(1) Molecular Carcinogenesis and Molecular Epidemiology of Cancer
The U.S.-Japan Workshop on Molecular Carcinogenesis and Molecular Epidemiology of Cancer was convened at The Orchid at Mauna Lani Hotel, Hawaii, February 14-15, 1998. An interactive and eclectic program that was co-organized by Drs. Tomoyuki Kitagawa and Curtis Harris (agenda and extended abstracts are enclosed).
After opening remarks by Drs. Kitagawa and Harris, Dr. Mikhail Denissenko presented evidence that electrophilic metabolites of certain chemical carcinogenesis, e.g., benzo[a]pyrene, preferentially form covalent DNA adducts at CpG dinucleotides which are sites of 5-methylcytosine and mutational hotspots in the p53 tumor suppressor gene. In addition to sites of preferential adduct formation, certain CpG are sites of slow DNA repair. Finally, p53 mutants vary in their pathobiological potency.
Dr. Minako Nagao described the mutational characteristics of food-borne carcinogens using an animal model of human colon carcinogenesis. Heterocyclic carcinogens, IQ or PhIP, induced mutations in the gatekeeper genes, APC or!!
!-catenin. Mutations occurred in one or the other gene and not both, which is consistent with the data in humans indicating that APC and!!!-catenin are in the same signal transduction pathway. She also reported mouse-specific and rat-specific mutational spectrum in the lacI transgene in the Big Blue mice and Big Blue rat. Dr. Fred Kadlubar reviewed the genetic polymorphisms in carcinogen-metabolizing genes and their role in DNA adduct formation and human colon, pancreas, and prostate carcinogenesis. He described gene-environment and gene-gene interactions that influence an individuals cancer risk. Genetic polymorphisms in cancer susceptibility genes, e.g., cytochrome p450 (CYP) genes, vary in their frequency among ethnic populations. Well cooked meat consumption and rapid acetylator phenotype increase the risk of colon cancer, whereas the slow acetylator phenotype increases the risk of bladder cancer in smokers. Dr. Kadlubar has also identified “at risk”
CYP1B1 alleles in prostate carcinoma.
Dr. Kei Nakachi discussed the molecular epidemiology of breast cancer. Abnormal transcripts of the FHIT gene was observed in 38% of Japanese breast cancer and was associated with an increased risk of a second breast cancer. Increased expression of IGF-I and IGF-II mRNA was positively correlated with the metastatic potential of breast cancer.
Dr. Hidetaka Eguchi described the role of apoptosis in breast carcinogenesis with special reference to pro-apoptotic Bak and Bc12 genes. Increased Bc12 expression was associated with estrogen receptor (ER) positive breast cancer. ER negative tumors exhibited decreased expression levels of both Bak and Bc12. The interaction of anti- and pro-apoptotic genes contributes to the molecular pathogenesis of breast cancer.
Dr. Peter Shields continued the discussion of breast cancer. He emphasized the gene-environment-lifestyle interactions including the observation of increased risk of breast cancer in women who are smokers and have the rapid acetylator genotype. Women smokers with the slow acetylator genotype are comparatively at decreased risk. Certain genotypes in the dopamine receptor and transporter genes are associated with nicotine addiction.
Dr. Kazuo Tajima described an ethnoepidemiologic approach to the risk factors of human cancers. The studies of migrants have demonstrated that they develop the general cancer pattern of the population in their new country of residence. However, this is not the case for hereditary cancers such as Wilms’ tumor and retinoblastoma. The lifestyle factors including diet and focused strategies for cancer prevention were presented.
Dr. Curtis Harris discussed the interaction of nitric oxide (NO) and p53 in human colon carcinogenesis. Increased expression of inducible nitric oxide synthase (NOS2) was associated with C to T transitions at CpG sites in the p53 tumor suppressor genes. High concentration of NO also induced apoptosis in human tumor cells with wild-type p53 but enhanced the tumorigenicity of human carcinomas with mutant p53.
Dr. Tomoyuki Kitagawa discussed cancer in aged people and the concept of Tenju-gann (Natural-end cancer). With the progress in primary prevention practice, carcinoma in old people may tend to be well-differentiated and slow growing. Aggressive cancer therapy for very old often merely shorten the lifespan and decrease in the quality of life in these cases. The concept of Tenju-gann, which regard cancer death of very old with minimal sufferings as a fitting departure from life, may help people to deal with the fatal neoplastic disease more realistically.
Dr. Richard Kolodner discussed genome instability, mutator genes and cancer susceptibility. Hereditary non-polyposis colon cancer (HNPCC) is the prototypic example of an inherited disease with genomic instability. In this case, germline mutations in DNA mismatch repair genes are responsible for cancer-proneness. DNA mismatch repair genes were first identified in yeast. Recent studies indicate that MSH6 mutants in yeast have a strong mutator phenotype but do not exhibit microsatellite instability, which is one of the hallmarks of HNPCC. Indeed, families have now been identified with germline mutations in hMSH6.
Dr. Yasuhito Yuasa reviewed the carcinogenic mechanism in HNPCC. Most families with HNPCC have germline mutations in hMSH2, hMLH1, hPMS1 and hPMS2. Two cases with a typical HNPCC and germline mutations in hMSH6 were described. The defect in DNA mismatch DNA repair in HNPCC is associated with inactivating mutations in both the pro-apoptotic Bax gene and the TGF-!!
!RII gene that is a member of the TGF!!!negative growth signal transduction pathway. Dr. Kenneth Kinsler described the APC pathway in colorectal tumorigenesis and the concept of gatekeeper and caretaker genes. APC is a gatekeeper gene and is mutant in about 85% of human colon cancer. APC sequesters!!
!-catenin and prevents its nuclear translocation. Mutations in APC or!!!-catenin, the latter occurs in about 10% of human colon cancer, allows!!!-catenin-TCF heterodimer to function as a transcription transactivator. Using the SAGE, they have identified expressed genes that are negatively or positively associated with colon cancer and are currently studying their function. Dr. Tetsuo Noda has analyzed the APC gene function by targeted mutagenesis in mice. An animal model of familial polyposis was developed using the CRE-recombinase strategy to knockout the APC gene containing genetically engineered loxP sites. Colon adenomas occurred in contrast to the min mice that develop multiple adenomas in the small intestine.
Dr. Jean Wang discussed tumor suppressors in DNA damage response. She described the ATM-CABL pathway that is activated by ionizing radiation but not by UV. The nuclear cABL is negatively regulated by Rb and positively regulated by ATM.
Dr. Lawrence Loeb discusses the Werner’s syndrome, WRN function and cancer risk. Premature aging and cancer-proneness is associated with Werner’s syndrome, which is the result of germline mutations in WRN. WRN codes for a DNA helicase that may be involved in DNA repair.
Dr. Hiroshi Maeda presented the evidence that many chronic inflammatory diseases are cancer prone. Chronic infections of bacteria or parasites, such as, Helicobacter pylori, Opisthorchis viverini and Schistosoma haematobium, are considered to be the cause of human gastric cancer, gallbladder/liver and the urinary bladder respectively. The inflammation-associated oxyradicals may be the endogenous carcinogens responsible for the increase risk of cancer.
Dr. Raymond DuBois reviewed the mechanism for chemoprevention of colorectal cancer by nonsteroidal anti-inflammatory drugs (NSAIDS). One target of NSAIDS is cyclooxygenase-2 (COX2). Increased expression of COX2 leads to PGE2 formation that inhibits apoptosis and enhances tumor growth.
The Workshop was highly interactive with lively discussion ranging from yeast genetics to classical cancer epidemiology. The eclectic topics and the diverse backgrounds of the participants proved to be a stimulating mix of science and personal interactions that has lead to several research collaborations.
PARTICIPANTS
UNITED STATES
Dr. Mikhail F. Denissenko
Department of Biology
Beckman Research Institute
City of Hope National Med. Ctr
1450 E. Duarte Road, Duarte, CA 91010-0269
Dr. Frederick F. Kadlubar
Div. of Molecular Epidemiology
N.C.T.R. HFT-100
Jefferson, AR 72079
Dr. Peter G. Shields
Laboratory of Human Carcinogenesis
National Cancer Institute
Building 37, Room 2C16, 37 Convent Drive
Bethesda, MD 20892
Dr. Curtis Harris
Chief, Laboratory of Human Carcinogenesis
National Cancer Institute
Building 37, Room 2CO5, 37 Convent Drive
Bethesda, MD 20892
Dr. Richard D. Kolodner
Div. of Human Cancer Genetics
Dana-Farber Cancer Institute
44 Biuney Street
Boston, MA 02115
Dr. Kenneth W. Kinzler
Department of Oncology
Johns Hopkins Univ. Sch. Of Med.
Room 111, 424 N. Bond Street
Baltimore. MD 21231
Dr. Stephen N. Thibodeau
Molecular Genetics Laboratory
Mayo Clinic
200 First Street, S.W.
Rochester, MN 55905
Dr. Jean Y.J. Wang
Department of Biology 0347
Univ. of California, San Diego
9500 Gilman Drive
La Jolla, CA 92093-0347
Dr. Lawrence A. Loeb
Department of Pathology
University of Washington, Box 357705
Seattle, WA 98195-7705
Dr. Raymond N. DuBois
Dept. of Med. GI Div
Vanderbilt Univ. Med. Ctr.
C-2104 MCN 11621st Ave. S.
Nashville, TN 37232-2279
JAPAN
Dr. Tomoyuki Kitagawa
Director
The Cancer Institute of Tokyo
1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-0012
Dr. Kei Nakachi
Vice-head
Department of Epidemiology
Saitama Canter Center Research Institute
818, Komuro, Ina, Saitama 362-0806
Dr. Yasuhito Yuasa
Professor
Department of Hygiene and Oncology
Tokyo Medical and Dental University School of Medicine
1-5-45 Yushima, Bunkyo-ku, Tokyo 113-0034
Dr. Tetsuo Noda
Chief
Department of Cell Biology
Cancer Institute of Tokyo
1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-0012
Dr. Kazuo Tajima
Chief
Division of Epidemiology
Aichi Cancer Center Research Institute
1-1 , Kanokodono, Chikusa-ku, Nagoya, Aichi 464-0021
Dr. Minako Nagao
Chief
National Cancer Center Research Institute
5- 1-1 , Tsukiji, Chuo-ku, Tokyo 104-0045
Dr. Hiroshi Maeda
Professor
Department of Microbiology
Kumamoto University School of Medicine
4-24-1, Kuhonji, Kumamoto 862-0976