High-incidence Populations Research Articles

Epstein‐Barr virus immune response in high‐risk nasopharyngeal carcinoma families in Greenland

Undifferentiated nasopharyngeal carcinoma is associated with Epstein-Barr virus (EBV) infection. Presence of EBV IgA antibodies is rare among healthy individuals and is used as a marker of nasopharyngeal carcinoma in high-incidence populations. Reasons for EBV IgA seropositivity are unknown, but high EBV IgA levels have been found among unaffected close family members and spouses to nasopharyngeal carcinoma patients in Chinese populations. In Greenland, a nasopharyngeal carcinoma-high-incidence area, we compared EBV serology and viral load in high-risk nasopharyngeal carcinoma family members (N = 20) and controls without nasopharyngeal carcinoma-affected relatives (N = 90). There was no significant difference in EBV viral loads between relatives and controls, and EBV was detected in plasma in 5.0% of relatives and 11.4% of controls. There was no significant difference in EBV serology, but the seroprevalence of EBV viral capsid antigen (VCA) IgA was high in both relatives (25.0%) and controls (20.5%). Compared with anti-VCA IgA-negative, anti-VCA IgA-positive individuals had significantly higher EBV viral loads in peripheral blood mononuclear cells (PBMCs) (P < 0.01). The very high prevalence of anti-VCA IgA indicates that this antibody is unsuitable for nasopharyngeal carcinoma screening among Inuits.

Disruption of the SLC26A3-mediated anion transport is associated with male subfertility

Male subfertility in congenital chloride diarrhea (CLD) was possible after identification of expression of an epithelial Cl-/HCO3- exchanger SLC26A3 in the male reproductive tract and by the observation that adult men with CLD had very few children. A prospective clinical and laboratory study among eight adult Finnish men with CLD revealed constant oligoasthenoteratozoospermia but normal spermatogenesis, high chloride and low pH in seminal plasma, and three spermatoceles, suggesting that male subfertility is a clinical manifestation of CLD and could be caused by an analogous defect in the epithelial Cl-/HCO3- and water transport, as described for the CLD intestine.

Screening for gastric cancer: does it make sense?

Gastric cancer remains the second most frequent and lethal malignancy worldwide, with a wide range of incidence rates in different populations. Reducing its incidence is a priority in many high-risk countries, and screening programmes are often advocated as an option. An effective screening programme should have the following characteristics: (i) the disease should be common in the population, otherwise the individual benefit will not offset the risk, cost and inconvenience of screening of the rest of the population; (ii) the diagnostic test(s) used should be safe, simple, inexpensive and reliable; and (iii) effective treatment should be available. With respect to gastric cancer, these conditions are not fulfilled completely in any population and therefore population-based screening does not appear to be a viable approach to the prevention of this neoplasia. In contrast, gastroscopic screening in selected high-risk subjects would seem appropriate. A more effective strategy, particularly in high-incidence populations, could be the widespread screening and treatment for Helicobacter pylori infection. This could result in the virtually complete elimination of chronic gastritis and its associated conditions, including most peptic ulcers, primary gastric B-cell lymphomas and a major portion of gastric epithelial tumours.

Infant diet and type 1 diabetes in China

Infant milk and food introduction may be linked to type 1 diabetes risk in high incidence populations. Dietary data through age 12 months was collected for 247 type 1 diabetic cases and 443 controls in China, a low incidence population, to determine if milk and solid food intake differed. Age range at introduction to milk and formulas was similar in cases and controls but solid food introduction more often occurred before age 3 months in cases. Logistic regression analyses showed soy milk formula consumption at 4–6 (OR=2.0; 95% CI: 1.1–3.4) and 7–12 months of age (OR=1.5; 95% CI: 1.0–2.1) was associated with a twofold higher risk of type 1 diabetes, while steamed bread consumption (4–6 months, OR=0.44; 95% CI: 0.28–0.68; 7–12 months, OR=0.48; 95% CI: 0.34–0.69) and higher SES (4–6 months, OR=0.55; 95% CI: 0.39–0.78; 7–12 months, OR=0.57; 95% CI: 0.40–0.83) were negatively associated. Drinking cow’s milk at 7–12 months (OR=0.60; 95% CI: 0.43–0.85) was negatively associated with type 1 diabetes while consuming vegetables at 4–6 months (OR=1.5; 95% CI: 1.0–2.2) was positively associated. Results suggest that infant milk and solid food intake are associated with type 1 diabetes in China. Prospective studies may determine how these dietary factors impact disease etiology, particularly for at-risk-populations.

A historical perspective of the glycosphingolipids and sphingolipidoses.

Glycosphingolipids are a polysaccharide chain between 1 and 40 carbohydrate residues long glycosidically linked to ceramide (a long-chain aliphatic amino-alcohol or sphingoid) that is embedded in the cell plasma membrane with the carbohydrate moiety on the outside. The sphingoid imparts rigidity to the membrane and the carbohydrate tails protect the cell surface and have functions in relation to cell adhesion, growth, regulation, differentiation, cell interaction, recognition and signalling. They provide adhesion sites for pathogens and change during oncogenic transformation. Ceramide is also a component of sphingomyelin. Glycosphingolipids are degraded by lysosomal hydrolysis. The sphingolipidoses are a series of diseases in which mutations affecting the enzymes catalysing the last 11 steps of this process causing abnormal compounds proximal to the metabolic block to accumulate intralysosomally. Thus, they are a sub-group of the lysosomal storage diseases. The degradation of sphingolipids containing three or less carbohydrate residues requires a sphingolipid activator protein and mutations affecting these proteins also cause abnormal glycosphingolipid storage. With one exception (Fabry disease, which is X linked) the sphingolipidoses are inherited autosomally. The phenotypic manifestations of the individual sphingolipidoses are variable although the more severe variants are usually the better known. They have generally been regarded as untreatable but notable therapeutic advances are being made by enzyme replacement therapy and regulating the rate of glycosphingolipid synthesis by inhibiting UDP-glucose-N-acylsphingosine D-glucosyl transferase (CerGlcT), which is the first reaction on the pathway of glycosphingolipid synthesis. The compounds used are N-alkylated iminosugars whose glucose and galactose stereochemistries inhibit CerGlcT. Prenatal and carrier state diagnosis, genetic counselling and the abortion of affected foetuses are reducing the incidence of some of the most severe sphingolipidoses in certain high-incidence populations.

Risk factors for ovarian cancer in taiwan: a case–control study in a low-incidence population

Objective We conducted a case–control study to identify risk factors for ovarian cancer in Taiwan, a low-incidence population where the incidence has been on the rise. Methods Cases were 86 women (age range 20–75, median 47) drawn from patients with primary, invasive epithelial ovarian cancer diagnosed between 1993 and 1998 in the Taipei metropolitan area, with the following histologic subtypes: 35% serous, 27% mucinous, 21% endometrioid, 15% clear cell, and 2% unspecified adenocarcinoma. Controls were 369 women (age range 20–75, median 44) selected from patients who were hospitalized at the same time for treatment of unrelated diseases. Subjects were interviewed in person regarding sociodemographic and reproductive characteristics, family and medical history, and diet. Results A strong inverse relationship of ovarian cancer to each live birth was observed (odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.20–0.89; OR = 0.30, 95% CI = 0.13–0.69; and OR = 0.18, 95% CI = 0.05–0.62 for parity of 1 or 2, 3–5, and >5, respectively). Menopause was associated with increased risk of disease (OR = 2.15, 95% CI = 1.21–3.83). A trend toward protection was seen with breastfeeding for more than 1 year (OR = 0.55, 95% CI = 0.29–1.01). No dietary factor was associated with an increased disease risk. Milk intake was associated with a decreased disease risk (OR = 0.45, 95% CI = 0.28–0.74). Conclusion The strong protective effect of parity was supported by this study, and the decline in parity is likely an important reason for the rising incidence of ovarian cancer in Taiwan. A decreased disease risk was also seen with milk intake. In addition, the difference in the distribution of histologic subtypes in this population compared with high-incidence populations may point to further differences in risk factors.

The rise of childhood type 1 diabetes in the 20th century.

The incidence of childhood type 1 diabetes increased worldwide in the closing decades of the 20th century, but the origins of this increase are poorly documented. A search through the early literature revealed a number of useful but neglected sources, particularly in Scandinavia. While these do not meet the exacting standards of more recent surveys, tentative conclusions can be drawn concerning long-term changes in the demography of the disease. Childhood type 1 diabetes was rare but well recognized before the introduction of insulin. Low incidence and prevalence rates were recorded in several countries over the period 1920-1950, and one carefully performed study showed no change in childhood incidence over the period 1925-1955. An almost simultaneous upturn was documented in several countries around the mid-century. The overall pattern since then is one of linear increase, with evidence of a plateau in some high-incidence populations and of a catch-up phenomenon in some low-incidence areas. Steep rises in the age-group under 5 years have been recorded recently. The disease process underlying type 1 diabetes has changed over time and continues to evolve. Understanding why and how this produced the pandemic of childhood diabetes would be an important step toward reversing it.

Worldwide increase in incidence of Type I diabetes--the analysis of the data on published incidence trends.

Several reports on the incidence of Type I (insulin-dependent) diabetes mellitus have suggested that the incidence is increasing. The aim of this study was to find out whether the incidence is increasing globally or restricted to a selected populations only and to estimate the magnitude of the change in incidence. During 1960 to 1996 37 studies in 27 countries were carried out. To fulfil the inclusion criteria the study periods ranged from 8-32 years. The temporal trend was fitted by linear regression, with the logarithm of the age-standardized incidence as the dependent variable and the calendar year as the independent variable. Then, the regression coefficient (x 100%) is approximately the average relative increase in incidence per year (as percentage). Results from the pooled data from all 37 populations showed that the overall increase in incidence was 3.0% per year (95% CI 2.6; 3.3, p = 0.0001). The statistically significant increase was found in 24 of 37 populations including all high incidence (> 14.6 per 100000 a year) populations. The relative increase was, however, steeper in the populations with a lower incidence. The correlation between logarithm of the incidence and the increase in incidence was r = -0.56, p = 0.0004. The incidence of Type I diabetes is increasing worldwide both in low and high incidence populations. By the year 2010 the incidence will be 50 per 100000 a year in Finland and also in many other populations it will exceed 30 per 100000 a year.

Different profiles of allelic losses in cervical carcinoma cases in Surinam and the Netherlands

BACKGROUND Cervical carcinoma is the second most common malignancy among women worldwide. The highest incidence rates are observed in developing countries. The increased susceptibility to cervical carcinoma in high incidence populations may result from several factors including human papillomavirus exposure and both inherited and acquired genetic traits. Using comparative molecular analysis of cervical carcinomas from Surinam, a high incidence area, and the Netherlands, a low incidence area, distinct molecular genetic profiles were studied in two populations with contrasting risk for the disease. METHODS In the two populations, the authors compared allelic loss as a marker for the involvement of putative tumor suppressor genes in 40 and 67 carcinoma specimens from Surinam and the Netherlands, respectively. Loss of heterozygosity (LOH) analysis was performed using polymorphic microsatellite markers at sites of known tumor suppressor genes (17p [p53], 13q [Rb, BRCA2], 16q [E-cadherin], and 17q [BRCA1]) and at chromosomes 3p, 6p, 6q, and 11q, which frequently are lost in cervical carcinoma. RESULTS Remarkable differences in LOH were found between both populations. The most prominent observation was the extremely high frequency of LOH, up to 72%, in the region of the major histocompatibility complex on chromosome 6p in specimens from Surinam. In the group of specimens from the Netherlands, only 45% of LOH was observed at this locus. In addition, LOH was detected significantly more frequently at 6q and 13q in the cases from Surinam whereas LOH was found more frequently at 17p in cases from the Netherlands. CONCLUSIONS The results of the current study show that heterogeneity exists in tumor-associated somatic genetic alterations between these two populations that may be indicative of the existence of multiple genetic pathways in cervical tumorigenesis. Cancer 1999;86:997–1004. © 1999 American Cancer Society.

Different profiles of allelic losses in cervical carcinoma cases in Surinam and the Netherlands

Cervical carcinoma is the second most common malignancy among women worldwide. The highest incidence rates are observed in developing countries. The increased susceptibility to cervical carcinoma in high incidence populations may result from several factors including human papillomavirus exposure and both inherited and acquired genetic traits. Using comparative molecular analysis of cervical carcinomas from Surinam, a high incidence area, and the Netherlands, a low incidence area, distinct molecular genetic profiles were studied in two populations with contrasting risk for the disease. In the two populations, the authors compared allelic loss as a marker for the involvement of putative tumor suppressor genes in 40 and 67 carcinoma specimens from Surinam and the Netherlands, respectively. Loss of heterozygosity (LOH) analysis was performed using polymorphic microsatellite markers at sites of known tumor suppressor genes (17p [p53], 13q [Rb, BRCA2], 16q [E-cadherin], and 17q [BRCA1]) and at chromosomes 3p, 6p, 6q, and 11q, which frequently are lost in cervical carcinoma. Remarkable differences in LOH were found between both populations. The most prominent observation was the extremely high frequency of LOH, up to 72%, in the region of the major histocompatibility complex on chromosome 6p in specimens from Surinam. In the group of specimens from the Netherlands, only 45% of LOH was observed at this locus. In addition, LOH was detected significantly more frequently at 6q and 13q in the cases from Surinam whereas LOH was found more frequently at 17p in cases from the Netherlands. The results of the current study show that heterogeneity exists in tumor-associated somatic genetic alterations between these two populations that may be indicative of the existence of multiple genetic pathways in cervical tumorigenesis.

Genetic Background of Congenital Chloride Diarrhea in High-Incidence Populations: Finland, Poland, and Saudi Arabia and Kuwait

Congenital chloride diarrhea (CLD) is an inherited intestinal disorder caused by mutations in the down-regulated in adenoma gene. In Finland, the disease is prevalent because of a founder effect, and all but one of the CLD-associated chromosomes carry the same mutation, V317del. In Poland, another area with a high incidence of CLD, as many as seven different mutations have been detected so far. A third known cluster of CLD, around the Persian Gulf, has not been genetically studied. We studied the allelic diversity of CLD in Poland, in Saudi Arabia and Kuwait, and in three isolated families from North America and Hong Kong. Altogether, eight novel mutations were identified, making a total of 19 known CLD gene mutations. The Polish major mutation I675-676ins was found in 47% of the Polish CLD-associated chromosomes. Haplotype analysis and clustering of the I675-676ins mutation supported a founder effect and common ancestral origin. As in Finland, a major founder effect was observed in Arab patients: 94% of the CLD-associated chromosomes carried a nonsense mutation, G187X, which occurred in either a conserved ancestral haplotype or its derivative. Our data confirm that the same locus is mutated in all cases of CLD studied so far. In Poland, a relatively common founder mutation is likely to highlight a set of rare mutations that would very rarely produce homozygosity alone. This suggests that mutations in the CLD locus are not rare events. Although the disease is thought to be rare, undiagnosed patients may not be uncommon.

Can supplementary dietary fibre suppress breast cancer growth?

Case-control studies in diverse populations around the world have reported a lower risk of breast cancer in association with higher intake of dietary fibre and complex carbohydrates. Although this has not been confirmed in prospective studies in the USA, the observations have prompted the hypothesis that prolonged use of dietary fibre supplements might reduce breast cancer risk in high-incidence populations. Several possible mechanisms of action have been suggested, all involving a reduction of bioactive oestrogen levels in the blood. The various mechanisms are not necessarily mutually exclusive. First, a high-fibre diet might reduce circulating oestrogen levels by reducing the enterohepatic recirculation of oestrogen. Second, many plants and vegetables contain isoflavones and lignans capable of conversion in the bowel into weak oestrogens that may compete with oestradiol for target binding-sites. Third, a high-fibre diet is less often associated with obesity, which tends to increase availability of the biologically active 16-alpha metabolites of oestrone. Fourth, a high-fibre diet usually has a lower content of fat and a higher content of antioxidant vitamins, which may protect against breast cancer risk. Finally, diets rich in fibre and complex carbohydrates have been shown to improve insulin sensitivity, with an associated reduction in circulating oestrogen levels. Synergism between these effects offers a possible mechanism by which a high fibre intake might suppress breast cancer growth in women.

Survival from invasive cutaneous malignant melanoma in western australia and the oxford region: A comparative histological study of high and low incidence populations

A detailed histological review of 196 cases of invasive cutaneous malignant melanoma diagnosed in Western Australia, a high incidence area, during 1975-76 and of 226 cases during the period 1972-76 from the Oxford Region, a low incidence area, was made by one pathologist using the same parameters for each series. Five-year survival rates were analysed with respect to histological features, sex and site, with and without correction for tumour thickness. The results showed higher overall survival rates in Western Australia, with marked differences in prognosis between males and females in the Oxford Region, and between Oxford males and patients of both sexes in Western Australia. These findings were in accord with the corresponding differences in tumour thickness, and they support the theory that survival rates from cutaneous malignant melanoma are higher in areas of high incidence because they are diagnosed and treated earlier.

Nutrition and cancer

The evidence from high and low incidence populations worldwide, the corresponding correlations with fat and caloric intake, the picture that has emerged from migrant studies and studies of singular populations—such as the Seventh Day Adventists, the analyses of trends in incidence and dietary changes in certain well-characterized populations, and emerging evidence from case-control and other studies on specific dietary factors, all provide defensible arguments for dietary implications in the causation of certain major human cancers, stomach, breast, and colon specifically, and for dietary recommendations toward prevention. The evidence is reinforced by experimental animal studies that have shown data supportive of the epidemiologic studies, and provided clues to the possible mechanisms of action. Thus, there would seem to be sufficient evidence to propose modifying the diet of Western countries to reduce total fat and increase dietary fiber on the lines of the prudent diet, and to introduce certain protective factors, such as an increase in green vegetables and Vitamin C.

Bacteria and the etiology of colonic cancer.

We have postulated that bacteria can produce carcinogens from the diet or from intestinal secretions. The gut bacterial flora are dependent on the diet and the diet therefore controls both the supply of substrate and the flora acting on it; thus this would explain the correlation between diet and the incidence of colon cancer. The most likely substrates are the bile acids. The fecal concentration of bile acids is dependent on the amount of dietary fat; people living in areas with a high incidence of colon cancer have higher fecal concentrations of bile acids than do people living in low incidence areas. Their fecal bile acids are also more highly degraded. We have postulated four types of desaturation reaction needed to produce a polycyclic aromatic hydrocarbon from the bile acid nucleus; all four have been demonstrated using human gut bacteria. The organisms carrying out the reactions are much more numerous in feces of high incidence populations than that of low incidence populations. Studies on individuals show that cancer patients have both high fecal bile acid concentrations and bacteria able to desaturate the bile acid nucleus; controls had either or neither of these properties but very rarely both.