Nicole M. Probst-Hensch

IGF-1, IGF-2 and IGFBP-3 in prediagnostic serum: association with colorectal cancer in a cohort of Chinese men in Shanghai

This is the first study to investigate the associations of IGF-1, IGF-2 and IGFBP-3 concentrations with the risk of colorectal cancer in prospectively collected blood samples from an Oriental population. Between 1986 and 1989 serum samples were collected at baseline from 18u2008244 men, aged 45–65 years, without a history of cancer and living in Shanghai, China. IGF-1, IGF-2 and IGFBP-3 were measured in the serum of 135 men who developed colorectal cancer over 12 years of follow-up and 661 control subjects drawn from the cohort, who were matched to the index cases by neighbourhood of residence, age, and year and month of sample collection. Serum IGF-1 was not associated with risk of colorectal cancer. IGF-2 and IGFBP-3, on the other hand, exhibited statistically significant, positive associations with colorectal cancer risk when cases were confined to those diagnosed within a relatively short time period after enrolment (within 8 years). After adjustment for body mass index, cigarette smoking and alcohol intake, men in the highest versus the lowest quintile of IGF-2 and IGFBP-3 showed odds ratios of 2.74 (95% Cl = 1.67–4.50; 2-sided P for trend = 0.0008) and 2.85 (95% Cl = 1.69–4.81; 2-sided P for trend = 0.01), respectively. Our data thus suggest that circulating IGF-2 and IGFBP-3 can serve as early indicators of impending colorectal cancer.

Meat preparation and colorectal adenomas in a large sigmoidoscopy-based case-control study in California (United States)

The often observed association between red meat and colorectal cancercould be due in part to mutagens, such as heterocyclic amines (HCA), that arepresent in cooked meat. HCAs are highly mutagenic and cause intestinal tumorsin animals. The hypothesis that HCAs are also carcinogenic to humans remainsto be substantiated in epidemiologic studies. We determined the associationsof meat preparation and frequency of intake (proxy variables for HCAexposure, since HCA concentration depends on the type of meat and the way itis cooked) with the prevalence of distal colorectal adenomas in asigmoidoscopy-based case-control study of 488 matched pairs of subjects fromtwo California (United States) Kaiser Permanente Medical Centers. A more thantwofold difference in adenoma prevalence between subjects at extreme ends ofestimated HCA intake was observed. For subjects who ate red meat more thanonce per week, fried it more than 10 percent of the time, and ate it with adarkly browned surface, compared with subjects who ate red meat one time orless per week, fried it 10 or less percent of the time, and ate it with alightly browned surface, the odds ratio was 2.2 (95 percent confidenceinterval = 1.1-4.3). Adenoma prevalence also increased with frequency offrying red meat (P trend = 0.004). These results are consistent with acarcinogenic effect of HCA.

IGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles multiethnic cohort

The insulin-like growth factor 1 gene (IGF1) is a strong candidate gene for a breast cancer susceptibility model. We investigated a dinucleotide repeat 969u2009bp upstream from the transcription start site of the IGF1 gene for possible associations with plasma IGF1 levels and breast cancer risk in a multiethnic group of postmenopausal women. Furthermore, we investigated the relation between race/ethnicity, mean plasma IGF1 levels and breast cancer rates in the Hawaii/Los Angeles Multiethnic Cohort. The mean age-adjusted IGF1 level among Latino-American women, 116u2009ngu2009ml−1, was statistically significantly lower than the mean age-adjusted IGF1 levels for each of the three other racial/ethnic groups, African-American, Japanese-American and Non-Latino White women (146, 144 and 145u2009ngu2009ml−1, respectively) (P<0.0001). Latino-American women have the lowest breast cancer rates of any racial/ethnic group in the cohort. These results support the investigation of an expansion of the hypothesis for an important role of IGF1 in breast cancer tumorigenesis to different racial/ethnic groups and to postmenopausal women. It is unlikely that any involvement of IGF1 in breast cancer aetiology is mediated by the IGF1 dinucleotide repeat polymorphism, which was not significantly associated with circulating IGF1 levels nor breast cancer risk in this study. Research into relevant determinants of IGF1 levels in the blood must continue.

Variants of N-acetyltransferase NAT1 and a case-control study of colorectal adenomas.

N-acetyltransferase NAT1, together with enzymes CYP1A2 and NAT2, helps convert heterocyclic amines to mutagens. Epidemiologic studies of the association of variants of these enzymes with colorectal cancer may provide indirect support for a heterocyclic amine mechanism. We used single strand conformation polymorphism and heteroduplex analysis to screen fro mutations in the NAT1 coding region in a case-control study (n = 932) of colorectal adenomas, which are precursors to cancer. Thirteen different single-base mutations were found: C97T, C190T, T402C, G445A-G459A-T640G ( a combination of three mutations), C559T, G560A, A613G, A752T, T777C, G781A, and A787G. Function of novel mutations was tested by bacterial production of enzymes and measurements of Km, Vmax, and stability. However, on 24-control individuals and 18 cases carried an inactivating NAT1 mutation. When combined with our data on the NAT2 acetylation polymorphism, we saw no evidence for an association between N-acetyltransferases and prevalence of adenomas. Larger sample sizes are required for further evaluation.

Ethnic differences in post-menopausal plasma oestrogen levels: high oestrone levels in Japanese-American women despite low weight

Breast cancer incidence in Japanese-American women is approaching that of US Whites. We investigated whether this shift is paralleled by similar post-menopausal plasma hormone levels in the two ethnic groups. We also included African-American and Latina women to further our understanding of possible ethnic differences in oestrogen metabolism. We measured androstenedione (A), oestrone (E1) and oestradiol (E2) in 30 Japanese-American, 39 non-Latina White (‘White’), 66 African-American and 58 Latina women. The (age-adjusted) geometric mean E1 levels were 34 pg ml–1 in Japanese-Americans, 28 pg ml–1 in Whites, 35 pg ml–1 in African-Americans and 31 pg ml–1in Latinas. After adjustment for body mass index, Japanese-Americans had the highest mean E1 value of all groups and this was statistically significantly greater than the value for Whites (Pt-test= 0.05). The geometric mean A concentrations were also highest in Japanese-Americans. There was little ethnic difference in E2 levels. In conclusion, post-menopausal plasma oestrogen levels in Japanese-American women are at least as high as those in Whites.

A sigmoidoscopy‐based case–control study of polyps: macronutrients, fiber and meat consumption

We conducted a large, sigmoidoscopy‐based case–control study to examine the relation of intake of macronutrients, meat, and fiber to occurrence of adenomas of the large bowel. Cases were subjects diagnosed for the first time with one or more histologically confirmed adenomas. Controls had no polyps of any type at sigmoidoscopy, had no history of polyps, and were individually matched to cases by gender, age, date of sigmoidoscopy, and Kaiser Center. The response rate was 84% for cases and 82% for controls. Complete dietary data for 488 matched pairs were available. All odds ratios are from matched analyses adjusted for energy. We observed positive associations with risk of adenomas for calories, animal fat, saturated fat, red meat, and the ratio of red meat to poultry and fish. Protective effects were observed for vegetable protein, carbohydrates, and dietary fiber. The fiber effects diminished after adjusting for fruits and vegetables. Results after mutually adjusting for the effects of saturated fat, fiber and the ratio of red meat to chicken and fish suggest that each of these variables has an effect on risk of adenomas that is independent of the other 2 exposures. Int. J. Cancer 73:497–502, 1997.

Insulin-like growth factor-1 promoter polymorphisms and colorectal cancer: a functional genomics approach

Rationale: Insulin-like growth factor-1 (IGF1) has been proposed to mediate the obesity-related carcinogenic effects of “Western lifestyle”. While genetic factors explain at least half of inter-individual IGF1 variation, the IGF1 polymorphisms hypothesised to underlie the variation in cancer incidence rates remain ill-defined. Methods: We used a comparative genomics approach to identify putative regulatory polymorphisms in the IGF1 promoter region within a rapidly westernising population, the Singapore Chinese. Association of IGF1 genotype with colorectal cancer risk was assessed among 298 colorectal cancer cases and 1142 controls nested within the Singapore Chinese Health Study. Results: We identified a common (minor allele frequencyu200a=u200a0.36) single-nucleotide polymorphism (SNP), IGF1-2995 C/A, within a consensus domain for an octamer binding factor (Oct1/Oct2) transcription factor binding site. Possession of one or two copies of the minor allele (genotypes AA and CA) conferred an approximate 40% decrease in risk in comparison to genotype CC (odds ratio, 0.59; 95% confidence interval, 0.45 to 0.77). This association was stronger for colon cancer than for rectal cancer (pheterogeneity<0.001) and for those who were physically active versus inactive (pinteractionu200a=u200a0.05). Models including other previously identified promoter polymorphisms did not provide a better prediction of colorectal cancer risk. Conclusions: Our results support the hypotheses that IGF1 plays a role in colonic carcinogenesis and that genetically inherited variation in IGF1 expression influences risk of colorectal cancer.

ESTROGEN-PROGESTIN REPLACEMENT THERAPY AND ENDOMETRIAL CANCER

BACKGROUNDnIt has been known for more than 20 years that estrogen replacement therapy substantially increases a womans risk of developing endometrial cancer. To reduce this increased risk, progestins have been added to estrogen replacement therapy for between 5 and 15 days (usually 7 or 10 days) per month in a sequential fashion (sequential estrogen-progestin replacement therapy) or with each dose of estrogen replacement therapy (continuous combined replacement therapy). At the present time, however, little is known about the effects of varying the number of days that progestin is used in sequential estrogen-progestin replacement therapy.nnnPURPOSEnWe sought to determine the effects of sequential estrogen-progestin replacement therapy and continuous combined replacement therapy on a womans risk of developing endometrial cancer.nnnMETHODSnA population-based, case-control study of 833 case subjects and 791 control subjects was conducted. Women were postmenopausal, white, and aged 50-74 years when first diagnosed with invasive endometrial cancer or were aged 50-74 years at the matching date for control subjects. All subjects were interviewed in person with the aid of a month-by-month calendar. Relative risks were estimated by odds ratios (ORs); ORs were adjusted simultaneously for the different forms of hormone replacement therapy and for the known endometrial cancer risk factors.nnnRESULTSnThe adjusted OR was 2.17 (95% confidence interval [CI] = 1.91-2.47) per 5 years of estrogen replacement therapy use (based on 422 users among the case subjects and 262 users among the control subjects). For women who received sequential estrogen-progestin replacement therapy with the progestin given for less than 10 days (effectively 7 days) per month, the adjusted OR was only slightly reduced to 1.87 (95% CI = 1.32-2.65) per 5 years of use (74 case subjects and 47 control subjects). However, when progestin was given for 10 or more days (effectively 10 days), there was essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.82-1.41) (79 case subjects and 88 control subjects). Continuous combined replacement therapy was also associated with essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.80-1.43) (94 case subjects and 81 control subjects).nnnCONCLUSIONSnThe progestin in sequential estrogen-progestin replacement therapy needs to be given for at least 10 days to block effectively any increased risk of endometrial cancer. Continuous combined estrogen-progestin therapy is similarly effective. Neither regimen reduces a womans underlying risk of endometrial cancer. The sharp distinction between the effects of less than 10 days (effectively 7 days) and 10 or more days (effectively 10 days) of progestin use in sequential estrogen-progestin replacement therapy suggests that the extent of endometrial sloughing may play a critical role in determining endometrial cancer risk.