When Paul Kleihues, M.D., became director of the International Agency for Research on Cancer in 1994, he set out to make IARC more flexible and responsive to a fast-moving scientific agenda.
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Initial concerns that top-flight researchers might balk at the lack of job security proved unfounded, Kleihues said, and he pointed out that IARC successfully recruited young scientists with stellar research records who thrive on independence. Even skeptics of the new strategy among the agencys staff and governing council have been convinced that it is right for the times, allowing IARC, a part of the World Health Organization, to move into emerging areas of research while maintaining longstanding programs in laboratory science and epidemiology.
"In the old days, the research topics really didnt change that often," he said. "You worked on chemical carcinogenesis in experimental animals for 10 or 15 years. But today, we must attend to different priorities. Mutation screening, genome analysis, proteomicsall these things have emerged within just a few years, and if the agency cannot respond to this changing scientific environment, we would lose the necessary flexibility."
IARCs cancer genetics program reflects the agencys mix of continuity and novel approaches. A major ongoing interest has been the gene for X-linked lymphoproliferative disease, in which mutations confer excessive sensitivity to Epstein-Barr virus infection (see News, Oct. 18, 1995).
IARC scientists were part of an international consortium that cloned the gene, called SH2D1A, in 1998. They recently created XLP knockout mice to study the genes functions in greater detail, which may help elucidate causes of other EBV-associated cancers such as Burkitts lymphoma and nasopharyngeal carcinoma.
Another knockout mouse was developed by Zhao-Qi Wang, Ph.D., of IARCs Laboratory of Gene-Environment Interactions, this one lacking the poly(ADP-ribose) polymerase, or PARP gene. The PARP protein senses DNA strand breaks and works with p53 in maintaining telomere function, chromosome stability, and tumor suppression. As reported in the June 2001 Molecular and Cellular Biology, the p53 and PARP double-knockout mice develop breast, lung, prostate, skin, and brain tumors with high frequency, similar to Li-Fraumeni syndrome in humans.
Overall, IARC is shifting its emphasis from single-gene, familial cancer syndromes like XLP to multigenic mechanisms of cancer. A vast data resource for these studies is the nine-country European Prospective Study of Nutrition and Cancer (EPIC), the largest ever epidemiologic and laboratory study of diet and cancer.
IARC has collected DNA samples, body measurements, and questionnaire data on diet, smoking, and other habits from 300,000 participants who are tracked by national cancer registries. The data are being used to examine single-nucleotide polymorphisms that may influence the relationship of diet to estrogen metabolism, and will be used to study a wide range of questions involving genetic susceptibility, environmental exposures, and their interactions.
"We are investing heavily in this area because we have this unique database," Kleihues said, and plans are being made for joint IARC-NCI studies of EPIC samples.
In June, IARC will host the European Conference on Nutrition and Cancer, with sessions on mechanisms of nutritional carcinogenesis and anticarcinogenesis, hormones, genenutrient interactions, body weight and physical activity, and dietary chemoprevention trials.
Pierre Hainaut, Ph.D., and colleagues in IARCs Molecular Carcinogenesis group recently resumed studies of esophageal cancer in Iran, which had been closed to the scientists since the Islamic revolution in 1978.
Iran is part of an "esophageal cancer belt" that extends to parts of China, where the causes of the high incidence are unknown but appear unrelated to the alcohol- and tobacco-caused esophageal tumors common in Western countries. In collaboration with U.S. and Iranian scientists, the group is studying tumor samples from these high-incidence areas to look for genetic fingerprints that may provide clues to the etiology (see News, Jan. 17, p. 86).
In The Gambia, where IARC has a longstanding program on hepatitis infection and hepatocellular carcinoma, researchers from NCI and IARC showed that an aflatoxin-associated "hotspot" mutation in the p53 gene can be detected in serum (published in the Journal, Jan. 19, 2000, p. 14853).
"Liver cancer develops very rapidly in these countries and we have few methods of early detection," Kleihues said. "Now we can detect aflatoxin-related mutations in the serum of patients before they reach the stage of liver cancer."
Next year, IARCs Carcinogen Identification and Evaluation Unit, which produces the authoritative, orange-covered monographs, will revisit the issue of tobacco smoking and cancer, last evaluated in 1985, and for the first time will include a thorough analysis of the evidence regarding environmental tobacco smoke.
"It seems to be an issue whose time has come," said Jerry Rice, Ph.D., the units chief. A substantial number of studies and meta-analyses (including a multicenter IARC study published in the Journal, Oct. 7, 1998, p. 144050) agree that there is a modest increase in risk of lung cancer, about 15%, in spouses of smokers, he said. The group will also look at new evidence about the role of smoking in cancers of the cervix, bladder, kidney, and other organ sites for which new data are available.
In addition, Rice said, "there is now the very strong, well-researched data about the benefits of stopping smoking," notably from Richard Peto and colleagues at Oxford University, England. Also on the units agenda are IARCs first formal evaluation of the relationship between cancer and nonionizing radiation (such as electromagnetic fields from power lines) in June 2001, and evaluations of relationships between cancer and manmade vitreous fibers in October and herbal medicines next February.
Major IARC publications in recent years have been the EUROCARE reports, which involve 45 European cancer registries in 17 countries and compare cancer survival among countries and regions.
"EUROCARE shows where the strengths and weaknesses lie and has an enormous impact on national cancer control policies," Kleihues said. "Some countries that are at the top in research suddenly see that their patients have a 10% lower survival rate over 5 years," spurring efforts to improve the translation of research advances to patient care.
The first two EUROCARE reports, published in 1995 and 1999, did not include information on stage at diagnosis, but EUROCARE-3 is planned to include this data, which will help separate the effects of early detection and treatment on survival.
The EUROCARE-2 report, carcinogen monographs, and other IARC publications (including the latest, Biomarkers in Cancer Chemoprevention, based on a workshop on that topic held at the Krebsforschungszentrum in Heidelberg, Germany, in February 2000) are available on IARCs Web site, http://www.iarc.fr/.
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