off.”
By studying mice and immune cells called macrophages, the team found that a protein called SIRT2 is responsible for deacetylating the NLRP3 inflammasome. Mice that were bred with a genetic mutation that prevented them from producing SIRT2 showed more signs of inflammation at the ripe old age of two than their normal counterparts. These mice also exhibited higher insulin resistance, a condition associated with type 2 diabetes and metabolic syndrome.
The team also studied older mice whose immune systems had been destroyed with radiation and then reconstituted with blood stem cells that produced either the deacetylated or the acetylated version of the NLRP3 inflammasome. Those who were given the deacetylated, or “off,” version of the inflammasome had improved insulin resistance after six weeks, indicating that switching off this immune machinery might actually reverse the course of metabolic disease.
“I think this finding has very important implications in treating major human chronic diseases,” Chen said. “It’s also a timely question to ask, because in the past year, many promising Alzheimer’s disease trials ended in failure. One possible explanation is that treatment starts too late, and it has gone to the point of no return. So, I think it’s more urgent than ever to understand the reversibility of aging-related conditions and use that knowledge to aid a drug development for aging-related diseases.”
Co-authors of the study include Ming He, Hou-Hsien Chiang and Hanzhi Luo, previously at UC Berkeley where the research was carried out; Zhifang Zheng, Mingdian Tan, Rika Ohkubo and Wei-Chieh Mu at UC Berkeley; Qi Qiao, Li Wang and Hao Wu at Harvard Medical School; and Shimin Zhao at Fudan University.
This research was supported in part by the National Institutes of Health under grants R01DK117481, R01DK101885, R01AG063404, R01AG 063389, DP1HD087988 and R01Al124491; the National Institute of Food and Agriculture; the France-Berkeley Fund, a Glenn/AFAR Scholarship; the Dr. and Mrs. James C.Y. Soong Fellowship; the Government Scholarship for Study Abroad (GSSA) from Taiwan; the ITO Foundation Scholarship and the Honjo International Scholarship.Ming He, Hou-Hsien Chiang, Hanzhi Luo, Zhifang Zheng, Qi Qiao, Li Wang, Mingdian Tan, Rika Ohkubo, Wei-Chieh Mu, Shimin Zhao, Hao Wu, Danica Chen. An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance. Cell Metabolism, 2020; DOI: 10.1016/j.cmet.2020.01.009
University of California – Berkeley. “Molecular ‘switch’ reverses chronic inflammation and aging.” ScienceDaily. ScienceDaily, 6 February 2020. <www.sciencedaily.com/releases/2020/02/200206144837.htm