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News Highlights

May 19, 2013

Women Smokers May Have Greater Risk
for Colon Cancer Then Men

Visiting Professor at the University of Hawaii Cancer Center Makes Discovery

Inger Torhild Gram, MD, PhD

HONOLULU, HI – A study conducted by Inger Torhild Gram, MD, PhD, visiting professor at the University of Hawaii Cancer Center found that female smokers may have a greater risk of developing colon cancer than male smokers. This data was recently published in Cancer Epidemiology, Biomarkers & Prevention a journal of the American Association for Cancer Research.

“Globally, during the last 50 years, the number of new colon cancer cases per year has exploded for both men and women,” said Inger Torhild Gram, MD, PhD, professor in the Department of Community Medicine at the University of Tromsø in Norway. “Our study is the first that shows women who smoke less than men still get more colon cancer.”

Gram and colleagues found that female smokers had a 19 percent increased risk compared with never-smokers, while male smokers had an 8 percent increased risk compared with never-smokers. They also found that the longer and more frequent a woman smoked also increased their risk of getting colon cancer.

Gram and her colleagues examined the association between cigarette smoking and colon cancer, by tumor location, in a large Norwegian cohort of more than 600,000 men and women. The participants from four surveys initiated by the National Health Screening Service of the Norwegian Institute of Public Health had a short health exam and completed questionnaires about smoking habits, physical activity and other lifestyle factors. The participants were followed by linkage to the Cancer Registry of Norway and the Central Population Register. During an average 14 years of follow-up, close to 4,000 new colon cancer cases were diagnosed.

In the next phase of this research, Gram and colleagues from the University of Hawaii Cancer Center will examine this association using data from the Cancer Center’s Multiethnic Cohort Study. “It will be very exciting to look at the different ethnicities,” said Gram. “We will be able to see across different ethnic groups, not just Caucasians.”

Gram hopes to have preliminary results in November 2013 to report back to the American Association for Cancer Research.

“The finding that women who smoke even a moderate number of cigarettes daily have an increased risk for colon cancer will account for a substantial number of new cases because colon cancer is such a common disease,” said Gram. “A causal relationship between smoking and colorectal cancer has recently been established by the International Agency for Research on Cancer of the World Health Organization, but unfortunately, this is not yet common knowledge, neither among health personnel nor the public.”

Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death in men and women combined in the United States, according to the National Cancer Institute (NCI), part of the U.S. National Institutes of Health. About 72 percent of cases arise in the colon and about 28 percent in the rectum.

About Inger Torhid Gram, MD, PhD

Inger Torhild Gram is a professor in the Department of Community Medicine at the University of Tromsø in Norway. While on sabbatical, she is a visiting professor at the University of Hawaii Cancer Center. This is her third visit to the University of Hawaii Cancer Center. She was previously at the Center from 2003 to 2004 and again from 2007 to 2008. 

Her study has been garnering extensive national as well as international news attention:

News Highlights

Mystery cancer: Inside the villages of the damned
What can explain the mysterious "houses of death" in Turkey? The answer may raise concerns across the world

16 April 2013 by Clare Wilson

WHEN Michele Carbone first visited the Cappadocia region of Turkey, he was struck by the beauty of the volcanic landscape, sculpted by wind and rain into picturesque caverns and rock towers. But the mountains hid a dark secret: some of the villages appeared to be cursed.

The inhabitants are plagued by a particularly nasty form of cancer, called mesothelioma. "When we wake up, we see if we've got a cough, because whoever coughs is considered ready to die," one of the villagers told Carbone. "If we see somebody cough when they're walking in the street, everybody looks at them and thinks they will be next."

People in neighboring settlements shun those from the "cancer villages" in case their condition is contagious. Some villagers emigrate but not everyone wants to or can afford to – and anyway, some suspect that leaving will not save them from their "fate".

Carbone, a pathologist at the University of Hawaii Cancer Center, was in Cappadocia to understand the origin of the villagers' illness. Mesothelioma usually occurs in people who have been exposed to asbestos, yet that is not the case here. For four decades scientists and doctors have been trying to solve this puzzle, and in the past few years the answers have started to emerge.

It's not just Cappadocia that will benefit. Asbestos products are now banned in most developed countries, but since this form of cancer takes decades to develop, the number of cases in these nations is still climbing. A similar fate awaits those still using the mineral. Finding out what's behind the cancer villages may reveal the way that this disease develops and perhaps even point to effective treatments.

What's more, the work has revealed a new source of cancer risk that could affect people around the globe. "It doesn't take a genius to figure out that in 30 or 40 years we're going to have a problem," Carbone warns.

A better understanding of mesothelioma is certainly needed. It is one of the deadliest cancers; people tend to live for about 12 months after diagnosis. The tumours form within the lining of the lungs, leading to an "absolutely horrendous" death, says Julian Peto, an epidemiologist who helped to demonstrate the need for restrictions on asbestos use in the 1970s.

It is the very quality that makes asbestos so useful – its extreme durability – that makes it so deadly. Once inhaled, its microscopic dust settles deep within the lungs and cannot be broken down by the body's normal clean-up mechanisms. Over time this leads to inflammation and eventually cancer.

Doom cohort

Asbestos was once a common building material, and so it is people who were in the construction industry between the 1950s and 80s who are most at risk in the West. As these people age, the prevalence of mesothelioma climbs. It is expected to peak in 2016 in the UK, for instance, at nearly 2500 deaths a year. "There's a doom cohort falling off the graph," says Peto, now at the London School of Hygiene and Tropical Medicine.

While asbestos is still mined in some countries, such as Russia and India, those that had banned the stuff could rest easy knowing that they had uprooted the cause of the cancer. At least, that was how it seemed before the recent discoveries in Cappadocia.

It was in the 1970s that a doctor from Ankara was called in to investigate the strange deaths in Cappadocia. The cancer villages are remote; a 5-hour bus journey from Turkey's capital. The soil is poor and the climate harsh, and most people work on the land or make ceramic pottery to sell to tourists. There was a saying about one of the villages: "The peasant of Karain falls ill with pain in the chest and belly, the shoulder drops, and he dies."

As well as helping those villagers with cancer as best they could, the doctor's team questioned the village leaders about the pattern of deaths. They established that in the three worst-affected villages, mesothelioma caused between a third and a half of all deaths. "That's mind-boggling," says Aubrey Miller at the US Environmental Protection Agency, who was later called in to help. "There's nothing else I can think of that has that level of disease associated with it."

Naturally the first thought was that people were somehow being exposed to asbestos. There was no asbestos mine nearby, but a small amount of the mineral was found in the whitewash on people's homes. A more detailed investigation showed, however, that there was no more asbestos in the cancer villages than in neighbouring hamlets.

Instead, the answer lay in the surreal volcanic landscape that is such an attraction to tourists. It hinges on a little-known fact: there are many more kinds of asbestos-like compounds than those that, strictly speaking, qualify for the name. The term asbestos was the commercial name given to six similar compounds that are all silicates: they can be sodium, magnesium, calcium or iron silicate. In nature, there are another 390 silicate minerals that also form the fine, durable dust that is so dangerous when inhaled. It is one of these compounds that is killing the people of Cappadocia.

The substance in question is called erionite and parts of Cappadocia are riddled with it. The erosion of this soft, white rock produces the picturesque chimneys and caverns so characteristic of the region. The three cancer villages happen to be near erionite outcrops, and since the rock is easy to quarry and carve up into blocks, the villagers have used it to build their houses.

That is where the story had got to by the time Carbone came along, but there was still a question: why did the disease seem to affect the inhabitants of some houses more than others? These houses appear cursed, with nearly all the inhabitants succumbing, one by one.

The working theory was that these so-called "houses of death" had been made from stone with more dangerous forms of erionite. Yet after the buildings were pulled down, the rubble was left where it fell, crumbling into white dust that blew around the streets. That should have exposed everyone in the village to the danger, but people in these families were still much more likely to develop cancer.

So Carbone set up a table in the village square and began interviewing residents about every aspect of their lives: what they ate and drank, where they worked, their medical background and family histories. His first hypothesis was that people needed two risk factors to get sick: as well as being exposed to erionite they also had to be infected with a virus called SV40, which may be a contributor to asbestos-caused cancer. But biopsies came back with no trace of the virus.

The villagers' family trees proved more fruitful, suggesting that there could be a genetic basis for the disease. This was a difficult inquiry to pursue, though, as there was no official register of births and deaths and the limited family histories only recorded people's fathers, ignoring the maternal line.

As the evidence accumulated, Carbone and his team published a paper in 2001 using data from six generations of families (The Lancet, vol 357, p 444). The pattern of disease suggested that a single gene raises vulnerability to mesothelioma in these people. The tendency for several generations to live in the same house could be what made it seem like certain homes were blighted.

The villagers weren't happy, though: they felt stigmatised. And other scientists accused the team of publishing their results too soon, as they had not yet identified the gene. In addition, the inheritance pattern didn't look quite right; a few people who were born elsewhere and had married in still got cancer.

Further detective work has eliminated some of the inconsistencies in the inheritance pattern. Some of those who had married in turned out to come from families with their own history of mesothelioma. The gene may be common in the area because isolation has led to high rates of intermarriage. "A lot of those folks are greatly related," says geneticist Joseph Testa at Fox Chase Cancer Center in Philadelphia, Pennsylvania, who worked with Carbone. And even people without the gene may eventually get the cancer simply because there is so much erionite floating around.

While the study attracted criticism, it nevertheless helped the team secure funding to continue studying the Cappadocians. It also allowed them to investigate two families in the US with high rates of mesothelioma, as well as certain other cancers, who didn't have an obvious source of asbestos exposure.

That work came to fruition in 2011, with the discovery that members of both American families have a mutation in a gene called BAP1. This gene normally acts as a brake on cell division, and so it makes sense that the mutated form leads to the excess cell growth that causes tumours.

This mutation seems to be a rare one, though, and it is not to blame in most people who get mesothelioma – including those in Cappadocia. Although the particular gene or genes implicated in the "houses of death" remains unknown, the US finding does suggest that the hunt will eventually pay off. "This is the first concrete evidence that a person's genetic make-up can affect susceptibility to this cancer," says Testa.

Indeed, he thinks there are probably many genes that affect our vulnerability to mesothelioma. That would explain why some people get the cancer after very little contact with asbestos, while others stay healthy after alarmingly high exposure. "I know asbestos workers that told me they threw asbestos snowballs at each other – and they never had mesothelioma," says Testa.

As well as helping to shed light on the genetics of cancer, the Cappadocians' plight also raised the red flag about the danger of erionite. Animal research suggests that, if anything, erionite is more likely to cause cancer than asbestos.

The mineral, which is formed by the action of water on volcanic ash, has been found in mountainous or rocky areas all over the world. In the US, concerns were first raised in North Dakota, where erionite is present in the western Killdeer mountains.

Over the past few decades gravel from these mountains has been used to surface roads, car parks and playgrounds in the sparsely populated Dunn County. "I don't think they know where all that gravel's gone," says Aubrey Miller, who helped run an Environmental Protection Agency investigation into the issue.

Since the EPA stepped in, the state has paved over most of the problem playgrounds and car parks, but some of the roads remain contaminated. As the road gravel gets worn away, it is being topped up with safe gravel, but some erionite must still be there, lurking underneath, and there are no current plans for a clean-up operation.

Many of these highways have seen a sharp increase in traffic thanks to the state's recent oil boom. Some roads that were barely used now have thousands of trucks a day churning up the dust. "If it was asbestos, there would be more public alarm," says Miller.

As yet, Dunn County doesn't seem to have a higher rate of mesothelioma than anywhere else in the US, but Miller points out that it is still early days for a cancer that takes decades to develop. Ominously, in 2010 the EPA found that two of the region's road workers had the beginnings of scars in their lungs similar to those caused by asbestos.

Outside of Dunn County, erionite deposits have so far been found in two other counties of North Dakota, as well as 12 other states. It has also been discovered in parts of Europe, Australia and New Zealand (see "A global concern"). As erionite has only recently come to our attention as a hazard, there is little information on which communities are at risk.

And what about the other 400 or so fibrous silicate minerals that exist in nature? "This whole group of minerals is a potential cause of concern but we just do not know enough about them yet to judge the risk," says Miller.

One thing we do know is that the problem of "traditional" mesothelioma, caused by asbestos, is going to be around for many more years to come. The Cappadocians and the US mesothelioma families may help point the way to better treatments, as clinical trials are quicker and easier when the volunteers have a high rate of the disease in question.

The main reason mesothelioma is so deadly is that it is usually only diagnosed at an advanced stage, when it is too late to cut it out of the chest without damaging vital organs. A blood test for compounds released by the cancer when it is still small might allow it to be detected early enough to be removed; one such compound was discovered a few months ago.

There may even be a way of spotting people with the BAP1 mutation with the naked eye. It was reported last year that two-thirds of people with the faulty gene have multiple benign skin growths that look like small fleshy warts, which are otherwise rare. "Clinicians need to be more aware of this symptom," says Testa.

As this work continues, it is already helping the residents of Cappadocia in a more direct way. They are gradually being moved away from the danger, so at least future generations will be spared. Of the three worst-affected villages, the biggest has been rebuilt in a new location, and a second village is in progress.

Carbone still visits the villages; he has friends there now and likes to go walking through that amazing landscape. But he can never completely relax. Writing of his experiences, he has said that "it is impossible to hold a baby without wondering if she or he will experience the same fate as the man you heard screaming a minute ago. It is impossible to forget any one of the patients."

This article appeared in print under the headline "Villages of the damned"

Clare Wilson is a features editor at New Scientist

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News Highlights

March 18, 2014

UH Cancer Center Director Receives National Award for Work on Mesothelioma
Foundation honors Dr. Michele Carbone's research into a rare and aggressive cancer

Dr. Michele Carbone

The Mesothelioma Applied Research Foundation conferred its Pioneer Award on Dr. Michele Carbone during its national conference in Alexandria, VA. In the photo with Dr. Carbone are, on the left, Sandy Robb, and on the right, Mary Hesdorffer, nurse practitioner and executive director of the Foundation.
Photo courtesty of Mesothelioma Applied Research Foundation

HONOLULU – University of Hawai'i Cancer Center Director Michele Carbone, MD, PhD, is the recipient of the 2014 Pioneer Award, a national honor bestowed by the Mesothelioma Applied Research Foundation.

The Foundation awarded Dr. Carbone the recognition for his extensive contributions to the field of mesothelioma research. Mesothelioma is a rare and aggressive form of cancer that develops in the lining of the lungs and other internal organs. It is known to be caused by exposure to mineral fibers such as asbestos and erionite.

The UH Cancer Center's thoracic oncology team, led by Dr. Carbone and Haining Yang, MD, PhD, has made seminal discoveries in the field of mesothelioma, including the identification of the gene, BAP1, as the cause of familial mesothelioma and melanoma, and of HMGB1 as the protein that promotes the growth of this malignancy. Dr. Carbone had previously worked with Dr. Izzetin Baris to uncover the mystery behind a devastating mesothelioma epidemic in certain villages in a remote area in Turkey. Their research lead the Turkish government to relocate the villagers to a safer location, and to the discovery that mesothelioma can be caused by a genetic predisposition that runs in families.

The Pioneer Award is the latest professional recognition for Dr. Carbone, who was recently ranked by as one of the top mesothelioma experts in the world. In February, he delivered the very prestigious Grand Rounds lecture at the MD Anderson Cancer Center in Texas, and hosted mesothelioma researchers from around the world during a symposium at the UH Cancer Center.

The Foundation's Pioneer Award honors scientific advances in the field of mesothelioma, with the goal of eradicating the life-ending and vicious effects of the disease. The award was presented to Dr. Carbone during the International Symposium on Malignant Mesothelioma in Alexandria, VA, where he delivered the keynote address.

The UH Cancer Center is one of 68 research institutions designated by the National Cancer Institute. Affiliated with the University of Hawai`i at Manoa, the center is dedicated to eliminating cancer through research, education, and improved patient care. Learn more at Like us on Facebook at Follow us on Twitter @UHCancerCenter.

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News Highlights

January 9, 2014

Excellence in Research Awards


Each month the Friends of the University of Hawai‘i Cancer Center award two investigators for recently published work with a check for $1,000.

David Ward, PhD and associate director for basic sciences and translational research, selects the winners based on the publication’s impact factor in major scientific journals.

After the selection, the chosen investigators give short presentations of their work to the Friend’s Board of Directors at their monthly meeting.

The Friend’s Board has been awarding scientists since June 2012. The winning recipients and links to their publications are (beginning with most recent):

January 2014
Erin O. Bantum, PhD, et al for “Surviving and Thriving with Cancer: Results from a Randomized Controlled Trial of an Online Health Behavior Change Program.” Journal: Journal of American Medical Research.

November 2013
Gertraud  Maskarinec, PhD, et al for “Methods for Assessing and Representing Mammographic Density: An Analysis of 4 Case-Control Studies.” Journal: American Journal of Epidemiology.

October 2013
Jayabal Panneerselvam, PhD, et al for “A Hidden Role of Inactivated FANCD2: Upregulating DeltaNp63.” Journal: Oncotarget, September 2013.;jsessionid=d0pulSj0cTQhM3w1SWIS.0

September 2013
James Turkson, PhD, et al for “Therapeutic modulators of STAT signalling for human diseases.” Journal: Nature Reviews Drug Discovery 12, 611-629 (2013).

Fang Qi, et al for “Continuous Exposure to Chrysotile Asbestos Can Cause Transformation of Human Mesothelial Cells via HMGB1 and TNF-α Signaling.” Journal: The American Journal of Pathology, 2013 Nov;183(5):1654-66.

August 2013
Pallav Pokhrel, PhD, et al for “Smokers who try E-Cigarettes to Quit Smoking: Findings from a Multiethnic Study in Hawaii.” Journal: American Journal of Public Health.

Hansong Wang, PhD, et al for “Fine-mapping of genome-wide association study-identified risk loci for colorectal cancer in African Americans.” Journal: Hum Mol Genet. 2013 Dec 15; 22(24):5048-55.

June 2013
Michele Carbone, MD, PhD, et al for “Asbestos is not asbestos: an unrecognized health hazard.” Journal: Lancet Oncology, 14, 578-581, 2013.

Lani Park, PhD, et al for “Association of the FTO Obesity Risk Variant rs8050136 with Percentage Energy Intake From Fat in Multiple Ethnic/Racial Populations.” Journal: American Journal of Epidemiology.

April 2013
Peiwen Fei, PhD, et al for “Recruitment of DNA polymerawe eta by FANCD2 in the early response to DNA damage.” Journal: Cell Cycle 12(5) 803-808; March 2013

March 2013

Andrea Fleig, PhD, et al for “TRMP7 is regulated by halides through its kinase domain. Running title: Halides inhibit TRPM7 and breast tumor cell growth.” Journal: Cellularand Molecular Life Sciences

Toshihiko Kawamori, MD, PhD, et al for “Effect of sphingosine kinase 1 inhibition on blood pressure.” Journal: The FASEB Journal

February 2013
Reinhold Penner, MD, PhD, et al for “ORAI3 silencing alters cell proliferation and cell cycle progression via c-myc pathway.” Journal: Biochim Biophys Acta.

Thomas A. Wills, PhD, et al for “Dual-Process Model of Early Substance Use: Test in Two Diverse Populations of Adolescents.” Journal: Health Psychology

January 2013
Joe Ramos, PhD, et al for “Englerin A selectively induces necrosis in human renal cancer cells” Journal” PLoS One

Joe Ramos, PhD, et al for “RSK2 protein suppresses integrin activation and fibronectin matrix assembly and promotes cell migration.” Journal: J Biol Chem

2012 Award Winners:

Sandi Kwee, MD, et al for “Choline Kinase Alpha and Hexokinases-2 Protein Expression in Hepatocellular Carcinoma: Association with Survival,” Journal: PLoS One

Scott Kuwada, MD, et al for “The atypical histone macroH2A1.2 interacts with HER-2 protein in cancer cells.”

Michele Carbone, MD, PhD, et al for “CSPG4 as a Target of Antibody-based Immunotherapy for Malignant Mesothelioma.” Journal: Clin Cancer Res.

Gertraud Maskarinec , PhD, et al for “Prediagnostic circulating carotenoid levels and the risk of non-Hodgkin lymphoma: the Multiethic Cohort.” Journal: Blood

Haining Yang, PhD, et al for “Cancer Cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma. Cancer Res. (This paper made the cover of the July 1st 2012 issue of Cancer Res.)

Herbert Yu, MD, PhD, Physical activity and breast cancer survival - an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1. Journal: Breast Cancer Res Treat

James Turkson, PhD, et al for “Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts.” Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9623-8.

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