Study helps explain increased melanoma risk in individuals with red hair

Researchers find that the same genetic mutation responsible for red hair also promotes a well-known cancer-causing pathway

2013-08-22

(Press-News.org) BOSTON -- A person's skin pigment, which determines hair color and skin tone, is influenced by the melanocortin-1 (MC1R) gene receptor. For the population's one to two percent of redheads, a mutation in MC1R accounts for their red hair color and typical light skin.

Now researchers from Beth Israel Deaconess Medical Center (BIDMC) and Boston University School of Medicine (BUSM) have discovered that the same MC1R mutation responsible for the red hair phenotype also promotes an important cancer-causing pathway. The new findings, reported on-line today in the journal Molecular Cell, help to explain the molecular mechanisms that underlie redheads' well-known risk of developing melanoma, providing new insights for treating and preventing this dangerous type of skin cancer.

Melanoma is the least common but the most lethal of skin cancers. Accounting for 75 percent of all skin-cancer deaths, melanoma originates in pigment-producing skin cells called melanocytes. Melanoma is believed to be a multi-step process (melanomagenesis) of genetic mutations that increase cell proliferation, cell differentiation and cell death and increase an individual's susceptibility to ultraviolet (UV) radiation. Two types of UV radiation – UVA and UVB – can mutate DNA in skin cells and lead to melanoma.

"In this current study, we have demonstrated that the mutation MC1R-RHC promotes the PI3K/Akt signaling pathway when a red-haired individual is exposed to UV radiation," explains co-senior author Wenyi Wei, PhD, an investigator in the Department of Pathology at BIDMC and Associate Professor of Pathology at Harvard Medical School. PI3K/Akt is a well-known cancer-causing pathway, implicated in breast cancer, ovarian cancer and lung cancer.

Previous work by the study's co-senior author Rutao Cui, MD, PhD, a member of the BUSM Department of Dermatology, had demonstrated that MC1R plays a key role in protecting melanocytes from UV-induced DNA damage. In this current study, Wei and Cui wanted to find out how this was happening.

Led by co-first authors, Lixin Wan, PhD, a member of the Wei laboratory at BIDMC and Juxiang Cao, PhD, a member of the Cui lab at BUSM, the scientific team embarked on a series of experiments in both cell cultures and mouse models. Their experiments showed that in normal circumstances, MC1R was binding to PTEN, a well-known tumor suppressor gene. PTEN acts to safeguard against cancer; without PTEN, the end result is elevated signaling in the cancer-causing P13K/Akt pathway.

The team then went on to demonstrate that MC1R-RHC mutations found in red-haired individuals lacked this protective mechanism. "As a result, upon UVB exposure, we saw an increased destruction of PTEN in the mutated pigment cells," says Wei. The team additionally found that in these same MC1R-RHC pigment cells, elevated PI3K/Akt activity was boosting cell proliferation and was synchronizing with another well-known cancer mutation in the BRAF gene (found in nearly 70 percent of human melanomas) to further accelerate cancer development. In support of these results, note Wei and Cui, another research group at Massachusetts General Hospital recently demonstrated that expression of the BRAF gene mutation in the melanocytes of mice carrying a mutated MC1R gene led to a high incidence of invasive melanomas.

"Together, our findings provide a possible molecular mechanism as to why red-haired individuals harboring MC1R mutations are much more susceptible to UV-induced skin damage than individuals with darker skin, resulting in a 10-to100-fold higher frequency of melanoma," says Wei.

The authors note that this newly established link between MC1R and PTEN will be a starting point for future studies, adding that it remains unclear why only MC1R genetic variants linked to the red hair phenotype – but not all MC1R variants – are unable to bind to PTEN following UV exposure.

"We think that MC1R variants, in combination with mutations in the BRAF gene, could be used as markers of an increased risk of developing melanoma," explains Wei. The authors add that these new findings suggest that drug inhibitors that target the PI3K/Akt signaling pathway might be used in combination with Vemurafenib, a drug that targets the BRAF oncogenic protein, to treat melanoma patients who have both BRAF and MCIR variants.

### Study coauthors include Xiangpeng Dai of BIDMC; BUSM investigators Byungwoo Ryu, Rhoda M. Alani and Stefania Lenna; Elke Hacker of the Queensland (Australia) University of Technology; Celia Jimenez-Cervantes of the University of Murcia, Spain; Yongjun Wang of the Longhua Hospital, Shanghai, China; Nick R. Leslie of Heriot Watt University, Edinburgh, UK; George X. Xu of the University of Pennsylvania; Hans R. Widlund of Brigham and Women's Hospital; Ken Dutton-Regester and Nicholas Hayward of Queensland (Australia) Institute of Medical Research; and Colin R. Goding of the University of Oxford, UK.

This work was supported by grants from the National Institutes of Health (1RO1CA137098; UL1-TR000157; GM089763), the American Cancer Society, the Harry J. Lloyd Charitable Trust, the National Health and Medical Research Council of Australia; the National Basic Research Program of China; the Key Program of Natural Science Foundation of China; and the Program for Changjiang Scholars and Innovative Research Team in University.

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School, and currently ranks third in National Institutes of Health funding among independent hospitals nationwide.

BIDMC has a network of community partners that includes Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Health Care, Commonwealth Hematology-Oncology, Beth Israel Deaconess HealthCare, Community Care Alliance, and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Senior Life and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www.bidmc.org.

ELSE PRESS RELEASES FROM THIS DATE:

Human brains are hardwired for empathy, friendship, study shows

2013-08-22

Perhaps one of the most defining features of humanity is our capacity for empathy – the ability to put ourselves in others' shoes. A new University of Virginia study strongly suggests that we are hardwired to empathize because we closely associate people who are close to us – friends, spouses, lovers – with our very selves. "With familiarity, other people become part of ourselves," said James Coan, a psychology professor in U.Va.'s College of Arts & Sciences who used functional magnetic resonance imaging brain scans to find that people closely correlate people to whom ...

23andMe conducts the first genetic study of non-syndromic striae distensae (stretch marks)

2013-08-22

Mountain View, Calif. –August 22nd, 2013 23andMe, the leading personal genetics company, has conducted the first genetic study of striae distensae (stretch marks). Researchers at the company identified four genetic markers significantly associated with the development of stretch marks that inform why some individuals are more susceptible to the skin condition. Estimates of the prevalence of stretch marks range from 50-80 percent, however the exact causes of stretch marks are still widely unknown. Many factors, including excessive skin distension (during pregnancy, ...

Beetles modify emissions of greenhouse gases from cow pats

2013-08-22

Cattle contribute to global warming by burping and farting large amounts of greenhouse gases. Some of the same gases are also emitted from cow pats on pastures. But now researchers from the University of Helsinki have found that beetles living in cow pats may reduce emissions of the key greenhouse gas - methane. Agriculture is one of the biggest sources of the anthropogenic greenhouse gases responsible for global warming. Among these, cattle farming for meat and milk are major sources of methane, a gas with a potent warming effect. Much of this methane comes from the ...

Relating animals to humans could help conservation projects

2013-08-22

In a paper published by the journal Biodiversity Conservation, the researchers also suggest that anthropomorphism is overlooked as a powerful tool for promoting low-profile species that are either endangered or require urgent attention. At present, anthropomorphism in conservation is limited to social, intelligent animals, such as chimpanzees, polar bears and dolphins. According to the research, this would imply that other species are not worthy of conservation because they are not like humans in the 'right' ways. However, by making conservationists more aware of how ...

Old concrete can protect nature

2013-08-22

Usually we think of demolished concrete walls and floors as environmental contaminants, but in fact this material may turn out to be a valuable resource in nature protection work. This is the conclusion from researchers from University of Southern Denmark after studying the ability of crushed concrete to bind phosphorus. "We have shown that crushed concrete can bind up to 90 per cent of phosphorus, "says PhD student and environmental engineer, Melanie Sønderup, Department of Biology at the University of Southern Denmark. Contributors to the research are also postdoc, ...

A mother's genes influence her child's aging

2013-08-22

As we grow older, not only the function of organs slows down. Also on a cellular level more and more damages occur. One reason is that DNA errors accumulate which cause defective cells. Now a team of researchers lead by Nils-Göran Larsson at the Max Planck Institute for Biology of Ageing in Cologne has shown that ageing is determined not only by the accumulation of DNA damage that occurs during lifetime but also by damage that we acquire from our mothers. In a study on mice, the researchers have shown that mutations of maternally inherited mitochondrial DNA influence the ...

First laser-like X-ray light from a solid

2013-08-22

Researchers have for the first time created an X-ray laser based on a solid. The method developed at DESY's free-electron laser FLASH opens up new avenues of investigation in materials research, as reported by the team of Prof. Alexander Föhlisch of the Helmholtz Zentrum Berlin (HZB) in the British scientific journal "Nature." "This technology makes it possible to analyse sensitive samples that otherwise are quickly destroyed by intense X-ray light," notes co-author Prof. Wilfried Wurth of the University of Hamburg and the Hamburg Center for Free-Electron Laser Science ...

Engaging in a brief cultural activity can reduce implicit prejudice

2013-08-22

A small cue of social connection to someone from another group — such as a shared interest — can help reduce prejudice immediately and up to six months later, according to new research published in Psychological Science, a journal of the Association for Psychological Science. "Our research shows that even a brief opportunity to take part in another group's culture can improve intergroup attitudes even months later," says psychological scientist and lead researcher Tiffany Brannon of Stanford University. Decades of research in psychology show that extended relationships ...

2 alternative treatments may help relieve postoperative nausea

2013-08-22

San Francisco, CA. (August 22, 2013) – Two simple, non-drug treatments—aromatherapy and intravenous administration of a simple sugar solution—may offer effective new approaches to relieving nausea and vomiting after surgery, report a pair of studies in the September issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS). "Aromatherapy is promising as an inexpensive, noninvasive treatment for postoperative nausea that can be administered and controlled by patients as needed," according to a research report by Dr Ronald ...

Study finds grandmothers who raise their grandkids struggle with depression

2013-08-22

Grandmothers who care for their grandkids fulltime need help for depression and family strains, report researchers from the Case Western Reserve University's Frances Payne Bolton School of Nursing. Carol Musil, PhD, RN, FAAN, professor of nursing, recently conducted one the longest-running studies on grandmothers in various family situations, from serving as their grandkids' fulltime caregivers to those not caring for their grandchildren as a comparison. "Although we expected the primary caregiver grandmothers raising grandchildren would have more strain and depressive ...

Study helps explain increased melanoma risk in individuals with red hair

ELSE PRESS RELEASES FROM THIS DATE:

LAST 30 PRESS RELEASES: