Faculty Bibliography

BACKGROUND: Case-control studies have reported inconsistent results concerning breast cancer risk and polymorphisms in genes that control endogenous estrogen biosynthesis. We report findings from the first family-based association study examining associations between female breast cancer risk and polymorphisms in two key estrogen-biosynthesis genes CYP17 (T-->C promoter polymorphism) and CYP19 (TTTA repeat polymorphism). METHODS: We conducted the study among 278 nuclear families containing one or more daughters with breast cancer, with a total of 1123 family members (702 with available constitutional DNA and questionnaire data and 421 without them). These nuclear families were selected from breast cancer families participating in the Metropolitan New York Registry, one of the six centers of the National Cancer Institute's Breast Cancer Family Registry. We used likelihood-based statistical methods to examine allelic associations. RESULTS: We found the CYP19 allele with 11 TTTA repeats to be associated with breast cancer risk in these families. We also found that maternal (but not paternal) carrier status of CYP19 alleles with 11 repeats tended to be associated with breast cancer risk in daughters (independently of the daughters' own genotype), suggesting a possible in utero effect of CYP19. We found no association of a woman's breast cancer risk either with her own or with her mother's CYP17 genotype. CONCLUSION: This family-based study indicates that a woman's personal and maternal carrier status of CYP19 11 TTTA repeat allele might be related to increased breast cancer risk. However, because this is the first study to report an association between CYP19 11 TTTA repeat allele and breast cancer, and because multiple comparisons have been made, the associations should be interpreted with caution and need confirmation in future family-based studies

We have developed a thirty-nine-item semi-quantitative food-frequency questionnaire (FFQ) to assess the dietary consumption of 11,746 men and women in a prospective cohort study that evaluates the health effects of As from drinking water in Bangladesh. In order to validate the FFQ, two 7 d food diaries (FD) were completed for 189 randomly selected cohort participants in two different seasons of the year. Nutrient values were converted based on both the United States Department of Agriculture's National Nutrient Database and a food composition table for the Indian subcontinent. Pearson product-moment and Spearman non-parametric rank correlation coefficients comparing food and nutrient consumptions estimated from FFQ and 7 d FD were calculated based on log-transformed consumption values with or without adjustment for total energy and correction for within-individual variation. Correlations of macronutrients and common micronutrients including total fat, monounsaturated fat, polyunsaturated fat, saturated fat, protein, carbohydrate, dietary fibre, Na, K, vitamin B6, vitamin B12, riboflavin, Mn, thiamin and Fe were moderately good, ranging from 0.30 to 0.76. However, correlations of other micronutrients were weak (<0.30). Large seasonal variations in intakes of retinol equivalents and vitamin C were observed. This analysis documents the degree of validity of the FFQ in measuring specific nutrient intakes in the study population. To our knowledge, the present study is the first to document the validity of a FFQ with the use of 7 d FD in a Bangladeshi population

Prostate cancer is the most commonly diagnosed cancer in men and one of the leading causes of cancer deaths. There is strong genetic evidence indicating that a large proportion of prostate cancers are caused by heritable factors but the search for prostate cancer susceptibility genes has thus far remained elusive. TGFBR1*6A, a common hypomorphic variant of the type I Transforming Growth Factor Beta receptor, is emerging as a tumor susceptibility allele that predisposes to the development of breast, colon and ovarian cancer. The association with prostate cancer has not yet been explored. A total of 907 cases and controls from New York City were genotyped to test the hypothesis that TGFBR1*6A may contribute to the development of prostate cancer. TGFBR1*6A allelic frequency among cases (0.086) was slightly higher than among controls (0.080) but the differences in TGFBR1*6A genotype distribution between cases and controls did not reach statistical significance (p = 0.67). Our data suggest that TGFBR1*6A does not contribute to the development of prostate cancer

Castleman's disease (angiofollicular lymphoid hyperplasia) is a rare heterogeneous group of lymphoproliferative disorders of uncertain cause. Most cases occur as mediastinal masses, although extrathoracic involvement has been reported. Castleman's disease involving the genitourinary tract, one of the most infrequent organ systems affected, has so far only been described in pararenal and retroperitoneal locations. We describe a patient with an unusual case of unicentric Castleman's disease that was located in a urachal remnant and bore a malignant appearance. The patient initially presented with abdominal pain and underwent laparoscopic radical excision of the urachal mass. Pathologic examination revealed Castleman's disease, hyaline-vascular type, with atypical lymphoid proliferation and follicular dendritic cell dysplasia. No evidence of concomitant lymphoma or sarcoma was found. Two years after surgical removal of the tumor, no recurrence was evident. To our knowledge, this is the first case of Castleman's disease presenting as a urachal tumor.

We assessed the potential burden of internal cancers due to arsenic exposure in Bangladesh. We estimated excess lifetime risks of death from liver, bladder, and lung cancers using an exposure distribution, death probabilities, and cancer mortality rates from Bangladesh and dose-specific relative risk estimates from Taiwan. Results indicated at least a doubling of lifetime mortality risk from liver, bladder, and lung cancers (229.6 vs 103.5 per 100 000 population) in Bangladesh owing to arsenic in drinking water

In this paper, we report findings from a family-based association study examining the association between polymorphisms in two key estrogen-metabolism genes CYP1B1 (codon 432 G --> C and codon 453 A --> G variants) and COMT (codon 158 G --> A variant) and female breast cancer. We conducted the study among 280 nuclear families containing one or more daughters with breast cancer with a total of 1124 family members (702 with available constitutional DNA and questionnaire data and 421 without). These nuclear families were selected from breast cancer families participating in the Metropolitan New York Registry (MNYR) - one of the six centers of NCI's Breast Cooperative Family Registry. We used likelihood-based statistical methods to examine the allelic associations. We found none of the variant alleles of the CYP1B1 and COMT genes to be associated with breast cancer in these families. This was consistent with results from matched case-control analyses using all available sib-ships in these families. However, we found that parental carrier status of the CYP1B1 codon 453 variant G allele and the COMT codon 158 variant A allele was associated with breast cancer risk in daughters (independent of the daughters' own genotype). In conclusion, findings from this family-based study indicate that a woman's own CYP1B1 or COMT genotypes are not associated with her breast cancer risk. Although the study found that parental carrier status of certain CYP1B1 or COMT genotypes might be associated with daughter's breast cancer risk, the biological basis as well as independent confirmation of this finding need to be investigated in future larger family-based studies before making meaningful inferences

Transcription factors belonging to the FoxH1 and Mixer families are required for facets of Nodal signaling during vertebrate mesendoderm induction. Here, we analyze whether zebrafish proteins related to FoxH1 [Schmalspur (Sur)] and Mixer [Bonnie and clyde (Bon)] act within or downstream of the Nodal signaling pathway, test whether these two factors have additive or overlapping activities, and determine whether FoxH1/Sur and Mixer/Bon can account for all Nodal signaling during embryogenesis. We find that sur expression is independent of Nodal signaling and that bon is expressed in the absence of Nodal signaling but requires Nodal signaling and Sur for enhanced, maintained expression. These results and the association of FoxH1 and Mixer/Bon with phosphorylated Smad2 support a role for these factors as components of the Nodal signaling pathway. In contrast to the relatively mild defects observed in single mutants, loss of both bon and sur results in a severe phenotype characterized by absence of prechordal plate, cardiac mesoderm, endoderm and ventral neuroectoderm. Analysis of Nodal-regulated proteins reveals that Bon and Sur have both distinct and overlapping regulatory roles. Some genes are regulated by both Bon and Sur, and others by either Bon or Sur. Complete loss of Nodal signaling results in a more severe phenotype than loss of both Bon and Sur, indicating that additional Smad-associated transcription factors remain to be identified that act as components of the Nodal signaling pathway

Chronic exposure to inorganic arsenic is known to cause non-melanocytic skin and internal cancers in humans. We examined whether genetic susceptibility, as determined by single nucleotide polymorphisms -463G-->A and -262C-->T in the oxidative stress genes myeloperoxidase (MPO) and catalase (CAT), respectively, are associated with the risk of arsenic-induced hyperkeratotic skin lesions-precursors of skin cancer-in a case-control study in Bangladesh. Carriers of the susceptible MPO and CAT genotypes were at elevated risk (OR 2.1 and 95% CI 0.7-6.2 for MPO; OR 1.9 and 95% CI 0.8-4.7 for CAT) of hyperkeratosis after adjustment for arsenic exposure and other covariates. Subjects carrying the high-risk MPO genotype and with high arsenic exposure were at almost six times (OR 5.8; 95% CI 1.1-30.1) elevated risk of developing hyperkeratosis as compared to those carrying the low-risk genotype and with low arsenic exposure. Similarly, highly exposed subjects carrying the high-risk CAT genotype were at more than four times (OR 4.6; 95% CI 1.4-15.6) elevated risk of developing hyperkeratosis as compared to those carrying the low-risk genotype and with low arsenic exposure. Our findings, although based on small numbers, suggest that the oxidative stress genes MPO and CAT may influence the risk of arsenic-induced premalignant hyperkeratotic skin lesions

This paper describes findings from a recently completed study of polycyclic aromatic hydrocarbon (PAH) exposure among city dwellers of Dhaka, Bangladesh. We measured PAH-DNA adducts in white blood cells (WBCs) as a marker of environmental and occupational PAH exposure in 46 rickshaw drivers (who pedal commercial unshielded three-wheelers for passenger transport) and 48 non-rickshaw drivers (comparison group) in Dhaka city. We performed enzyme-linked immunosorbent assay (ELISA) to quantify immunologically the WBC PAH-DNA adducts. Rickshaw drivers had a significantly higher WBC PAH-DNA adducts level than the non-rickshaw drivers. Among rickshaw drivers, adduct levels tended to be positively associated with the duration of residence in the city and cigarette smoking. No such trends were observed among non-rickshaw drivers. In conclusion, the results suggest that urban residents who are occupationally exposed to traffic pollution in Dhaka are at potentially higher risk of health effects from exposure to carcinogenic PAH compounds.

Chronic exposure to inorganic arsenic is known to cause non-melanocytic skin and internal cancers in humans. An estimated 50-70 million people in Bangladesh have been chronically exposed to arsenic from drinking water and are at risk of skin and other cancers. We undertook the first study to examine whether genetic susceptibility, as determined by the codon 751 SNP (A-->C) of the DNA repair gene XPD, influences the risk of arsenic-induced hyperkeratotic skin lesions, precursors of skin cancer, in a case-control study of 29 hyperkeratosis cases and 105 healthy controls from the same community in an area of Bangladesh. As expected, there was a monotonic increase in risk of hyperkeratosis in relation to urinary arsenic measures but the XPD genotype was not independently associated with the risk. However, the increase in hyperkeratosis risk in relation to urinary arsenic measures genotype was borderline significant for urinary total arsenic (P for trend=0.06) and statistically significant for urinary creatinine adjusted arsenic (P for trend=0.01) among subjects with the XPD A allele (AA) but not among subjects with the other XPD genotypes. Among AA carriers, the risk for the highest arsenic exposed group compared with the lowest was more than 7-fold for urinary total arsenic and about 11-fold for urinary creatinine adjusted arsenic. In conclusion, our findings suggest that the DNA repair gene XPD may influence the risk of arsenic-induced premalignant hyperkeratotic skin lesions. Future larger studies are needed to confirm this novel finding and investigate how combinations of different candidate genes and/or other host and environmental factors may influence the risk of arsenic induced skin and other cancers