The presence of certain bacteria in the mouth may reveal increased risk for pancreatic cancer and enable earlier, more precise treatment. This is the main finding of a study led by researchers at NYU Langone’s Laura and Isaac Perlmutter Cancer Center.

Pancreatic cancer patients are known to be susceptible to gum disease, cavities, and poor oral health in general, say the study authors. That vulnerability led the research team to search for direct links between the makeup of bacteria driving oral disease and subsequent development of pancreatic cancer, a disease that often escapes early diagnosis and causes 40,000 U.S. deaths annually.

“Our study offers the first direct evidence that specific changes in the microbial mix in the mouth—the oral microbiome—represent a likely risk factor for pancreatic cancer along with older age, male gender, smoking, African-American race, and a family history of the disease,” says senior investigator and epidemiologist Jiyoung Ahn, PhD.

Specifically, researchers found that men and women whose oral microbiomes included Porphyromonas gingivalis had an overall 59 percent greater risk of developing pancreatic cancer than those whose microbiomes did not contain the bacterium. Similarly, oral microbiomes containing Aggregatibacter actinomycetemcomitans were at least 50 percent more likely overall to develop the disease. Doctoral student and lead investigator Xiaozhou Fan, MS, says both types of bacteria have been tied in the past to periodontitis, a disease characterized by inflammation of the gums.

“These bacterial changes in the mouth could potentially show us who is most at risk of developing pancreatic cancer,” adds Ahn, an associate professor at NYU Langone and associate director of population sciences at the Perlmutter Cancer Center.

In another study, Ahn and her colleagues showed that cigarette smoking was linked to dramatic, although reversible, changes in the amount and mix of bacteria in the oral microbiome. But she cautions that further research is needed to determine if there is any cause-and-effect relationship, or how or whether such smoking-related changes alter the immune system or otherwise trigger cancer-causing activities in the pancreas.

Laura and Isaac Perlmutter Cancer Center nyulangone.org/press-releases/pancreatic-cancer-risk-tied-to-specific-mouth-bacteria

Ludwig researchers working in collaboration with colleagues in Australia and the US have shown that fragments of tumour DNA circulating in the blood can be used to gauge the risk of colorectal cancer recurrence and the efficacy of chemotherapy following surgery. The finding is an important step toward the development of a non-invasive and more effective test for the detection, monitoring and treatment of cancer.

‘Prior studies, including ones from our group, have shown that this technique is sensitive enough to detect tumour DNA fragments in patients with advanced cancer,” Bert Vogelstein, co-director of the Ludwig Center at Johns Hopkins and one of the study leaders. “But this new study gets us one major step closer to the real goal, because it suggests that it can detect residual disease in early stage patients well before conventional clinical or radiologic criteria can.’

The decision of whether a stage II colon cancer patient should be treated with adjuvant, or post-operation, chemotherapy remains one of the most challenging areas in colorectal oncology. Such assessments are currently made by combining a number of clinical and pathologic features—such as the tumour’s appearance under the microscope, including how far it has spread through the bowel wall—or looking for the presence of cancer-specific genetic markers that have prognostic significance.

However, current methods are imprecise, and as a result doctors tend to err on the side of caution. Currently, up to 40 percent of stage II patients undergo the rigors and risks of adjuvant chemotherapy even though only a small fraction of them are destined to experience a cancer relapse.

‘The routine procedure is to give six months of chemotherapy, but we don’t have any way of knowing if the treatment is effective,’ said Jeanne Tie, a Ludwig investigator at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Victoria, Australia, and lead author of the study.

Cancer cells often shed their DNA into the blood when they die, and recent advances in technology have made it possible to capture and profile these relatively rare fragments of DNA. Mutations in such circulating tumour DNA (ctDNA) can serve as extremely specific cancer biomarkers.

‘We have to be able to pick out a single tumour DNA among ten thousand normal DNA fragments,’ Tie said. ‘That’s the level of sensitivity that we needed to get down to, and that wasn’t possible until now.’

For the current study, Tie and her colleagues collected tumour samples from 230 patients with stage II colorectal cancer. They analysed the DNA of the tumour specimens and then designed personalized assays to target each patient’s particular genetic mutations.

The assays were applied to blood samples taken from the patients four to 10 weeks after surgery to remove tumours. Twenty of the 230 patients tested positive for ctDNA, and of this group, 80 percent experienced cancer relapse within about two years. Of the 164 patients whose blood tested negative for ctDNA, only 10 percent relapsed.

‘A positive ctDNA test is an indicator that cancer cells from the original tumor are hiding somewhere in the body,’ said Peter Gibbs, a Ludwig investigator at WEHI who co-led the study with Tie and Vogelstein.

The team also looked at whether ctDNA could be used to gauge the impact of chemotherapy treatments. Six of the patients who tested positive for ctDNA following surgery also underwent adjuvant chemotherapy. The scientists continued to collect blood samples from these patients and found that in two patients, ctDNA readings changed from positive after surgery to negative following chemotherapy.

‘To an oncologist, that’s probably the most exciting aspect of a ctDNA screening test—that it can be used not only to determine the risk of recurrence, but also as a real-time marker of chemotherapy benefits,’ said Gibbs.

In the current study, the ctDNA assays were custom-tailored to each patient’s unique cancer mutations, but the scientists are also developing a ctDNA screening test that covers frequently occurring colorectal cancer mutations.

‘When such a generic test is developed, it could still catch more than 90 percent of colorectal cancers, and it would eliminate the need to retrieve and test individual tumour samples, thus saving time, effort and money,’ Gibbs said.

www.ludwigcancerresearch.org/news/new-screening-test-using-blood-biomarkers-may-identify-risk-colon-cancer-recurrence-early

Changes in benign tissues next to prostate tumours may provide an early warning for patients at higher risk for biochemical recurrence after a radical prostatectomy, a study by researchers at Case Western Reserve University and Johns Hopkins Medical Institutions shows.

Biochemical recurrence, which is increasing prostate-specific antigen (PSA) levels, can be used to predict which prostate cancer patients will develop local recurrence, distant metastases and death.
In a small sampling, image analysis of the adjacent tissue was a better predictor than the current standard for prognosis following the prostatectomy.
If preliminary findings are confirmed by further studies, they may help doctors decide sooner which patients need more follow-up therapies after surgery or should return for more regular monitoring.
“In a sense, this study is validating what a lot of people think regarding these cancers—that there is a field effect, as if the tumour has hard-to-see tentacles that can affect the patient and outcomes,” said Anant Madabhushi, the F. Alex Nason professor II of biomedical engineering at Case Western Reserve and leader of the research.

Madabhushi worked with Case Western Reserve’s George Lee, a research assistant professor, and Sahirzeeshan Ali, a PhD student, and Johns Hopkins Medical Institutions’ Robert W. Veltri, associate professor of urology, and Jonathan I. Epstein, the Reinhard Professor of Urologic Pathology. Their study is published in the journal European Urology Focus.

The researchers analyzed records from 70 patients who underwent radical prostatectomies from 2000 to 2004 with up to 14 years follow-up. They digitized images of the resected prostate specimens and analysed the tumour regions and surrounding tissue that appeared to be benign.
Of the group studied, 22 suffered from biochemical recurrence, metastasis or died.

The scientists used computers to search for and identify image features that may be undetectable with the human eye, but which may correlate with a biochemical recurrence. They used the top 10 features to develop a risk score.

They were surprised to find that nuclear shape and architecture in the benign-looking tissue were greater predictors of recurrence than features found in the tumour, Madabhushi said. “Its an amazing finding, completely unexpected.”
Among the risk calculators used to assess prostate cancer recurrence is a nomogram of variables known to influence recurrence, and a Gleason score, which is based on the cancer tissue pattern compared to normal tissue.
“We were able to do better than nomograms and the Gleason score,” Madabhushi said.
But by combining the benign-field features with tumour features extracted from patient’s pathology images and Gleason scoring, they were able to further improve the prediction of recurrence.

Case Western Reserve University blog.case.edu/think/2016/07/06/changes_in_benign_tissue_next_to_prostate_tumours_may_predict_biomedical_recurrence_of_cancer_scientists_find

A single chemical receptor in the brain is responsible for a range of symptoms in mice that are reminiscent of obsessive-compulsive disorder (OCD), according to a Duke University study.

The findings provide a new mechanistic understanding of OCD and other psychiatric disorders and suggest that they are highly amenable to treatment using a class of drugs that has already been investigated in clinical trials.

“These new findings are enormously hopeful for considering how to approach neurodevelopmental diseases and behavioural and thought disorders,” said the study’s senior investigator Nicole Calakos, M.D., Ph.D., an associate professor of neurology and neurobiology at the Duke University Medical Center.

OCD, which affects 3.3 million people in the United States, is an anxiety disorder that is characterized by intrusive, obsessive thoughts and repeated compulsive behaviours that collectively interfere with a person’s ability to function in daily life.

In 2007, Duke researchers (led by Guoping Feng, who is now at the Massachusetts Institute of Technology) created a new mouse model of OCD by deleting a gene that codes for Sapap3, a protein that helps organize the connections between neurons so that the cells can communicate.

Similar to the way some people with OCD wash their hands excessively, the Sapap3-lacking mouse grooms itself excessively and shows signs of anxiety. Although researchers praised the new model for its remarkable similarity to a human psychiatric disorder, and have begun using it to study OCD, questions remain about how the loss of the Sapap3 gene leads to the grooming behaviours.

In the new study, Calakos’s team found that over-activity of a single type of receptor for neurotransmitters — mGluR5, found in a brain region involved in compulsive behaviours — was the major driver for the abnormal behaviours. When researchers gave Sapap3-lacking mice a chemical that blocks mGluR5, the grooming and anxiety behaviours abated.

“The reversibility of the symptoms was immediate — on a minute time frame,” Calakos said. In contrast, the original study describing Sapap3-lacking mice found that antidepressants could help treat symptoms but on the time scale of weeks, as is typical with these drugs in patients.

The immediate effects seen in the new study were also surprising, given that the brains of these mice appear developmentally immature and neurodevelopmental diseases are not typically thought of as being easily reversible, Calakos said.

Intriguingly, by taking normal laboratory mice and giving them a drug that boosted mGluR5 activity, Calakos’s team could instantaneously recreate the same excessive grooming and anxiety behaviours they saw in the Sapap3-lacking mice.

The researchers found that without a functioning Sapap3 protein, the mGluR5 receptor is always on. That, in turn, makes the brain regions involved in compulsion overactive. In particular, a group of neurons that give the “green light” for an action, like face-washing, is working overtime.

Calakos said that mGluR5 should be considered for the treatment of compulsive behaviours. “But which people and which compulsive behaviours? We don’t know yet,” she added.

Duke University today.duke.edu/2016/07/ocdreceptor

Distribution of single nucleotide variant (SNV) counts detected through exome sequencing of melanoma samples, grouped by the presence of R alleles of the MC1R locus shown as a boxplot with median, quartiles, whiskers and outliers.

For the first time, researchers at the Wellcome Trust Sanger Institute and University of Leeds have proved that gene variants associated with red hair, pale skin and freckles are linked to a higher number of genetic mutations in skin cancers. The burden of mutations associated with these variants is comparable to an extra 21 years of sun exposure in people without this variant.

The research showed that even a single copy of a red hair-associated MC1R gene variant increased the number of mutations in melanoma skin cancer; the most serious form of skin cancer. Many non-red haired people carry these common variants and the study shows that everyone needs to be careful about sun exposure.

Red-headed people make up between one and two percent of the world’s population but about 6 per cent of the UK population. They have two copies of a variant of the MC1R gene which affects the type of melanin pigment they produce, leading to red hair, freckles, pale skin and a strong tendency to burn in the sun.

“It has been known for a while that a person with red hair has an increased likelihood of developing skin cancer, but this is the first time that the gene has been proven to be associated with skin cancers with more mutations.’

‘Unexpectedly, we also showed that people with only a single copy of the gene variant still have a much higher number of tumour mutations than the rest of the population.  This is one of the first examples of a common genetic profile having a large impact on a cancer genome and could help better identify people at higher risk of developing skin cancer.”

Dr David Adams, joint lead researcher at the Wellcome Trust Sanger Institute
The researchers analysed publically available data-sets of tumour DNA sequences collected from more than 400 people. They found an average of 42 per cent more sun-associated mutations in tumours from people carrying the gene variant.

“This is the first study to look at how the inherited MC1R gene affects the number of spontaneous mutations in skin cancers and has significant implications for understanding how skin cancers form. It has only been possible due to the large-scale data available. The tumours were sequenced in the USA, from patients all over the world and the data was made freely accessible to all researchers. This study illustrates how important international collaboration and free public access to data-sets is to research.”

Exposure to ultraviolet light from either sunlight or sunbeds causes damage to DNA and it has been thought that the type of skin pigment associated with red-heads could allow more UV to reach the DNA.  While this may be one mechanism of damage, the study also revealed that the MC1R gene variation not only increased the number of spontaneous mutations caused by ultraviolet light, but also raised the level of other mutations in the tumours.  This suggests that biological processes exist in cancer development in people with MC1R variation that are not solely related to ultraviolet light.

“This important research explains why red-haired people have to be so careful about covering up in strong sun. It also underlines that it isn’t just people with red hair who need to protect themselves from too much sun. People who tend to burn rather than tan, or who have fair skin, hair or eyes, or who have freckles or moles are also at higher risk.’

Sanger Institute www.sanger.ac.uk/news/view/red-hair-gene-variant-drives-skin-cancer-mutations