Term Paper: Huge Cancer Epidemiology Huge Study

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[. . .] When reported, the adjusted effect estimate was included in the analysis in preference to the unadjusted one. If odds ratios were not reported, we computed unadjusted odds ratios from the data presented. Analyses were conducted by using Stata statistical software, release 7.0 (189). Heterogeneity was assessed by the Q test, with a fixed-effects model used if p ? 0.1 and a random-effects model used if p < 0.1. The I2 statistic was also calculated as a measure of consistency between studies (190). Except for the association between breast cancer and the 3801T-C polymorphism, the estimates of effect in the first published study were similar to those for the cumulative meta-analyses.

Study characteristics

Four studies took place in Japan, two in Taiwan, six in the United States, and one each in Canada, Brazil, France, Greece, and the United Kingdom. Thirteen studies analyzed the 3801T-C polymorphism (2,484 cases), 10 analyzed the Ile462Val polymorphism (3,535 cases), two analyzed the 3205T-C polymorphism (280 cases), and three analyzed the Thr461Asp polymorphism (2,245 cases).

In one study, case DNA was derived from tumor specimens; in the remainder, and for all control series, DNA came from blood samples. Of the U.S. studies, two involved subjects of whom the majority (or all) were White, three included more than one ethnic group (analyzed separately in two studies), and, in one, ethnicity was not reported. One study included postmenopausal women only; all others either consisted of both pre- and postmenopausal women (n = 6) or did not describe the subjects' menopausal status (n = 10). Eleven studies included fewer than 200 breast cancer cases.

In 15 studies, cases were recruited from clinics or hospital series; in one study, cases were identified from a cancer registry; and one study was nested within the Nurses' Health Study. Without information on all potentially eligible cases in the population, it is difficult to assess the generalizability of the results. At least four control series included "volunteers" from either an unspecified source or a convenient population such as medical workers -- a potential source of bias. Seven studies presented estimates adjusted for potential confounding factors.

In general, the studies considered the polymorphisms separately. Therefore, the effect of one polymorphism may have been overshadowed by the effects of others, whereas construction of haplotypes may have revealed effects that were not apparent by analyzing single polymorphisms. Studies of the Ile462Val polymorphism may have suffered from some minor misclassification due to the undetected presence of the Thr461Asp polymorphism.

3801T-C (CYP1A1*2A, CYP1A1*2B)

Most studies found no evidence of an association between the 3801T-C polymorphism and breast cancer risk. In Taiwan, women with the C/C genotype had a raised risk compared with other genotypes combined. African-American women with the C/C genotype also had an increased risk compared with those with the T/T genotype, but this study included only 25 cases. The 3801C variant was associated with reduced risk for Japanese and non-White Brazilian women. However, in both studies, the cases were surgical series, and controls were not population based.

Their meta-analysis included eight studies for which data were available for all three genotypes separately. Breast cancer risk did not differ from unity for C/C versus T/T (random-effects relative risk (RR) = 0.97, 95% CI: 0.52, 1.80; Q = 15.26, p = 0.08) or for T/C versus T/T (random-effects RR = 0.91, 95% CI: 0.70, 1.19; Q = 17.34, p = 0.07). The I2 statistics for these analyses were 41% and 42%, respectively, indicating moderate heterogeneity across studies.

Ile462Val (CYP1A1*2B, CYP1A1*2C)

A Japanese study found a significantly reduced risk for women with the Ile/Val genotype compared with the Ile/Ile genotype (RR = 0.66, 95% CI: 0.44, 0.99). However, meta-analysis found no association between breast cancer risk and the Val/Val (fixed-effects RR = 1.04, 95% CI: 0.63, 1.74; Q = 4.59, p = 0.33, I2 = 13%) or Ile/Val (fixed-effects RR = 0.92, 95% CI: 0.76, 1.10; Q = 11.57, p = 0.17, I2 = 31%) genotypes vs. The Ile/Ile genotype.

3205T-C (CYP1A1*3)

There was no association between the 3205C variant and breast cancer in the two available studies However, these studies each included small series (n = 27 and n = 59) of African-American breast cancer cases.

Thr461Asp (CYP1A1*4)

In a Canadian study, carriers of the Asp variant had an increased breast cancer risk (adjusted RR = 3.3, 95% CI: 1.1, 9.7). Results of the other studies, in White American women and African-American women, and in White women in England, were null. Meta-analysis found no association between disease risk and the Asp/Asp (fixed-effects RR = 0.95, 95% CI: 0.20, 4.49; Q = 0.52, p = 0.77, I2 = 0%) or Thr/Asp (fixed-effects RR = 1.12, 95% CI: 0.87, 1.43; Q = 0.89, p = 0.64, I2 = 0%) genotypes vs. The Thr/Thr genotype.

Combinations of genotypes

Taioli et al. assessed the impact of combinations of 3801T-C, Ile462Val, and 3205T-C genotypes on breast cancer risk. Compared with homozygotes for the 3801T, Ile, and 3205T alleles, only the 3801C/C genotype was associated with increased risk for African-American women (RR = 5.8, 95% CI: 1.0, 36.0), but the effect estimate was imprecise.

One study combined Ile462Val and Thr461Asp genotypes and found no significant effect in any of the three combined genotype groups relative to the group with the Ile/Ile and Thr/Thr genotypes. Another study assessed disease risk for subjects with either the Val or Asp variant; no significant association was found in White women or African-American women.

Subgroup analyses

Menopausal status, age at menarche, and estrogen and progesterone receptor status.

In a Taiwanese study, the association of the 3801C/C genotype with raised disease risk was evident in postmenopausal, but not premenopausal, women, and further analysis suggested that the relation might be more pronounced for women experiencing early menarche. Other studies found no association between the 3801C variant and breast cancer when subjects were stratified by menopausal status or age at menarche. There was no evidence for an association with the Ile462Val polymorphism for either pre- or postmenopausal women. In a Canadian study, the increased risk associated with the Thr461Asp polymorphism was evident for postmenopausal women only; however, a study in the United Kingdom found no difference in Thr461Asp genotypic risks by menopausal status. There were no significant associations between CYP1A1 polymorphisms and estrogen or progesterone receptor status.

Age at diagnosis and clinical characteristics.

Studies investigating CYP1A1 genotype and age at diagnosis of breast cancer have produced inconsistent results. The 3801C variant has been significantly associated with a higher frequency of lymph-node metastasis and the Val variant with a higher frequency of small tumors (<2 cm), while neither variant was associated with histology or histologic grade. Other studies found no association between the four polymorphisms and tumor size, stage, type, grade, or nodal status or between 3801T-C or Ile462Val and tumor type or stage of disease.

Survival

In a British study of 1,793 incident or prevalent breast cancer cases, the Ile462Val polymorphism was not related to survival (191). The hazard ratio was reduced for Thr/Asp heterozygotes compared with Thr/Thr homozygotes, but not significantly (hazard ratio = 0.67, 95% CI: 0.33, 1.37).

Interactions

If CYP1A1 is involved in breast cancer, it may influence disease risk by interacting with exposure (or indicators of exposure) to PAHs or estrogen, for example, or with other genes involved in the metabolism of carcinogens, estrogens, or other hormones. Sample size is particularly important in this context. For instance, to detect a multiplicative interaction, very large sample sizes are required for adequate power. Although the sample size needed to detect other types of interactions may be smaller, a priori it is not usually clear what model of interaction would be predicted.

Gene-environment interactions

Smoking.

In five studies investigating genotype-smoking interactions, two found evidence of an interaction. In Ambrosone et al.'s study, adjusted relative risks for Val carriers vs. Ile/Ile homozygotes among nonsmokers, light smokers (<29 pack-years of exposure), and heavy smokers (?29 pack-years) were 1.3 (95% CI: 0.62, 2.70), 5.2 (95% CI: 1.16, 23.56), and 0.9 (95% CI: 0.24, 3.09), respectively, but no formal test of interaction was conducted. Ishibe et al. found no interaction between pack-years of smoking and either 3801T-C or Ile462Val polymorphisms, but they observed effect modification for smoking status at diagnosis and age at which smoking started. Risk was significantly raised for current smokers carrying the 3801C variant versus 3801T/T nonsmokers (p for interaction = 0.06) and for women with either variant who started smoking before age 18 years versus 3801T/T nonsmokers (p for interaction = 0.04) and Ile/Ile nonsmokers (p for interaction = 0.08).

The numbers analyzed in the studies of genotype-smoking interactions were small, and interpretation is difficult because of differences in the way in which interactions were assessed (stratifying by smoking status or genotype, or using a single reference group of smoking status and genotype combined) and in categorization of smoking status. For example, the interaction patterns observed by Ambrosone et al. Or… [END OF PREVIEW]

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Huge Cancer Epidemiology Huge Study.  (2011, April 13).  Retrieved May 19, 2019, from https://www.essaytown.com/subjects/paper/huge-cancer-epidemiology-study/6882327

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"Huge Cancer Epidemiology Huge Study."  13 April 2011.  Web.  19 May 2019. <https://www.essaytown.com/subjects/paper/huge-cancer-epidemiology-study/6882327>.

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"Huge Cancer Epidemiology Huge Study."  Essaytown.com.  April 13, 2011.  Accessed May 19, 2019.
https://www.essaytown.com/subjects/paper/huge-cancer-epidemiology-study/6882327.