Showing papers by "International Agency for Research on Cancer published in 2000"

World Health Organization classification of tumors.

Abstract: World Health Organization Collaborating Centerfor International Histological Classification of Tu-mors, Armed Forces Institute of Pathology, Wash-ington, DC.Address for reprints: Leslie H. Sobin, M.D., ArmedForces Institute of Pathology, Alaska Avenue and14th Street, Building 54, Room 3009, Washington,DC 20306-6000.Received March 23, 2000; accepted March 23,2000.

p53 and human cancer: the first ten thousand mutations.

Abstract: Publisher Summary The p53 protein is a tight, hydrophobic central globule containing the DNA binding domain, flanked by accessible N- and C-terminal regions This protein is expressed in all cell types but has a rapid turnover and is latent under normal conditions p53 is mutated in most common human malignancies and behaves as a multifunctional transcription factor involved in the control of cell cycle, programmed cell death, senescence, differentiation and development, transcription, DNA replication, DNA repair, and maintenance of genomic stability p53 is converted to an active form in response to a number of physical or chemical DNA-damaging agents such as X or gamma irradiation, UV rays, oxidizing agents, cytotoxic drugs, and cancer-causing chemicals Induction of p53 implies nuclear retention, accumulation of the protein as a result of post-translational stabilization, and allosteric conversion to a form with high sequence-specific DNA-binding capacity p53 is activated in response to DNA damage, thus acting as a “guardian of the genome” against genotoxic stress The chapter describes a three-step model of pS3 activation by stress signals The downstream pS3 signaling is mediated by transcriptional activation of specific genes and by complex formation between p53 and heterologous proteins The mutations and variations in the p53 gene are due to p53 polymorphisms, somatic mutations, and germline mutations in p53 The chapter also accounts for p53 mutations in sporadic cancers focussing on host-environment interactions The chapter concludes with the potential clinical applications of the detection of p53 mutations in human tissues

Serum C-Peptide, Insulin-Like Growth Factor (IGF)-I, IGF-Binding Proteins, and Colorectal Cancer Risk in Women

Abstract: BACKGROUND Leading a Western lifestyle, being overweight, and being sedentary are associated with an increased risk of colorectal cancer. Recent theories propose that the effects of these risk factors may be mediated by increases in circulating insulin levels and in the bioactivity of insulin-like growth factor (IGF)-I. To test this hypothesis, we conducted a case-control study nested within a cohort of 14 275 women in New York. METHODS We used blood samples that had been obtained from these women from March 1985 through June 1991 and stored in a biorepository. C-peptide (a marker for insulin secretion), IGF-I, and IGF-binding proteins (IGFBPs)-1, -2, and -3 were assayed in the serum of 102 women who subsequently developed colorectal cancer and 200 matched control subjects. Logistic regression was used to relate cancer risk to these peptide levels, by adjustment for other risk factors. All statistical tests used are two-sided. RESULTS Colorectal cancer risk increased with increasing levels of C-peptide (P:(trend) =.001), up to an odds ratio (OR) of 2. 92 (95% confidence interval [CI] = 1.26-6.75) for the highest versus the lowest quintiles, after adjustment for smoking. For colon cancer alone (75 case subjects and 146 control subjects), ORs increased up to 3.96 (95% CI = 1.49-10.50; P:(trend) <.001) for the highest versus the lowest quintiles. A statistically significant decrease in colorectal cancer risk was observed for increasing levels of IGFBP-1 (P:(trend) =.02; OR in the upper quintile = 0.48 [95% CI = 0.23-1. 00]), as well as for the highest quintile of IGFBP-2 levels (P:(trend) =.06; OR = 0.38 [95% CI = 0.15-0.94]). Colorectal cancer risk showed a modest but statistically nonsignificant positive association with levels of IGF-I and was statistically significantly increased for the highest quintile of IGFBP-3 (OR = 2.46 [95% CI = 1. 09-5.57]). CONCLUSIONS Chronically high levels of circulating insulin and IGFs associated with a Western lifestyle may increase colorectal cancer risk, possibly by decreasing IGFBP-1 and increasing the bioactivity of IGF-I.

Population-Based Study of Human Papillomavirus Infection and Cervical Neoplasia in Rural Costa Rica

Abstract: Background: Human papillomavirus (HPV) is the main cause of cervical neoplasia. Because few population-based studies have investigated the prevalence of type-specific infection in relation to cervical disease, we studied a high-risk population, estimating the prevalence of HPV infection and the risk associated with various HPV types. Methods: We screened 9175 women in Guanacaste, Costa Rica, to obtain a referent standard final diagnosis, and tested 3024 women for more than 40 types of HPV with a polymerase chain reaction-based system. Results: Among women with normal cytology, HPV infections peaked first in women younger than 25 years, and they peaked again at age 55 years or older with predominantly non-cancer-associated types of HPV and uncharacterized HPV types. Low-grade squamous intraepithelial lesions (LSILs) (n = 189) decreased consistently with age. The prevalence of high-grade squamous intraepithelial lesions (HSILs) (n = 128) peaked first around age 30 years and again at age 65 years or older. Seventy-three percent of LSILs were HPV positive, with HPV16 being the predominant type (16% of positive subjects). HPV was found in 89% of HSILs and 88% of cancers, with HPV16 being strongly predominant (51% and 53% of positive subjects). Virtually all HSILs and cancers had cancer-associated HPV types, with high odds ratios (ORs) and attributable fractions around 80%. Risk for HPV16 was particularly high (OR for HSILs = 320, 95% confidence interval [CI] = 97-1000; OR for cancer = 710, 95% CI = 110-4500). Conclusions: We confirm the early decline of HPV infection with age but note increased prevalence after menopause, which could be related to a second peak of HSILs, an observation that warrants further investigation. At least 80% of HPVs involved in cervical carcinogenesis in this population have been characterized. Polyvalent vaccines including the main cancer-associated HPV types may be able to prevent most cases of cervical disease in this region.

HPV DNA testing in cervical cancer screening. Results from women in a high-risk province of Costa Rica.

Abstract: ContextHuman papillomaviruses (HPVs) are known to cause most cervical cancer worldwide, but the utility of HPV DNA testing in cervical cancer prevention has not been determined.ObjectiveTo provide comprehensive data on the screening performance of HPV testing for the most common carcinogenic types, at different levels of analytic sensitivity.DesignLaboratory analysis conducted during 1993-1995, using 3 cytologic techniques and cervicography, followed by colposcopic examination of women with any abnormal cervical finding, to detect all high-grade intraepithelial lesions and cancer (reference standard of clinically significant disease). The HPV testing was performed subsequently with masking regarding clinical findings.SettingGuanacaste Province, Costa Rica, a region with a high age-adjusted incidence of cervical cancer.ParticipantsOf 11,742 randomly selected women, 8554 nonpregnant, sexually active women without hysterectomies underwent initial HPV DNA testing using the original Hybrid Capture Tube test; a stratified subsample of 1119 specimens was retested using the more analytically sensitive second generation assay, the Hybrid Capture II test.Main Outcome MeasuresReceiver operating characteristic analysis of detection of cervical high-grade intraepithelial lesions and cancer by HPV DNA testing based on different cut points of positivity.ResultsAn analytic sensitivity of 1.0 pg/mL using the second generation assay would have permitted detection of 88.4% of 138 high-grade lesions and cancers (all 12 cancers were HPV-positive), with colposcopic referral of 12.3% of women. Papanicolaou testing using atypical squamous cells of undetermined significance as a cut point for referral resulted in 77.7% sensitivity and 94.2% specificity, with 6.9% referred. Specificity of the second generation assay for positivity for high-grade lesions and cancer was 89.0%, with 33.8% of remaining HPV DNA–positive subjects having low-grade or equivocal microscopically evident lesions. The higher detection threshold of 10 pg/mL used with the original assay had a sensitivity of 74.8% and a specificity of 93.4%. Lower levels of detection with the second generation assay (<1 pg/mL) proved clinically nonspecific without gains in diagnostic sensitivity.ConclusionsIn this study population, a cut point of 1.0 pg/mL using the second generation assay permitted sensitive detection of cervical high-grade lesions and cancer, yielding an apparently optimal trade-off between high sensitivity and reasonable specificity for this test. The test will perform best in settings in which sensitive detection of high-grade lesions and cancer is paramount. Because HPV prevalence varies by population, HPV testing positive predictive value for detection of high-grade lesions and cancer will vary accordingly, with implications for utility relative to other cervical cancer screening methods.

Plasma Insulin-Like Growth Factor-I, Insulin-Like Growth Factor-Binding Proteins, and Prostate Cancer Risk: a Prospective Study

Abstract: Background: Recent studies have suggested that men with elevated plasma levels of insulin-like growth factor-I (IGF-I) may have an increased risk of prostate cancer. Furthermore, IGF-binding proteins (IGFBPs) and insulin can modulate the activity of IGF-I. In this study, we sought to determine the role of IGF-I as well as IGFBPs-1, -2, and -3 and insulin as possible etiologic factors for prostate cancer. Methods: We conducted a nested case-control study within the Northern Sweden Health and Disease Cohort Study. We measured levels of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and insulin in plasma samples from 149 men who had a diagnosis of prostate cancer between 1 month and 10 years after blood collection and among 298 control men. All statistical tests are two-sided. Results: Case subjects had statistically significantly higher mean levels of IGF-I than control subjects (229 ng/mL; 95% confidence interval [CI] = 218-240 ng/mL] versus 214 ng/mL [95% CI = 208-221 ng/mL]; P = .02) and IGFBP-3 (2611 ng/mL [95% CI = 2518-2704 ng/mL] versus 2498 ng/mL [95% CI = 2437-2560 ng/mL]; P = .04). Conditional logistic regression analyses showed increases in prostate cancer risk with rising levels of IGF-I (P for trend = .02) and IGFBP-3 (P for trend = .03). In case subjects younger than 59 years at the time of blood collection, the risk associated with increased IGF-I was higher (P for trend = .01), whereas the risk associated with increased IGFBP-3 was lower (P for trend = .44) than the corresponding risks in the full cohort. Prostate cancer risk was not associated with levels of IGFBP-1, IGFBP-2, or insulin. Conclusions: Prostate cancer risk is increased in men with elevated plasma IGF-I. This association was particularly strong in younger men in this study, suggesting that circulating IGF-I may be specifically involved in the early pathogenesis of prostate cancer.

Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-control studies.

Abstract: The primary risk factor for bladder cancer is cigarette smoking. Using a combined analysis of 11 case-control studies, we have accurately measured the relationship between cigarette smoking and bladder cancer in men. Available smoking information on 2,600 male bladder cancer cases and 5,524 male controls included duration of smoking habit, number of cigarettes smoked per day and time since cessation of smoking habit for ex-smokers. There was a linear increasing risk of bladder cancer with increasing duration of smoking, ranging from an odds ratio (OR) of 1.96 after 20 years of smoking (95% confidence interval [CI] 1.48–2.61) to 5.57 after 60 years (CI 4.18–7.44). A dose relationship was observed between number of cigarettes smoked per day and bladder cancer up to a threshold limit of 15–20 cigarettes per day, OR = 4.50 (CI 3.81–5.33), after which no increased risk was observed. An immediate decrease in risk of bladder cancer was observed for those who gave up smoking. This decrease was over 30% after 1–4 years, OR = 0.65 (0.53–0.79), and was over 60% after 25 years of cessation, OR = 0.37 (0.30–0.45). However, even after 25 years, the decrease in risk did not reach the level of the never-smokers, OR = 0.20. (0.17–0.24). The proportion of bladder cancer cases attributable to ever-smoking was 0.66 (0.61–0.70) for all men and 0.73 (0.66–0.79) for men younger than 60. These estimates are higher than previously calculated. Int. J. Cancer 86:289–294, 2000. © 2000 Wiley-Liss, Inc.

Trends in cancer incidence in Kyadondo County, Uganda, 1960-1997.

Abstract: Incidence rates of different cancers have been calculated for the population of Kyadondo County (Kampala, Uganda) for four time periods (1960-1966; 1967-1971; 1991-1994; 1995-1997), spanning 38 years in total. The period coincides with marked social and lifestyle changes and with the emergence of the AIDS epidemic. Most cancers have increased in incidence over time, the only exceptions being cancers of the bladder and penis. Apart from these, the most common cancers in the early years were cervix, oesophagus and liver; all three have remained common, with the first two showing quite marked increases in incidence, as have cancers of the breast and prostate. These changes have been overshadowed by the dramatic effects of the AIDS epidemic, with Kaposi's sarcoma emerging as the most common cancer in both sexes in the 1990s, and a large increase in incidence of squamous cell cancers of the conjunctiva. In the most recent period, there also seems to have been an increase in the incidence of non-Hodgkin lymphomas. So far, lung cancer remains rare. Cancer control in Uganda, as elsewhere in sub-Saharan Africa, faces a threefold challenge. With little improvement in the incidence of cancers associated with infection and poverty (liver, cervix, oesophagus), it must face the burden of AIDS-associated cancers, while coping with the emergence of cancers associated with Westernization of lifestyles (large bowel, breast and prostate).

Lead and cancer in humans: Where are we now?†

Abstract: Background Lead is only weakly mutagenic, but in vitro it inhibits DNA repair and acts synergistically with other mutagens. Lead acetate administered orally, cutaneously, or intraperitoneally causes kidney cancer, brain cancer (gliomas), and lung cancer in rodents, and acts synergistically with other carcinogens. Most cytogenetic studies of exposed workers have shown increases in chromosome aberrations or sister chromatid exchange, including some studies with positive-exposure response trends. There are eight studies of cancer mortality or incidence among highly exposed workers; most are cohort studies of lead smelter or battery workers exposed decades ago. Methods We reviewed the epidemologic studies with regard to cancer. Results These studies provide some evidence of increased risk of lung cancer (RR = 1.30, 1.15-1.46, 675 observed deaths) and stomach cancer (combined RR = 1.34, 1.14-1.57, 181 observed). However, the lung cancer findings are not consistent across studies, and confounding by arsenic may affect the study with the highest lung cancer RR. Exclusion of that study yields a combined lung cancer RR of 1.14 (1.04-1.73). There is little evidence of increased risk of kidney cancer (combined RR=1.01, 0.72-1.42, 40 observed) or brain cancer (combined RR=1.06, 0.81-1.40, 69 observed). However, two studies show a two-fold increase in kidney cancer, and one study shows a significant excess of gliomas. IARC classified lead as a possible human carcinogen based on sufficient animal data and insufficient human data in 1987. Six of the eight studies cited above have been published since 1987. Conclusion Overall, there is only weak evidence associating lead with cancer; the most likely candidates are lung cancer, stomach cancer, and gliomas.

Standardization of the 24-hour diet recall calibration method used in the european prospective investigation into cancer and nutrition (EPIC): general concepts and preliminary results.

Abstract: Objectives: Despite increasing interest in the concept of calibration in dietary surveys, there is still little experience in the use and standardization of a common reference dietary method, especially in international studies. In this paper, we present the general theoretical framework and the approaches developed to standardize the computer-assisted 24 h diet recall method (EPIC-SOFT) used to collect about 37 000 24-h dietary recall measurements (24-HDR) from the 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). In addition, an analysis of variance was performed to examine the level of standardization of EPIC-SOFT across the 90 interviewers involved in the study. Methods: The analysis of variance used a random effects model in which mean energy intake per interviewer was used as the dependent variable, while age, body mass index (BMI), energy requirement, week day, season, special diet, special day, physical activity and the EPIC-SOFT version were used as independent variables. The analysis was performed separately for men and women. Results: The results show no statistical difference between interviewers in all countries for men and five out of eight countries for women, after adjustment for physical activity and the EPIC-SOFT program version used, and the exclusion of one interviewer in Germany (for men), and one in Denmark (for women). These results showed an interviewer effect in certain countries and a significant difference between gender, suggesting an underlying respondent’s effect due to the higher under-reporting among women that was consistently observed in EPIC. However, the actual difference between interviewer and country mean energy intakes is about 10%. Furthermore, no statistical differences in mean energy intakes were observed across centres from the same country, except in Italy and Germany for men, and France and Spain for women, where the populations were recruited from areas scattered throughout the countries. Conclusion: Despite these encouraging results and the efforts to standardize the 24-HDR interview method, conscious or unconscious behaviour of respondents and/or interviewer bias cannot be prevented entirely. Further evaluation of the reliability of EPIC-SOFT measurements will be conducted through validation against independent biological markers (nitrogen, potassium). European Journal of Clinical Nutrition (2000) 54, 900–917

Serum insulin-like growth factor-I and breast cancer.

Abstract: Insulin-like growth factor I (IGF-I) is a systemic hormone with potent mitogenic and anti-apoptotic properties, which could influence the proliferative behavior of normal breast cells. Limited epidemiological observations suggest that the hormone may play a role in the etiology of breast cancer, especially at pre-menopausal ages. In a prospective case-control study nested within a cohort of New York City women, IGF-I, IGF-binding protein 3 (IGFBP-3) and C peptide were measured in frozen serum samples from 172 pre-menopausal and 115 post-menopausal subjects who were subsequently diagnosed with breast cancer. Subjects were eligible if diagnosed 6 months or more after recruitment into the study (7 to 120 months). Cohort members who matched the cases on age, menopausal status, date of blood sampling and day of menstrual cycle at blood collection served as controls. Post-menopausal breast cancer was not associated with serum IGF-I, IGFBP-3 or C-peptide levels. However, the risk of breast cancer increased with increasing serum concentrations of IGF-I in pre-menopausal women. The odds ratio (OR) for the highest quartile of IGF-I (>256 ng/ml) compared to the lowest (<168 ng/ml) was 1.60 [95% confidence interval (CI) 0.91-2. 81]. The OR decreased to 1.49 (95% CI 0.80-2.79) after adjustment for IGFBP-3. In analyses restricted to subjects who were pre-menopausal at the time of blood sampling and whose cancer was diagnosed before age 50, the top vs. bottom quartile OR increased appreciably to 2.30 (95% CI 1.07-4.94). Adjustment for IGFBP-3 reduced the OR to 1.90 (95% CI 0.82-4.42). There was no association between pre-menopausal breast cancer and IGFBP-3, IGF-I:IGFBP-3 ratio or non-fasting levels of C peptide. Elevated circulating levels of IGF-I may be an indicator of increased risk of breast cancer occurring before age 50.

Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy : role of gap-junctional intercellular communication

Abstract: Antitumor suicide gene therapy is one of the emerging strategies against cancer. It consists of the introduction into cancer cells of a gene capable of converting a nontoxic prodrug into a cytotoxic drug. Because this therapeutic gene cannot be easily introduced into the whole cell population of a tumor, the successful eradication of tumors depends on a phenomenon called the "bystander effect," by which the introduced gene can affect even cells in which it is not itself present. From a therapeutic point of view, it may be crucial to enhance this phenomenon through various means to achieve tumor eradication. One such suicide gene, the thymidine kinase gene from the herpes simplex virus, in combination with the prodrug ganciclovir, has been extensively and successfully used in some animal models exhibiting a strong bystander effect. Among the mechanisms involved in this phenomenon, gap junctional intercellular communication (GJIC) is directly involved in the transfer of the toxic metabolites of ganciclovir, which pass directly from herpes simplex virus thymidine kinase-expressing cells to surrounding cells that do not express it. Because GJIC appears to be a mediator of the bystander effect both in vitro and in vivo, here we review possible molecular strategies for enhancing the extent of tumor cell death by increasing the intratumoral GJIC capacity.

International trends in incidence of cervical cancer: II. Squamous-cell carcinoma

Abstract: Time trends in the incidence of squamous-cell carcinomas of the cervix during the period 1973-1991 were examined using data provided by 60 population-based cancer registries from 32 defined populations in 25 countries. Three components of the incidence trend were studied: age, calendar period of diagnosis and birth cohort. Cumulative incidence rates per 1,000 person-years for 2 groups, age ranges 25-49 and 50-74 years, were calculated from the model that best described the incidence data. A significant decline in incidence was noted in the American populations (except for US Hispanic), Australia, the non-Maori women of New Zealand, northern and western Europe (except Italy and Spain, where the rates remain stable) and Asian populations (except Malay women of Singapore, who have stable rates). These trends were of similar magnitude for the whole age range studied (25-74 years). An increasing trend, mainly restricted to younger women, was found for Slovakia, Jewish women born in Israel and the United Kingdom. In Slovenia, the increasing trend was observed for all age groups. The predominant pattern shown by cancer registries in developed countries is of a reduction in the incidence of squamous cervical cancer. This could be, at least partially, attributed to the widespread practice of screening for cervical lesions. The major exception to the pattern is observed in the United Kingdom, though the increasing incidence in young women has changed to a decrease in recent years. There are only a few series covering a long period of time in developing countries, but there is little evidence for a major impact of screening.

APC mutations in sporadic medulloblastomas.

Abstract: The cerebellar medulloblastoma (WHO Grade IV) is a highly malignant, invasive embryonal tumor with preferential manifestation in children. Several molecular alterations appear to be involved, including isochromosome 17q and the p53, PTCH , and β-catenin gene mutations. In this study, 46 sporadic medulloblastomas were screened for the presence of mutations in genes of the Wnt signaling pathway ( APC and β-catenin). Single-strand conformational polymorphism (SSCP) analysis followed by direct DNA sequencing revealed 3 miscoding APC mutations in 2 (4.3%) medulloblastomas. One case contained a GCA→GTA mutation at codon 1296 (Ala→Val), and another case had double point mutations at codons 1472 (GTA→ATA, Val→Ile) and 1495 (AGT→GGT, Ser→Gly). Miscoding β-catenin mutations were detected in 4 tumors (8.7%). Three of these were located at codon 33 (TCT →TTT, Ser→Phe. and another at codon 37 (TCT→GCT, Ser→Ala). Adenomatous polyposis coli ( APC ) gene and β-catenin mutations were mutually exclusive and occurred in a total of 6 of 46 cases (13%). Although germline APC mutations are a well established cause of familial colon and brain tumors (Turcot syndrome), this study provides the first evidence that APC mutations are also operative in a subset of sporadic medulloblastomas.

Lead as a carcinogen: experimental evidence and mechanisms of action.

Abstract: Recent epidemiological and experimental work confirms that inorganic lead compounds are associated with increased risks of tumorigenesis. In animals, these risks can be induced at doses that are not associated with organ toxicity and in mice that do not produce alpha-2 urinary globulin in the kidney. Thus the mechanisms of lead carcinogenicity are unlikely to be fully explained as toxicity-related sequelae of high dose exposure or as a rat-specific response involving overexpression of a renal protein. Plausible mechanisms of lead carcinogenicity include direct DNA damage, clastogenicity, or inhibition of DNA synthesis or repair. Lead may also generate reactive oxygen species and cause oxidative damage to DNA. Recent data indicate that lead can substitute for zinc in several proteins that function as transcriptional regulators, including protamines. Lead further reduces the binding of these proteins to recognition elements in genomic DNA, which suggests an epigenetic involvement of lead in altered gene expression. These events may be of particular relevance in transplacental exposures and later cancer.

Cancer incidence in karachi, pakistan: first results from karachi cancer registry

Abstract: No cancer incidence data from Pakistan have been published in the 5 decades since independence. Incidence data for the period 1995-1997 from the population of the Karachi South district (1.7 million) are presented here. A total of 4,268 new cancer cases were registered during this period: 2,160 cases in males and 2,108 cases in females. Overall, 95.3% of the incident cases were microscopically verified. The incidence rates for all cancers combined were 80.5 per 100,000 (crude) and 136.7 per 100,000 (age- standardised rates [ASR]) for males and 91.8 (crude) and 163.2 per 100,000 (ASR) for females. In males, lung cancer (ASR 20.3) was the most frequently recorded malignancy followed by oral cavity (ASR 13.8) and larynx cancer (ASR 8.6). In females, breast was the most common site of cancer, accounting for one third of female cancers (ASR 51.7), followed by oral cavity (ASR 14.1) and ovarian cancer (ASR 10.2). Karachi reports the highest incidence of breast cancer for any Asian population, except Jews in Israel. Tobacco smoking is estimated to be responsible for 40% of cancers in males and tobacco chewing for a further substantial proportion of head and neck cancers.

Classic kaposi sarcoma: epidemiology and risk factors.

Abstract: BACKGROUND Although Kaposi sarcoma (KS) initially was described over a century ago, its biology remains enigmatic and conflicting. Whereas the classic type occurs mainly in older men of Mediterranean or Eastern European backgrounds and is not linked to impairment of the host immune response, iatrogenic and human immunodeficiency virus (HIV)-associated KS are linked to such conditions. A recently discovered pathogen, KS-associated herpesvirus (KSHV) (also known as human herpesvirus 8 [HHV8]), is found in tissues from all four forms of KS (classic, iatrogenic, endemic [African], and HIV-associated). This universal detection of KSHV/HHV8 suggests a central role for the virus in the development of KS and a common etiology for all KS types. The epidemiology and risk factors of classic KS, along with the biology of KSHV/HHV8 and the prevalence of the virus among different populations, is presented. METHODS The current review is based on multiple information sources, electronic health data in all languages from 1966 onward, and previously published scientific reports from the Americas, Europe, and Africa. RESULTS Nearly 5000 cases of morphologically characterized classic KS have been reported in Europe, Mediterranean countries, and the Americas up to 1998. Geographic location, ethnicity, time interval, age, and gender heavily influence the incidence rate of classic KS. The rate of incidence of nonacquired immunodeficiency syndrome-associated KS correlates with the KSHV/HHV8 seroprevalence in the general population. CONCLUSIONS Many contributory factors undoubtedly have etiologic and pathogenic significance in the development of classic KS; however, the interplay between these factors has complicated the understanding of the induction and development of the disease as well as the significance of each factor. As with other cell-transforming human DNA viruses, infection with KSHV/HHV8 alone is not sufficient for the development of KS and additional cofactors are required. Cancer 2000;88:500–17. © 2000 American Cancer Society.

The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2.

Abstract: Breast cancers arising in carriers of mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, differ histologically from each other and from breast cancers unselected for a family history. However, a substantial proportion of families with multiple cases of breast cancer is not attributable to these two genes (non-BRCA1/2 families). We have now characterized the pathology of 82 breast cancers from non-BRCA1/2 families. Breast cancers in non-BRCA1/2 families were of lower grade (P = 0.0018), showed fewer mitoses (P < 0.0001), less nuclear pleomorphism (P = 0.0014), less lymphocytic infiltrate (P < 0.0001), a lesser extent of the tumor with a continuous pushing margin (P = 0.004), a lesser extent of the tumor composed of solid sheets of cells (P = 0.0047), less necrosis (P = 0.002), and wereparison with BRCA2 tumors, non-BRCA1/2 tumors were lower grade (P = 0.017) and exhibited less pleomorphism (P = 0.01) and more tubule formation (P = 0.05). In comparison with control breast cancers unselected for a family history of the disease, non-BRCA1/2 tumors were of significantly lower grade (P = 0.001), showed less pleomorphism (P = 0.0002), and had a lower mitotic count (P = 0.003). The results indicate that non-BRCA1/2 breast cancers differ histologically from both BRCA1 and BRCA2 breast cancers and are overall of lower grade. They also suggest that non-BRCA1/2 breast cancers differ from nonfamilial breast cancers, but these differences may be attributable to various types of bias.

Genetic Profile of Gliosarcomas

Abstract: There are distinct genetic pathways leading to the glioblastoma, the most malignant astrocytic brain tumor. Primary (de novo) glioblastomas develop in older patients and are characterized by epidermal growth factor (EGF) receptor amplification/overexpression, p16 deletion, and PTEN mutations, whereas secondary glioblastomas that progressed from low-grade or anaplastic astrocytoma develop in younger patients and frequently contain p53 mutations. In this study, we assessed the genetic profile of gliosarcoma, a rare glioblastoma variant characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation. Single-strand conformation polymorphism followed by direct DNA sequencing revealed p53 mutations in five of 19 gliosarcomas (26%) and PTEN mutations in seven cases (37%). Homozygous p16 deletion was detected by differential polymerase chain reaction in seven (37%) gliosarcomas. The overall incidence of alterations in the Rb pathway (p16 deletion, CDK4 amplification, or loss of pRb immunoreactivity) was 53%, and these changes were mutually exclusive. Coamplification of CDK4 and MDM2 was detected in one gliosarcoma. None of the gliosarcomas showed amplification or overexpression of the EGF receptor. Thus gliosarcomas exhibit a genetic profile similar to that of primary (de novo) glioblastomas, except for the absence of EGFR amplification/overexpression. Identical PTEN mutations in the gliomatous and sarcomatous tumor components were found in two cases. Other biopsies contained p16 deletions, an identical p53 mutation, or coamplification of MDM2 and CDK4 in both tumor areas. This strongly supports the concept of a monoclonal origin of gliosarcomas and an evolution of the sarcomatous component due to aberrant mesenchymal differentiation in a highly malignant astrocytic neoplasm.

NMDA But Not Non-NMDA Excitotoxicity is Mediated by Poly(ADP-Ribose) Polymerase

Abstract: Poly(ADP-ribose) polymerase (PARP-1), a nuclear enzyme that facilitates DNA repair, may be instrumental in acute neuronal cell death in a variety of insults including, cerebral ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, and CNS trauma. Excitotoxicity is thought to underlie these and other toxic models of neuronal death. Different glutamate agonists may trigger different downstream pathways toward neurotoxicity. We examine the role of PARP-1 in NMDA- and non-NMDA-mediated excitotoxicity. NMDA and non-NMDA agonists were stereotactically delivered into the striatum of mice lacking PARP-1 and control mice in acute (48 hr) and chronic (3 week) toxicity paradigms. Mice lacking PARP-1 are highly resistant to the excitoxicity induced by NMDA but are as equally susceptible to AMPA excitotoxicity as wild-type mice. Restoring PARP-1 protein in mice lacking PARP-1 by viral transfection restored susceptibility to NMDA, supporting the requirement of PARP-1 in NMDA neurotoxicity. Furthermore, Western blot analyses demonstrate that PARP-1 is activated after NMDA delivery but not after AMPA administration. Consistent with the theory that nitric oxide (NO) and peroxynitrite are prominent in NMDA-induced neurotoxicity, PARP-1 was not activated in mice lacking the gene for neuronal NO synthase after NMDA administration. These results suggest a selective role of PARP-1 in glutamate excitoxicity, and strategies of inhibiting PARP-1 in NMDA-mediated neurotoxicity may offer substantial acute and chronic neuroprotection.

Metalloregulation of the tumor suppressor protein p53: zinc mediates the renaturation of p53 after exposure to metal chelators in vitro and in intact cells.

Abstract: The tumor suppressor p53 is a transcription factor which binds DNA through a structurally complex domain stabilized by a zinc atom. Zinc chelation disrupts the architecture of this domain, inducing the protein to adopt an immunological phenotype identical to that of many mutant forms of p53. In this report, we used 65Zn to show that incorporation of zinc within the protein was required for folding in the 'wild-type' conformation capable of specific DNA-binding. Using a cellular assay, we show that addition of extracellular zinc at concentrations within the physiological range (5 microM) was required for renaturation and reactivation of wild-type p53. Among other divalent metals tested (Cd2+, Cu2+, Co2+, Fe2+ and Ni2+), only Co2+ at 125 microM had a similar effect. Recombinant metallothionein (MT), a metal chelator protein, was found to modulate p53 conformation in vitro. In cultured cells, overexpression of MT by transfection could modulate p53 transcriptional activity. Taken together, these results suggest that zinc binding plays a regulatory role in the control of p53 folding and DNA-binding activity.

Genetic steps in the development of squamous cell carcinoma of the esophagus.

Abstract: Esophageal squamous cell carcinoma (ESCC) is a frequent form of cancer that shows striking variations in geographic distribution, reflecting exposure to specific environmental factors that are still poorly defined. ESCC develops as the result of a sequence of histopathological changes that typically involves esophagitis, atrophy, mild to severe dysplasia, carcinoma in situ and finally, invasive cancer. Genetic changes associated with the development of ESCC include mutation of the p53 gene, disruption of cell-cycle control in G1 by several mechanisms (inactivation of p16MTS1, amplification of Cyclin D1, alterations of RB), activation of oncogenes (e.g., EGFR, c-MYC) and inactivation of several tumor suppressor genes. Loss of heterozygosity on chromosome 17q25 has been linked with tylosis, a rare autosomal dominant syndrome associated with high predisposition to ESCC. Whether this locus is also involved in sporadic ESCC remains to be elucidated. Chronic esophagitis is a frequent occurrence in populations at high risk of ESCC. These lesions often show focal accumulation of p53 protein and in some instances, patches of positive cells in esophagitis area at the margins of tumors were found to contain a mutation in the p53 gene. This observation is consistent with field cancerization in the esophagus and suggests that esophagitis may represent an interesting target for early detection of ESCC as well as for intervention strategies.

Influence of mate drinking, hot beverages and diet on esophageal cancer risk in South America.

Abstract: To estimate the effects of consuming hot beverages, including mate (an infusion of the herb Ilex paraguayensis), tea, coffee and coffee with milk, and other food items on esophageal cancer risk, we analyzed data from 830 cases and 1,779 controls participating in a series of 5 hospital-based case-control studies of squamous-cell carcinoma of the esophagus conducted in high-risk areas of South America. After adjusting for the strong effects of tobacco and alcohol consumption, both heavy mate drinking (>1 l/day) and self-reported very hot mate drinking were significantly associated with esophageal cancer risk in men and women. The magnitude and strength of the association for mate amount and, to a lesser extent, mate temperature were higher for women than men. The joint effects of mate amount and mate temperature were more than multiplicative, following a statistically significant synergistic interaction (p = 0.02) which was particularly evident among heavy drinkers (>1.50 l/day) of very hot mate (odds ratio = 4.14, 95% confidence interval: 2.24-7.67) compared to light drinkers (<0.50 l/day) of cold/warm/hot mate. Consumption of other very hot beverages, such as tea and coffee with milk but not coffee alone, was also significantly associated with an increased risk, in the 2- to 4-fold range. Statistically significant protective associations were identified for high consumption of vegetables, fruits, cereals and tea. In contrast, frequent consumption of meat, animal fats and salt was associated with a moderately increased risk. This pooled analysis adds evidence for a carcinogenic effect of chronic thermal injury in the esophagus induced by the consumption of very hot drinks, including mate. Our study further confirms the protective effect of a dietary pattern characterized by daily consumption of fruits and vegetables and low consumption of meat and animal fats.

The breast cancer information core: database design, structure, and scope.

Abstract: The Breast Cancer Information Core (BIC) is an open access, on-line mutation database for breast cancer susceptibility genes In addition to creating a catalogue of all mutations and polymorphisms in breast cancer susceptibility genes, a principle aim of the BIC is to facilitate the detection and characterization of these genes by providing technical support in the form of mutation detection protocols, primer sequences, and reagent access Additional information at the site includes a literature review compiled from published studies, links to other internet-based, breast cancer information and research resources, and an interactive discussion forum which enables investigators to post or respond to questions and/or comments on a bulletin board Hum Mutat 16:123-131, 2000 Published 2000 Wiley-Liss, Inc

Occupational exposures and pancreatic cancer: a meta-analysis.

Abstract: Objectives—Consolidation of epidemiological data on pancreatic cancer and worksite exposures. Methods—Publications during 1969‐98 were surveyed. Studies without verified exposures were excluded. Meta-analyses were conducted on data from 92 studies covering 161 populations, with results for 23 agents or groups of agents. With a standard format, five epidemiologists extracted risk estimates and variables of the structure and quality of each study. The extracted data were centrally checked. Random meta-models were applied. Results—Based on 20 populations, exposure to chlorinated hydrocarbon (CHC) solvents and related compounds was associated with a meta-risk ratio (MRR) of 1.4 (95% confidence interval (95% CI) 1.0 to 1.8). Nickel and nickel compounds were considered in four populations (1.9; 1.2 to 3.2). Excesses were found also for chromium and chromium compounds (1.4; 0.9 to 2.3), polycyclic aromatic hydrocarbons (PAHs) (1.5; 0.9 to 2.5), organochlorine insecticides (1.5; 0.6 to 3.7), silica dust (1.4; 0.9 to 2.0), and aliphatic and alicyclic hydrocarbon solvents (1.3; 0.8 to 2.8). Evidence on pancreatic carcinogenicity was weak or non-positive for the following agents: acrylonitrile (1.1; 0.0 to 6.2); arsenic (1.0; 0.6 to 1.5); asbestos (1.1; 0.9 to 1.5); diesel engine exhaust (1.0; 0.9 to 1.3); electromagnetic fields (1.1; 0.8 to 1.4); formaldehyde (0.8; 0.5 to 1.0); flour dust (1.1; 0.3 to 3.2); cadmium and cadmium compounds (0.7; 0.4 to 1.4); gasoline (1.0; 0.8 to 1.2); herbicides (1.0; 0.8 to 1.3); iron and iron compounds (1.3; 0.7 to 2.5); lead and lead compounds (1.1; 0.8 to 1.5); man-made vitreous fibres (1.0; 0.6 to 1.6); oil mist (0.9; 0.8 to 1.0); and wood dust (1.1; 0.9 to 2.5). The occupational aetiological fraction of pancreatic cancer was estimated at 12%. In a subpopulation exposed to CHC solvents and related compounds, it was 29%; to chromium and chromium compounds, 23%; to nickel and nickel compounds, 47%; to insecticides, 33%; and to PAHs, 33%. Conclusion—Occupational exposures may increase risk of pancreatic cancer. High quality studies are called for on interactions between occupational, environmental, and lifestyle factors as well as interactions between genes and the environment. (Occup Environ Med 2000;57:316‐324)

The cancer-preventive potential of Panax ginseng: a review of human and experimental evidence.

Abstract: Objective: We have reviewed the potential cancer-preventive and other relevant properties of Panax ginseng C. A. Meyer, which has been traditionally used as a natural tonic in Oriental countries. Data identification and study selection: Publications on Panax ginseng and its relation to cancer were obtained from the Medline database (1983–1998) and by checking reference lists to find earlier reports. The reports cover experimental models and human studies on cancer-preventive activity, carcinogenicity and other beneficial or adverse effects. In addition, possible mechanisms of chemoprevention by ginseng were considered. Results: Published results from a cohort and two case–control studies in Korea suggest that the intake of ginseng may reduce the risk of several types of cancer. When ginseng was tested in animal models, a reduction in cancer incidence and multiplicity at various sites was noted. Panax ginseng and its chemical constituents have been tested for their inhibiting effect on putative carcinogenesis mechanisms (e.g., cell proliferation and apoptosis, immunosurveillance, angiogenesis); in most experiments inhibitory effects were found. Conclusion: While Panax ginseng C. A. Meyer has shown cancer-preventive effects both in experimental models and in epidemiological studies, the evidence is currently not conclusive as to its cancer-preventive activity in humans. The available evidence warrants further research into the possible role of ginseng in the prevention of human cancer and carcinogenesis.

Gene expression profiling of low-grade diffuse astrocytomas by cDNA arrays.

Abstract: Diffuse astrocytoma WHO grade II is a well-differentiated, slowly growing tumor that has an inherent tendency to progress to anaplastic astrocytoma (WHO grade III) and, eventually, to glioblastoma (WHO grade IV). Little is known about its molecular basis, except for p53 mutations that are found in >60% of cases. In a search for additional genetic alterations, we carried out gene expression profiling of 11 diffuse astrocytomas using cDNA expression arrays. Expression of six genes (TIMP3, c-myc, EGFR, DR-nm23, nm23-H4, and GDNPF) was detected in 64-100% of diffuse astrocytomas, but not in nontumorous brain tissue. Seven genes (AAD14, SPARC, LRP, PDGFR-alpha, 60S ribosomal protein L5, PTN, and hBAP) were found to be up-regulated more than 2-fold in 20-60% of cases, whereas 11 genes (IFI 9-27, protein kinase CLK, TDGF1, BIN1, GAB1, TYRO3, LDH-A, adducin 3, GUK1, CDC10, and KRT8) were down-regulated to less than 50% of normal levels in 64-100% of cases. Semiquantitative conventional reverse transcription-PCR was performed for 11 genes, 9 of which showed an expression profile similar to that obtained with cDNA expression arrays. Immunohistochemical staining for SPARC showed cytoplasmic immunoreactivity of neoplastic cells in all diffuse astrocytomas analyzed. These results indicate significant changes in gene expression in diffuse astrocytomas, but it remains to be shown which of these are causally related to the transformation of glial cells.