(1) Seminar on "Cancer Clusters: US-Japan Experiences"
Our purpose was to examine the role of cancer clusters (due to the environment or heredity) in pointing the way to novel laboratory research into the origins of human cancer The workshop was organized by Dr. Robert W. Miller and Dr. Haruo Sugano and held at the El Dorado Hotel in Santa Fe, New Mexico, on February 14–15, 1994. Two reports from Japan were of particular interest. Dr. Makoto Goto described an excess of soft-tissue and thyroid cancer in Werner’s syndrome (premature aging beginning at about age 25 and advancing rapidly thereafter). Elsewhere in the world the syndrome is rare, but Dr. Goto has identified about 400 cases in Japan where cousin-marriages contributed to the high frequency of this autosomal recessive trait. Eighty-one people had 94 cancers plus six with meningioma; four others had myelodysplasia, two of them with meningioma. There were marked excesses of soft-tissue sarcomas, thyroid cancer, cholangiocarcinoma, osteosarcoma, and melanoma (12 acral on the feet and two in the nasal cavity). Among those with multiple primaries, a new syndrome was apparent: thyroid cancer with leiomyosarcoma (2 cases), osteosarcoma (2 cases) and leiomyosarcoma plus osteosarcoma (1 case). Dr. Miller will help Dr. Goto prepare a paper on the cancer findings for publication in The Lancet. Werner's syndrome in Japan represents a national (genetically induced) cluster due to cousin marriages there. It was decided to hold a US-Japan Workshop m 1995 on differences m the types of cancers that are excessive in Werner's, Bloom’s, and Fanconi’s syndromes.
Dr. Shunro Sonoda, described two effects of the virus, HTLV-1, which in people of Kyushu with HLA haplotypes found in about 2 percent of the general population developed adult T-cell leukemia, and others, with different haplotypes found in a majority of the population, developed myelopathy, sometimes in children. This observation may be relevant to the reciprocal relationship between the frequencies of lymphoma (low) and autoimmune diseases (high) in Asians as compared with Caucasians. A workshop on this subject is being planned for 1995. The observations concerning HTLV-1 are drawn from clustering of cases due to ethnic (genetic) susceptibility to a virus that is oncogenic or neuropathic.
Dr. Kunio Aoki opened the workshop with a review of type-specific geographic cancer clusters in Japan, in relation to environmental influences. Two high-rate areas for esophageal cancer in Honshu and one in Kyushu appeared to be related to smoking, alcohol use, salty foods and hot food or drinks. An exceptionally high frequency of biliary tract cancer in and around Niigata is suspected to be related to drinking water contaminated with agrochemicals. With regard to familial clusters, the frequency of a family history among patients with stomach cancer was 12 percent; lung or liver, 2 percent; and breast cancer, 1.2 percent (low compared with the U.S.)
Dr. Robert W. Miller noted that virtually every known human carcinogen was first identified by an alert observer, not necessarily a clinician. Random geographic clusters, however are so common that CDC, after studying 108, from 1961-82, was unable to find the cause of any. There are innumerable random clusters of cancer in the U.S. every year. Investigating them etiologically is costly and, because they occur by chance, scientifically barren. The highest yield of new information is from familial (genetic) clusters which have led to recognition of tumor suppressor genes. Their somatic-cell counterparts are now known to be involved in the genesis of a substantial proportion of common non-familial cancers affecting lung, breast, colon, and bone, among others.
The potential carcinogenicity of EMF was reviewed by Dr. Miller, who presented the report of Dr. Leonard Sagan, absent due to illness. As judged in 1992 by independent expert committees in the U.K. and U.S., there is no convincing evidence that EMF is carcinogenic to humans. No biological mechanism is known by which exposure to EMF might induce cancer. Thus the immense expenditures of human and financial resources used to study this matter, which grew from a study of a possible cluster of childhood leukemia in Denver homes near power-1ines, has yielded little. It is important to distinguish clusters with a good chance of being environmentally induced, from random clustering—a judgment, unavoidably imperfect, based on experience and intuition concerning peculiarities in the occurrence of cancer.
Dr. Miller also spoke on the cluster of respiratory cancer due to occupational exposure to mustard gas during its manufacture in Japan during the war. He spoke in place of Dr. Michio Yamakido, who missed his airplane connection due to a snowstorm in Tokyo. Dr. Miller collaborated with the Hiroshima University group in showing the magnitude of the excess cancers from this exposure—now more than 75 cases among about 500 mustard-gas workers. This exemplifies how a true cluster was traced to its cause—by an intern at Hiroshima University Hospital who asked a 30-year-old man with pulmonary carcinoma why he might have developed this neoplasm so young. The patient suggested the wartime occupational exposure as the explanation. This experience exemplifies the discovery of an environmental cause through the investigation of a cancer cluster by an alert clinician.
An aid to identifying geographic clusters of cancers from U.S. cancer mortality data by county was described by Dr. Forrest Pommerenke. He and his collaborators have created diskettes for personal computers (PC) to display state maps by county in color that show mortality rates and numbers from 1950–87 by age, sex, race, five-year time-periods, and cancer site. The user can easily tailor-make maps by selecting from these variables. For example, seven deaths from mesothelioma were found among white women 50–59 years old in Lancaster County, PA, from 1960–69. The maps were developed to allow health officials and others to target measures for cancer prevention and to detect people in their areas with the highest rates for specific cancers ; e.g. screening of non-white women for cervical cancer in Duval-Jacksonville County, FL, could reduce their mortality from this cause by about 60 percent, to the level for white women. As new biomarkers are developed for early detection of cancer, they can be tested in counties with the highest mortality rates as shown by the maps.
A pharmaceutical-induced cluster of patients given Thorotrast before 1946 for diagnostic radiology showed no significant excess of lung cancer as would be expected due to continuous alpha irradiation (radon-220), according to a study by Dr. Yuichi Ishikawa and his associates. This finding suggests that the excess found in uranium miners exposed to radon-222 is due to an interaction involving mine dusts, cigarette-smoking, diesel and blasting fumes, etc. This conclusion is in accord with recent reports of no excess in lung cancer related to residential radon exposure in the U.S.
The intestinal type of stomach cancer clusters in high-risk groups, as among the Japanese. Dr. Haruo Sugano stated that the temporal decrease in the incidence of gastric cancer in Japan has been greater for the intestinal than for the diffuse type, more so in the gastric antrum than in the intermediate area and the corpus, and more in females than males These observations indicate that the environment has a greater influence on the occurrence of the intestinal type than on the diffuse type and illustrates the importance of pathology studies by subtype and subsite.
Case-control studies sometimes suggest that preconception exposure of a parent may cause cancer in the child, although no biological mechanism is known to explain this effect Dr. John J. Mulvihill called attention to an environmental cluster of birth defects which might be due to preconception exposure. Recently, in a Hungarian village, 11 of 15 children were born with birth defects after their mothers had eaten fish that were removed from ponds treated with trichlorfon (an insecticide that slowly releases a potent anticholinesterase) and returned to the pond. There were three sets of twins. Down's syndrome was concordant in one pair, discordant in another, and also affected one singleton. The origin of nondisjunction was identifiable in two cases, both of which showed an error in maternal meiosis II instead of meiosis I, which supports an environmental influence (Lancet 1993:341:539–42). He also summarized biodosimeters being used in studies of somatic cell mutations in workers substantially exposed to radiation in Chernobyl: glycophorin A, chromosome dicentrics, micronuclei in lymphocytes, and chromosomal translocations studied by fluorescence in situ hybridization (FISH) of chromosome-specific DNA probes and G-banding. With regard to future study of germline mutations when new laboratory techniques are developed, it was recommended that DNA be collected and stored now from persons and their parents when a parent was exposed to mutagens such as radiation or cancer chemotherapy.
CDC is rapidly developing new tests of blood levels for chemical exposures, as reported by Dr. Karen K. Steinberg. The results are a great aid to risk assessment, which enables public health policy to be based on reliable high- and low-dose human exposure data supplemented by animal studies. Through the use of data from the first and second National Health and Nutrition Studies (NHANES II and III), the fall of blood lead levels in children was found to parallel the reduction of lead in gasoline, now 99.8 percent lead-free. Because clinical studies of lead poisoning related IQ and behavioral deficits to lower and lower blood lead levels, the threshold for childhood lead poisoning has been decreased from 30µ/D1 to 25µ1 in 1985 and then to 10µ/D1 in 1991. Good measurements led to disease-preventing legislation.
Studies of Vietnam veterans revealed their dioxin blood levels to be the same as those of men who did not serve in Vietnam, a finding which showed a laboriously estimated military exposure index to be unreliable and apt to yield invalid conclusions. The study was discontinued at a great savings. Air Force pilots (Ranch Hand Study) were heavily exposed in handling Agent Orange and had elevated blood levels which showed the biological half-1ife of dioxin to be seven years. For a population-based evaluation of exposures (The Priority Toxicant Reference Range Study), CDC measured 32 volatile organic compounds and 13 nonorganochloride pesticides in specimens from persons in NHANES III. In addition, genetic susceptibility to environmental toxicants is being evaluated in four assays for mutagens: HPRT, GPA, HLA-A, and hemoglobin!!
!. These developments are important to the study of clusters, as for example, in the vicinity of toxic waste dumps. Dr. David Malkin in speaking of recent advances in understanding the biology of the Li-Fraumeni syndrome (LFS), exemplified the role of the laboratory in explaining familial clusters of diverse cancers. Not all classical LFS families have detectable germline mutations in the p53 gene, and those that do, have them in various locations, with some hotspots within the gene. In 22 families with classic LFS, 15 had p53 mutations. Of the remaining seven, four had a defect in a promoter region, and one of these with three osteosarcoma-affected children may be due to an unknown osteosarcoma gene. Patients with sporadic tumors and no family history of LFS sometimes have p53 germline mutations, as in studies of three of six adrenocortical carcinoma (ACC) in children, 3 of 31 rhabdomyosarcomas, 6 of 235 osteosarcomas and 8 of 51 gliomas, including 6 of 19 that were multifocal. Mouse models with germline mutation of the p53 gene survive, but beginning at nine months of age, develop an excess of cancers, including types seen in the human. The ACC series is being extended by a multihospital collaboration. Attention was called to the accumulation of cases at Memorial Sloan Kettering Cancer Center, which has since been able to compile 18 cases with paraffin blocks available for study.
A further example of laboratory research to advance understanding of carcinogenesis based on familial clusters of cancers was presented by Dr. Yusuke Nakamura, who spoke on the genetics of gastrointestinal cancer. His group has examined mutations of the adenomatous polyposis coli (APC) gene in 150 patients with familial adenomatous polyposis (FAP) and in patients with colorectal and other cancers. Among the findings: about one-third of FAP patients had no detectable mutation; mutations in the other two-thirds occurred mainly in the first half of the coding region and resulted in truncation of the APC gene product; there was no correlation with the phenotype of FAP patients (such as those with manifestations outside the colon); more than 80 percent of base substitutions in the APC gene were from cytosine to other nucleotides, mutations clustered within the segment from codon 1286 to 1513; and the frequency of somatic APC point-mutations at CpG sites in U.S. patients was much higher than in Japanese. In other studies, a high frequency of genetic instability during carcinogenesis due to replication error (RER) was found at four microsatellite marker loci on chromosomes 2, 3 and 17 in 6 of 9 pancreatic tumors and 22 of 57 cases of gastric cancer, more frequent in poorly differentiated cases than in well differentiated cases. Such instability may enhance biological understanding and provide prognostic information.
Dr. Michael Alavanja summarized the workshop by noting that clusters may be environmentally induced as illustrated here by reports of a chemical, mustard gas; a virus HTLV-1; diet; or a physical agent, Thorotrast. Familial clustering, which has been a powerful source of new information on carcinogenesis, was illustrated by Li-Fraumeni syndrome of diverse and multiple primary cancers and by Werner's syndrome of premature aging and diverse cancers often with multiple primaries. The most frequent cause of cancer clusters is chance however, which alarms the public and is a great drain on resources. Clusters related to EMF exposure are apparently in this category, as was the cluster of childhood leukemia related to paternal work exposure in a nuclear facility before conception of the child. Although such paternal exposure has not been shown to be a cause of cancer in the human, it has occurred in animal experimentation and, as presented here may account for a high rate of birth defects, especially Down's syndrome, from an intense chemical exposure in a small Hungarian village. Absence of a cluster where one is expected can be informative, as illustrated by the absence of an increase in lung cancer due to Thorotrast (radon-220) exposure at carcinogenic levels of residential radon exposure. Geographic clusters can be identified in the U.S. by using a diskette for personal computers to depict tailor-made maps of cancer mortality by county, age, sex, color, calendar interval, and cancer type. These maps help direct local cancer control efforts by focusing on counties where rates are very high. CDC is developing a battery of tests for measuring blood levels of chemicals that may cause clusters, as from toxic dumps, and testing for host susceptibility to somatic cell mutagens. The role of the environment in the genesis of stomach cancer in Japan, greater for the intestinal than the diffuse type, illustrated the importance by studying cancer by subtype. Molecular studies of familial gastrointestinal cancer and of replication errors at four microsatellite marker loci are advancing understanding of the carcinogenic processes involved, and may be of prognostic value.
Clinical peculiarities in cancer occurrence, expanded through epidemiology have opened substantial new avenues for laboratory research. In return, epidemiologic research enriched by laboratory measures, now seems lacking without them.
PARTICIPANTS
United States
Dr. Michael C.R. Alavanja
Special Assistant
National Cancer Institute
Executive Plaza North, Room 543
Bethesda, MD 20892
Dr. David Malkin
The Hospital for Sick Children
555 University Avenue
Toronto, Ontario
Canada M5G 1X8
Dr. Robert W. Miller
Chief, Clinical Epidemiology Branch
National Cancer Institute
Executive Plaza North, Room 400
Bethesda, MD 20892 USA
Dr. John J. Mulvihill
Department of Human Genetics
Graduate School of Public Health
130 DeSoto Street
Pittsburgh, PA 15261
Dr. Forrest Pommerenke
Medical College of Wisconsin
8701 Watertown Plank Road
Milwaukee, WI 53226
Dr. Leonard A. Sagan
Environment Division
Electric Power Research Institute
3412 Hulview Avenue
P.O. Box 10412
Palo Alto, CA 94303
Dr. Karen Steinberg
Chief of Molecular and Biology Branch
Division of Laboratory Health Sciences
MS-F50
Center for Disease Control and Prevention
4770 Buford Highway, NE
Atlanta, GA 30341
JAPAN
Dr. Kunio Aoki
President
Aichi Cancer Center
1-1 Kanokoden, Chikusa-ku, Nagoya 164
Dr. Makoto Goto
Director, Division of Rheumatic Diseases
Tokyo Metropolitan Otsuka Hospital
2-8- I Minami-Otsuka, Toshima-ku, Tokyo 170
Dr. Yuichi Ishikawa
Associate, Department of Pathology
Cancer Institute
1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170
Dr. Yusuke Nakamura
Head, Department of Biochemistry
Cancer Institute
1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170
Dr. Toshiro Sonoda
Faculty of Medicine
Kagoshima University
8-35-1 Sakuragaoka, Kagoshima 890
Dr. Haruo Sugano
Director Emeritus
Cancer Institute
1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170
Dr. Michio Yamakido
Hiroshima University School of Medicine
1-2-3 Kasumi, Minami-ku, Hiroshima 734
(2) Workshop on "Ethnic Differences in Cancer Occurrence"
A workshop on "Ethnic Differences in Cancer Occurrence," held at the Hyatt Regency Hotel in Honolulu on March 24–25, 1994, also sought to link some of the largest of these differences to new laboratory procedures. The workshp was organized by Dr. Robert W. Miller and Dr. Kunio Aoki.
The question of the reciprocal relationship between the frequencies of lymphoma and autoimmune disease was reviewed in detail by Dr. Stuart C. Finch. It was decided to hold a US-Japan Workshop on this subject in 1995 and for Drs. Miller and Finch to prepare for publication a review of what is known in the meantime.
Dr. Suketami Tominaga summarized the Comprehensive 10-year Strategy for Cancer Control initiated in 1983 by the Japanese Government. The objectives were to 1) clarify carcinogenic mechanisms to be applied to prevention, diagnosis and treatment; 2) train young researchers; 3) promote international collaborative studies; and 4) provide a supplement back-up system to supply experimental materials. Under the Special International Scientific Program (item 3) through 1993 fifty projects have been conducted in 55 countries 43 of which are developing countries. Major projects concern viruses and parasites in the genesis of cancer, natural carcinogens or promoters, migrant studies, etiology and prevention of cancers of special interest, and diagnosis and treatment of cancer by new agents or methods. The influence of the ten-year strategy on international collaborative studies can be seen in the papers from Japan presented at this workshop.
Dr. Robert W. Miller noted that ethnic differences in cancer occurrence, often dramatic, have long been known from epidemiologic observations. As advances are made in laboratory techniques, they can be used to explain these differences. This opportunity is waiting to be more fully pursued. For 30 years, ever since the Tokyo Metropolitan Childhood Cancer Registry was established, it has been known that Wilms' tumor (WT) is only half as frequent in Japan (and other Asian countries) than among U.S. Whites. When cytogenetic studies became feasible, a deletion of the short arm of chromosome 11 was found in the WT-aniridia syndrome through which a WT gene was located and cloned. This progress was made possible by advances in molecular biology, which is now being applied to understanding the genetic mechanism, as explained at this workshop by Dr. Saunders. Differences in the distribution of xeroderma pigmentosum (XP) by subtype (complementation group) in Japan explains differences in risk of UV-induced skin cancer and other clinical features of the disease. Molecular differences in one (of the seven) complementation groups are related to clinical differences in Japan as compared with Tunisia, as will be described by Dr. Takebe at this workshop. Among the marked ethnic differences, as yet unexplored in the laboratory, is the near absence of Ewing's sarcoma and testicular cancer in non-whites, the rarity of cutaneous spreading melanoma in Asians, the low frequency of B-cell lymphproliferative diseases in Asia and a seemingly reciprocal excess of (lymphocyte-mediated) autoimmune diseases, as discussed here by Dr. Finch. Ethnic differences in cancer occurrence may be due to the environment or to heredity (ethnic groups are in a sense are very large families).
Dr. Kunio Aoki spoke on migrant studies, which indicate an environmental influence when rates change after migration from Japan or a heredity influence when there is no change. Mortality from stomach cancer is decreasing among native and U.S. Japanese, but the decline began about 40 years earlier in the U.S. Cancer of the large intestines increased in incidence and mortality in Nissei and Issei, and differences have been noted by subsite. A similar increase is expected among native Japanese. Hepatocarcinoma rates are much higher in Japan than among U.S. Japanese. Leukemia is more frequent among Hawaiian than among native Japanese. Leukemia rates have increased in Japan since 1955, whereas other hematopoietic diseases have declined in frequency. Age at migration may be young, indicating that initiation is early in life, and promotion may occur at any age thereafter.
In the U.S., comparison of type-specific cancer rates can be made for a variety of ethnic groups. Using data from the SEER Program, Dr. John L. Young, Jr., showed unusually high or low incidence rates in Blacks as compared with Whites, 1986–90: