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Study Identifies 40 New Genetic Variants

Collaboration involved researchers from more than 130 institutions globally.

December 3, 2018

The most comprehensive genomewide association study, or GWAS, of colorectal cancer risk to date has discovered 40 new genetic variants and validated 55 previously identified variants that signal an increased risk of colon cancer.

The study, published today in Nature Genetics, also has identified the first rare protective variant for instances of sporadic colorectal cancer, i.e., those not associated with a known familial risk syndrome, and which account for the vast majority of colorectal cancer cases.

Genetic variants occur from differences in our DNA. Most variants are believed to be benign, some are known to be associated with various diseases, and the significance of many others is unknown. While individual genetic variants have little impact on disease risk, several combined variants can become clinically relevant, and this could have an impact on future personalized screening recommendations.

Together, the findings are a significant step toward creating personalized screening strategies and better informing drug development for colorectal cancer. The study identified several loci, the physical location of the gene on a chromosome, near proposed drug targets and genes in pathways not previously known to be causally linked to colorectal cancer.

“A study of this magnitude was possible only through collaboration with our partners from institutions around the world,” said Ulrike “Riki” Peters, PhD, MPH, associate director of the Public Health Sciences Division at the Fred Hutchinson Cancer Research Center, the institution which led the study. “Understanding the genetic architecture of colorectal cancer will revolutionize how we assess risk and treatment for this disease, which is the second most deadly cancer in the United States.”

In Pursuit of New Colorectal Cancer Treatment Targets

In 2009, Dr. Peters initiated and has since led the Genetics and Epidemiology of Colorectal Cancer Consortium, the world’s largest molecular genetic consortium for colorectal cancer. Using GWAS results to inform cancer drug development, the authors believe, could improve the drug-development success rate and even lead to chemoprevention drugs for high-risk individuals.

“There’s great potential in using GWAS results to inform target discovery for anticancer drugs. For diseases like type 2 diabetes and heart disease, the GWAS approach drives the discovery of new biology and potential drug targets,” explained Jeroen Huyghe, PhD, who co-led the study’s statistical genetic analysis and is a staff scientist at Fred Hutch.

“To date, the search for new targets for cancer therapy has been limited to focusing primarily on the molecular characteristics of cancer cells. We think there is a huge opportunity in using the GWAS approach to inform drug development for colorectal cancer,” says Huyghe...

Click here to continue reading this article sourced from Everyday Health.

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Your 'Second Brain' is in your gut

The human gut microbiome impacts human brain health in numerous ways - watch this video from Hashem Al-Ghaili and click here to see more from the Science Nature Pages Facebook page.

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Colon cancer is caused by bacteria and cell stress

Researchers at Technical University Munich have reported findings related to the development of colon cancer. "We originally wanted to study the role of bacteria in the intestines in the development of intestinal inflammation," explains Professor Dirk Haller from the Department of Nutrition and Immunology at the Weihenstephan Science Centre of the TUM. "However, the surprising result for us was the discovery that bacteria, together with stress in cells, caused tumours (exclusively in the colon) and without the involvement of inflammation."

The investigations were initially carried out using a mouse model. In germ-free animals in which the activated transcription factor ATF6 regulated stress in the intestinal mucosa (intestinal epithelium), no change could be observed. But as soon as the microbiota were transplanted back into germ-free animals, tumours developed in the colons of the mice. Using Koch's postulates, Haller and his team were able to show that microorganisms are involved in the development of cancer in the colon.

The transcription factor ATF6 regulates stress in cells, and the intensity and duration of activation is increased with diseases. "However, it is not cell stress alone that leads to tumour growth, but the combination of stress and microbiota that favours cancer growth," says Haller, head of ZIEL—the Institute for Food & Health at TUM.

ATF6 incidence found to be increased in colon cancer patients

Subsequently, in cooperation with the clinic on the right side of the Isar (Prof. Janssen), the data of 541 patients with colon cancer were examined. In those cases in which the level of transcription factor ATF6 was significantly increased, triggering stress, the recurrence rate after surgery increased: About 10 percent of patients were at risk of developing colon cancer a second time.

"In certain patients, the protein ATF6 could serve as a diagnostic marker for an increased risk of  and could indicate the start of therapy at an early stage," said Prof. Haller—a microbial therapy is conceivable, when we know more about the composition of the bacterial flora. What now became clear, however: Chronic inflammation has no effect on  development in the colon."

More information: O.I. Coleman et al, Activated ATF6 Induces Intestinal Dysbiosis and Innate Immune Response to Promote Colorectal Tumorigenesis, Gastroenterology (2018).  DOI: 10.1053/j.gastro.2018.07.028 

Journal reference: Gastroenterology search and more info website

Provided by: Technical University Munich

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Diagnosing colon cancer by dropping blood on a thin film

Asan Medical Center said its researchers have developed a technology to diagnose colorectal cancer by dropping a drop of blood on a hand-sized piece of ultra-thin plastic film.

The research team, led by Professor Park In-ja of Colon and Rectal Surgery Department and Professor Shin Yong of Convergence Medicine Department, was able to separate cell-free nucleic acid (CFNA) using the film, which allows a low-cost diagnosis of the disease, the hospital said.

Moreover, the new technology’s diagnosis of the colorectal cancer is more precise than conventional diagnostic devices that use blood, Asan Medical Center said.

Cancer patients tend to have high concentrations of CFNA than ordinary people. Existing devices for the separation of CFNA require other equipment such as a centrifuge, a vacuum pump, and a direct current power supply.

However, the researchers’ new technology, which uses the characteristics of a substance called “DTBP” that binds selectively to CFNA in the blood, separates CFNA when a drop of blood is placed on an ultra-thin plastic film half a size of a grown-up man’s hand. The technology does not need any extra equipment, saving costs for patients.

The research team divided 14 colorectal cancer patients into two groups and compared the new technology’s diagnostic accuracy with that of conventional devices. The results showed a meaningful difference.

The researchers took tissue samples from 14 colon cancer patients and comparing the next generation sequencing (NGS) test results with the new diagnostic method using blood. The conventional CFNA separation technique showed 57 percent diagnostic accuracy, while the newly developed platform technology achieved 71 percent accuracy.

While it took about one hour to isolate CFNA from blood to diagnose colon cancer using the conventional method, the research team’s technique took only about 20 minutes because of the simplicity of placing a drop of blood on to the thin film, the hospital said.

“Korea ranks first in colorectal cancer incidence in the world. But early detection of the disease can raise cure rate significantly. Patients with colon cancer show a high recurrence rate, so it is imperative to keep track of the disease,” said Shin. “We developed a technology that costs less than a biopsy and has higher accuracy than existing devices that diagnose colorectal cancer with blood.”

Shin said the new technology could be applied to other types of cancer. “It will take some time to commercialize it, but we will continue our research so that physicians can easily and accurately diagnose cancer with the CFNA isolation platform technology and that cancer patients can receive the treatment quickly,” he added.

The research has been published in the online version of the international journal, Advanced Science.

Kwak Sung-sun  Published 2018.10.02  11:14  Updated 2018.10.02 12:48

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