An international team of scientists hopes its latest discovery will change oral cancer’s high mortality rate in developing countries. Researchers from the University of Otago, New Zealand, and the Indian Statistical Institute (ISI), Kolkata, recently discovered epigenetic markers that are distinctly different in oral cancer tissues compared to the adjacent healthy tissues in patients.
Finding these biomarkers is strongly associated with patient survival, says co-author Aniruddha Chatterjee of Otago's Department of Pathology Epigenetics. Non-genetic influences on gene expression is a powerful mechanism capable of altering gene expression in cancer cells without changes to the DNA sequence and can cause tumor progression. "This phenomenon is relatively new and under studied, particularly in oral cancer,” Chatterjee says. “This study is one of the first to identify epigenetic markers in oral cancer using cutting-edge approaches."
For the study, published in the journal Epigenomics, the team recruited 16 oral cancer patients in India who were either tobacco smokers or chewers or of mixed habits. They took samples of both tumor and normal, adjacent tissue from them. After isolating the DNA in the samples, the researchers discovered regions with altered epigenetic profiles in tumor cells compared to normal cells.
The Power Of Collaboration
They looked at one epigenetic mechanism - DNA methylation - which refers to the addition of methyl groups to DNA like bookmarks. The way these bookmarks are arranged could dictate the expression of genes and the spread of abnormal cells. "By validating in a larger cancer cohort, we have shown that a subset of these biomarkers is significantly associated with poor prognosis of patients," Chatterjee added. The findings could help save thousands of lives by identifying cancer cells early.
Of the 300,000 cases of tobacco-associated oral cancer detected globally, 86 percent are from India, according to the 2019 report of India Against Cancer. Late diagnosis and poor prognosis are key problems associated with the high mortality rate of this cancer in developing countries, says Lead Author Dr. Roshni Roy of the ISI. The group was surprised to find such distinct differences in the oral cancer tissues as compared to adjacent healthy tissue from the same patients. "We were also surprised to see that small molecules, called microRNA, were methylated or demethylated in the tumors from smokers or chewers or mixed habitués, suggesting that therapeutic intervention might be different in patients depending on the way the tobacco was abused," Roy added.
The study emphasized the power of collaboration between the ISI and Otago. Following an Otago project to streamline and develop methods and tools for analyzing large-scale DNA methylation data, Professor Bidyut Roy from the ISI approached Dr. Chatterjee and Professor Mike Eccles, also of Otago's Department of Pathology, to utilize Otago's unique expertise in the area. "This project was very interesting and it was a fantastic opportunity to work with this team in India and eventually produce a useful outcome,” Chatterjee added. “I was born and raised in India but New Zealand is home now, so for me it was very satisfying personally as well to work with real patient samples in India with Dr. Roy and his team and tackle this important issue."
E-Cigarettes And An Increased Risk Of Oral Cancer
Tobacco use remains a leading cause of oral cancer but the tobacco landscape is evolving with increasing use of non-cigarette tobacco products and dual-use of multiple product types. Co-authors Benjamin Chaffee and Neal Benowitz, both from the University of California, San Francisco, evaluated exposure to known carcinogens according to recent use of different tobacco product types, alone or in combination. The findings were published in the presentation "Nicotine and Carcinogen Exposure by Tobacco Product Type and Dual-Use."
Data was analyzed from the Population Assessment of Tobacco and Health which includes a sample of U.S. adults who provided urine specimens for analysis of tobacco-specific nitrosamines (TSNAs) N'-nitrosonornicotine (NNN), a known oral and esophageal carcinogen, 4-(methynitrosamino)-1-(3)-pyridyle-1-butanol (NNAL), a metabolite of lung carcinogen (NNK) and total nicotine equivalents. Participants were categorized according to use of combustible - which includes cigarettes, cigars, water pipes, pipes, blunts - marijuana-containing cigars – smokeless, which includes moist snuff, chewing tobacco and snus, e-cigarettes and nicotine replacement products. For each product, recent use was defined as within the prior three days and non-use defined as none within 30 days.
All tobacco use categories demonstrated elevated nicotine and TSNA concentrations relative to non-users. TSNA exposures were highest among smokeless tobacco users, whether used or together with other product types. Exclusive e-cigarette users were exposed to lower NNN and NNAL levels than other product users, despite comparable nicotine exposure. However, most e-cigarette users concurrently used combustible tobacco resulting in TSNA exposure similar to exclusive cigarette smokers. The analysis shows that the vast majority of non-cigarette tobacco users are exposed to carcinogen levels comparable to or exceeding exposure among exclusive cigarette smokers - levels that are likely to place users at substantial risk.
Magic Mouthwash For Mouth Sore Pain
In a recent study published in JAMA, “magic mouthwash,” - an oral rinse containing diphenhydramine, lidocaine and antacids - significantly reduced pain from oral mucositis, mouth sores, in patients receiving radiation therapy for cancers of the head and neck when compared to plaecbo. The clinical trial was led by Robert Miller, M.D., an emeritus Mayo Clinic radiation oncologist. “Our group published a study in 2012 showing that an oral rinse of doxepin reduced oral mucositis-related pain, compared to placebo,” Miller says. “However, there were no large randomized controlled trials studying the potential benefits of magic mouthwash.”
Two hundred and seventy-five patients were studied between November 2014 and May 2016. They found that pain related to oral mucositis was significantly less following both doxepin and magic mouthwash rinses versus placebo. They also found that both doxepin and magic mouthwash rinses were well-tolerated by patients. “Radiation therapy may cause mouth sores because it is designed to kill rapidly growing cells, such as cancer cells,” says co-author, Terence Sio, M.D., a Mayo Clinic radiation oncologist in Arizona. “Unfortunately, healthy cells in your mouth also divide and grow rapidly, and may be damaged during radiation therapy, which can cause discomfort. We're glad to have identified a proven method to help treat the discomfort of this side effect.”
Taking The Sting Out Of Mouth Ulcers
A large breakthrough was made recently in the genetic understanding of mouth ulcers which could provide potential for a new drug to prevent or heal the painful lesions. Mouth ulcers affect up to 25 percent of young adults and a higher proportion of children. Previous research has shown that mouth ulcers are partially heritable, but until now there has been little evidence linking specific genes or genomic regions to mouth ulcers.
The study, carried out by an international team of scientists and led by researchers at the University of Bristol, attempted to pinpoint areas of the genome associated with triggering mouth ulcers by looking systematically across the DNA code. By looking at mouth ulcers in different populations in the United Kingdon, the United States and Australia, the researchers aimed to find genes which were consistently linked to mouth ulcers. The research was published in Nature Communications.
The team identified genetic variants associated with the condition by analyzing genetic data derived from over 450,000 participants in the UK Biobank and replicated these findings in over 350,000 participants in USA-based data collection 23andMe. They discovered 97 common genetic variations across the genome that predispose people to mouth ulcers. The study went on to look at three further studies, including Bristol's Children of the 90s (ALSPAC) study, which showed confirmatory results. These variations are enriched in genes that have previously been linked to regulation of the body's immune system. "Currently, there are few satisfactory drug treatments for mouth ulcers as current medication options are non specific and can lead to side effects, says Tom Dudding, Wellcome Trust Clinical Research Fellow in the Bristol Medical School: Population Health Sciences (PHS) and Bristol Dental School and joint first author of the paper.
The field has gone from very little genetic understanding of mouth ulcers to having up to 97 areas of the genome which may provide an excellent basis for future research. "Importantly, our findings also show that several of the genes related to mouth ulcers are in pathways which are already targeted by drugs that are used to treat other diseases such as rheumatoid arthritis and psoriasis,” Dudding added. “There is the potential that drugs like these could be used to treat mouth ulcers, although further work is required to demonstrate this."
Link Between Common Oral Bacteria And Colon Cancer
Researchers at the Columbia University College of Dental Medicine recently determined how F. nucleatum - a common oral bacteria often implicated in tooth decay - accelerates the growth of colon cancer. The study - published in the journal EMBO Reports - could make it easier to identify and treat more aggressive colon cancers. It also helps explain why some cases advance far more quickly than others, thanks to the same bacteria found in dental plaque. Colon cancer is the second leading cause of cancer death in the U.S. and researchers have long known that the disease is caused by genetic mutations that typically accumulate over the course of a decade. “Mutations are just part of the story,” says study leader Yiping W. Han, Ph.D., professor of microbial sciences at Columbia University’s College of Dental Medicine and Vagelos College of Physicians & Surgeons. “Other factors, including microbes, can also play a role.”
Scientists have also demonstrated that about a third of colorectal cancers are associated with a common oral bacterium called F. nucleatum. Those cases are often the most aggressive, but nobody knew why. In a prior study, Han’s research team discovered that the bacterium makes a molecule called FadA adhesin, triggering a signaling pathway in colon cells that has been implicated in several cancers. They also found that FadA adhesin only stimulates the growth of cancerous cells, not healthy cells. “We needed to find out why F. nucleatum only seemed to interact with the cancerous cells,” Han added.
In the current study, the researchers found in cell cultures that noncancerous colon cells lack a protein, called Annexin A1, which stimulates cancer growth. They then confirmed both in vitro and later in mice that disabling Annexin A1 prevented F. nucleatum from binding to the cancer cells, slowing their growth. The researchers also discovered that F. nucleatum increases production of Annexin A1, attracting more of the bacteria. “We identified a positive feedback loop that worsens the cancer’s progression,” Han says. “We propose a two-hit model, where genetic mutations are the first hit. F. nucleatum serves as the second hit, accelerating the cancer signaling pathway and speeding tumor growth.”
The researchers then looked at an RNA-sequencing dataset, available through the National Center for Biotechnology Information of 466 patients with primary colon cancer. Patients with increased Annexin A1 expression had a worse prognosis, regardless of the cancer grade and stage, age, or sex. The researchers are currently looking for ways to develop Annexin A1 as a biomarker for more aggressive cancers and as a potential target for developing new treatments for colon and other types of cancer.
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