Bhramar Mukherjee

Calculation of Risk of Colorectal and Endometrial Cancer Among Patients With Lynch Syndrome

BACKGROUND & AIMS Lynch syndrome is the most common hereditary colorectal cancer (CRC) syndrome. Some previous estimates of lifetime risk for CRC and endometrial cancer (EC) did not control for ascertainment and were susceptible to bias toward overestimated risk. METHODS We studied 147 families with mismatch repair gene mutations (55 MLH1, 81 MSH2, and 11 MSH6) identified at 2 US cancer genetics clinics. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general population using modified segregation analysis. The likelihood for each pedigree was conditioned on the proband and first-degree relatives affected with CRC to reduce ascertainment bias and overestimation of penetrance. RESULTS We analyzed 628 cases of CRC, diagnosed at the median ages of 42 and 47 years for men and women, respectively. The cumulative risk of CRC was 66.08% (95% confidence interval [CI], 59.47%-76.17%) for men and 42.71% (95% CI, 36.57%-52.83%) for women, with overall HRs of 148.4 and 51.1, respectively. CRC risk was highest for males with mutations in MLH1. There were 155 cases of EC, diagnosed at a median age of 47.5 years. The cumulative risk of EC was 39.39% (95% CI, 30.78%-46.94%) with an overall HR of 39.0 (95% CI, 30.4-50.2). For women, the cumulative risk of CRC or EC was 73.42% (95% CI, 63.76%-80.54%). CONCLUSIONS Lifetime risks of CRC and EC in mismatch repair gene mutation carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer surveillance is necessary.

Risk of pancreatic cancer in families with Lynch syndrome

CONTEXT Lynch syndrome is an inherited cause of colorectal cancer caused by mutations of DNA mismatch repair (MMR) genes. A number of extracolonic tumors have been associated with the disorder, including pancreatic cancer; however, the risk of pancreatic cancer in Lynch syndrome is uncertain and not quantified. OBJECTIVE To estimate pancreatic cancer risk in families with germline MMR gene mutations. DESIGN, SETTING, AND PATIENTS Cancer histories of probands and their relatives were evaluated in MMR gene mutation carriers in the familial cancer registries of the Dana-Farber Cancer Institute (n = 80), Boston, Massachusetts, and University of Michigan Comprehensive Cancer Center (n = 67), Ann Arbor, Michigan. Families enrolled before the study start date (June 2008) were eligible. Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk were calculated and compared with the general population using modified segregation analysis, with correction for ascertainment. MAIN OUTCOME MEASURES Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk. RESULTS Data on 6342 individuals from 147 families with MMR gene mutations were analyzed. Thirty-one families (21.1%) reported at least 1 case of pancreatic cancer. Forty-seven pancreatic cancers were reported (21 men and 26 women), with no sex-related difference in age of diagnosis (51.5 vs 56.5 years for men and women, respectively). The cumulative risk of pancreatic cancer in these families with gene mutations was 1.31% (95% confidence interval [CI], 0.31%-2.32%) up to age 50 years and 3.68% (95% CI, 1.45%-5.88%) up to age 70 years, which represents an 8.6-fold increase (95% CI, 4.7-15.7) compared with the general population. CONCLUSIONS Among 147 families with germline MMR gene mutations, the risk of pancreatic cancer was increased compared with the US population. Individuals with MMR gene mutations and a family history of pancreatic cancer are appropriate to include in studies to further define the risk of premalignant and malignant pancreatic neoplasms and potential benefits and limitations of surveillance.

Distribution, Variability, and Predictors of Urinary Concentrations of Phenols and Parabens among Pregnant Women in Puerto Rico

Puerto Rico has higher rates of a range of endocrine-related diseases and disorders compared to the United States. However, little is known to date about human exposures to known or potential endocrine disrupting chemicals (EDCs) in Puerto Rico. We recruited 105 pregnant women in Northern Puerto Rico who provided urine samples and questionnaire data at three times (18 ± 2, 22 ± 2, and 26 ± 2 weeks) during gestation. We measured the urinary concentrations of five phenols and three parabens: 2,4-dichlorophenol (24-DCP), 2,5-dichlorophenol (25-DCP), benzophenone-3 (BP-3), bisphenol A (BPA), triclosan (TCS), butyl paraben (B-PB), methyl paraben (M-PB), and propyl paraben (P-PB). The frequent detection of these chemicals suggests that exposure is highly prevalent among these Puerto Rican pregnant women. Urinary concentrations of TCS, BP-3, and 25-DCP were higher than among women of reproductive age in the US general population, while concentrations of BPA, 24-DCP, and parabens were similar. Intraclass correlation coefficients (ICC) varied widely between biomarkers; BPA had the lowest ICC (0.24) and BP-3 had the highest (0.62), followed by 25-DCP (0.49) and TCS (0.47). We found positive associations between biomarker concentrations with self-reported use of liquid soap (TCS), sunscreen (BP-3), lotion (BP-3 and parabens), and cosmetics (parabens). Our results can inform future epidemiology studies and strategies to reduce exposure to these chemicals or their precursors.

MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers

Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in the double strand break (DSB) repair gene MRE11. We assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in MRE11 may sensitize CRC cells to poly(ADP-ribose) polymerase (PARP-1) inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP-1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between MRE11 expression levels and cytotoxicity to ABT-888 at 10 μM was observed (R² = 0.915, P < 0.001). Using two experimental approaches, including short hairpin RNA knocking down MRE11 in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant MRE11, we experimentally tried to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug-response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in MRE11 show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs.

Associations between brominated flame retardants in house dust and hormone levels in men

Brominated flame retardants (BFRs) are used in the manufacture of a variety of materials and consumer products in order to meet fire safety standards. BFRs may persist in the environment and have been detected in wildlife, humans and indoor dust and air. Some BFRs have demonstrated endocrine and reproductive effects in animals, but human studies are limited. In this exploratory study, we measured serum hormone levels and flame retardant concentrations [31 polybrominated diphenyl ether (PBDE) congeners and 6 alternate flame retardants] in house dust from men recruited through a US infertility clinic. PBDE congeners in dust were grouped by commercial mixtures (i.e. penta-, octa- and deca-BDE). In multivariable linear regression models adjusted by age and body mass index (BMI), significant positive associations were found between house dust concentrations of pentaBDEs and serum levels of free T4, total T3, estradiol, and sex hormone binding globulin (SHBG), along with an inverse association with follicle stimulating hormone (FSH). There were also positive associations of octaBDE concentrations with serum free T4, thyroid stimulating hormone (TSH), luteinizing hormone (LH) and testosterone and an inverse association of decaBDE concentrations with testosterone. Hexabromocyclododecane (HBCD) was associated with decreased SHBG and increased free androgen index. Dust concentrations of bis-tribromophenoxyethane (BTBPE) and tetrabromo-diethylhexylphthalate (TBPH) were positively associated with total T3. These findings are consistent with our previous report of associations between PBDEs (BDE 47, 99 and 100) in house dust and hormone levels in men, and further suggest that exposure to contaminants in indoor dust may be leading to endocrine disruption in men.

Testing Gene-Environment Interaction in Large-Scale Case-Control Association Studies: Possible Choices and Comparisons

Several methods for screening gene-environment interaction have recently been proposed that address the issue of using gene-environment independence in a data-adaptive way. In this report, the authors present a comparative simulation study of power and type I error properties of 3 classes of procedures: 1) the standard 1-step case-control method; 2) the case-only method that requires an assumption of gene-environment independence for the underlying population; and 3) a variety of hybrid methods, including empirical-Bayes, 2-step, and model averaging, that aim at gaining power by exploiting the assumption of gene-environment independence and yet can protect against false positives when the independence assumption is violated. These studies suggest that, although the case-only method generally has maximum power, it has the potential to create substantial false positives in large-scale studies even when a small fraction of markers are associated with the exposure under study in the underlying population. All the hybrid methods perform well in protecting against such false positives and yet can retain substantial power advantages over standard case-control tests. The authors conclude that, for future genome-wide scans for gene-environment interactions, major power gain is possible by using alternatives to standard case-control analysis. Whether a case-only type scan or one of the hybrid methods should be used depends on the strength and direction of gene-environment interaction and association, the level of tolerance for false positives, and the nature of replication strategies.

Urinary phthalate metabolite concentrations among pregnant women in Northern Puerto Rico: Distribution, temporal variability, and predictors

BACKGROUND Phthalate contamination exists in the North Coast karst aquifer system in Puerto Rico. In light of potential health impacts associated with phthalate exposure, targeted action for elimination of exposure sources may be warranted, especially for sensitive populations such as pregnant women. However, information on exposure to phthalates from a variety of sources in Puerto Rico is lacking. The objective of this study was to determine concentrations and predictors of urinary phthalate biomarkers measured at multiple times during pregnancy among women living in the Northern karst area of Puerto Rico. METHODS We recruited 139 pregnant women in Northern Puerto Rico and collected urine samples and questionnaire data at three separate visits (18 ± 2 weeks, 22 ± 2 weeks, and 26 ± 2 weeks of gestation). Urine samples were analyzed for eleven phthalate metabolites: mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl phthalate, mono-2-ethyl-5-oxohexyl phthalate, mono-2-ethyl-5-carboxypentyl phthalate, mono-ethyl phthalate (MEP), mono-n-butyl phthalate, mono-benzyl phthalate, mono-isobutyl phthalate, mono-3-carboxypropyl phthalate (MCPP), mono carboxyisononyl phthalate (MCNP), and mono carboxyisooctyl phthalate (MCOP). RESULTS Detectable concentrations of phthalate metabolites among pregnant women living in Puerto Rico was prevalent, and metabolite concentrations tended to be higher than or similar to those measured in women of reproductive age from the general US population. Intraclass correlation coefficients ranged from very weak (MCNP; 0.05) to moderate (MEP; 0.44) reproducibility among all phthalate metabolites. We observed significant or suggestive positive associations between urinary phthalate metabolite concentrations and water usage/storage habits (MEP, MCNP, MCOP), use of personal care products (MEP), and consumption of certain food items (MCPP, MCNP, and MCOP). CONCLUSIONS To our knowledge this is the first study to report concentrations, temporal variability, and predictors of phthalate biomarkers among pregnant women in Puerto Rico. Preliminary results suggest several potentially important exposure sources to phthalates in this population and future analysis from this ongoing prospective cohort will help to inform targeted approaches to reduce exposure.

Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth

BACKGROUND Preterm birth is a significant public health problem, affecting over 1 in 10 live births and contributing largely to infant mortality and morbidity. Everyday exposure to environmental chemicals such as phthalates could contribute to prematurity, and may be modifiable. In the present study we examine variability in phthalate exposure across gestation and identify windows of susceptibility for the relationship with preterm birth. METHODS Women were recruited early in pregnancy as part of a prospective, longitudinal birth cohort at the Brigham and Womens Hospital in Boston, Massachusetts. Urine samples were collected at up to 4 time points during gestation for phthalate measurement, and birth outcomes were recorded at delivery. From this population we selected all 130 cases of preterm birth, defined as delivery before 37 weeks of completed gestation, as well as 352 random controls. RESULTS Urinary phthalate metabolite levels were moderately variable over pregnancy, but levels measured at multiple time points were associated with increased odds of preterm birth. Adjusted odds ratios (aOR) for spontaneous preterm birth were strongest in association with phthalate metabolite concentrations measured at the beginning of the third trimester (aOR for summed di-2-ethylhexyl phthalate metabolites [∑DEHP]=1.33, 95% confidence interval [CI]=1.02, 1.73). Odds ratios for placental preterm birth, defined as delivery with presentation of preeclampsia or intrauterine growth restriction, were slightly elevated in the first trimester for DEHP metabolites (aOR for ∑DEHP=1.33, 95% CI=0.99, 1.78). CONCLUSIONS Pregnant women with exposure to phthalates both early and late in pregnancy are at an increased risk of delivering preterm, but mechanisms may differ based on etiology.

Tests for Gene-Environment Interaction From Case-Control Data: A Novel Study of Type I Error, Power and Designs

To evaluate the risk of a disease associated with the joint effects of genetic susceptibility and environmental exposures, epidemiologic researchers often test for non‐multiplicative gene‐environment effects from case‐control studies. In this article, we present a comparative study of four alternative tests for interactions: (i) the standard case‐control method; (ii) the case‐only method, which requires an assumption of gene‐environment independence for the underlying population; (iii) a two‐step method that decides between the case‐only and case‐control estimators depending on a statistical test for the gene‐environment independence assumption and (iv) a novel empirical‐Bayes (EB) method that combines the case‐control and case‐only estimators depending on the sample size and strength of the gene‐environment association in the data. We evaluate the methods in terms of integrated Type I error and power, averaged with respect to varying scenarios for gene‐environment association that are likely to appear in practice. These unique studies suggest that the novel EB procedure overall is a promising approach for detection of gene‐environment interactions from case‐control studies. In particular, the EB procedure, unlike the case‐only or two‐step methods, can closely maintain a desired Type I error under realistic scenarios of gene‐environment dependence and yet can be substantially more powerful than the traditional case‐control analysis when the gene‐environment independence assumption is satisfied, exactly or approximately. Our studies also reveal potential utility of some non‐traditional case‐control designs that samples controls at a smaller rate than the cases. Apart from the simulation studies, we also illustrate the different methods by analyzing interactions of two commonly studied genes, N‐acetyl transferase type 2 and glutathione s‐transferase M1, with smoking and dietary exposures, in a large case‐control study of colorectal cancer. Genet. Epidemiol. 2008. Published 2008 Wiley‐Liss, Inc.

Elevated Risk of Prostate Cancer Among Men With Lynch Syndrome

PURPOSE Prostate cancer has been described as a component tumor of Lynch syndrome (LS), with tumors obtained from mutation carriers demonstrating the DNA mismatch repair deficiency phenotype. Previous studies quantifying prostate cancer risk in LS have provided conflicting results. METHODS We examined cancer histories of probands and their first- through fourth-degree relatives for 198 independent mutation-positive LS families enrolled in two US familial cancer registries. Modified segregation analysis was used to calculate age-specific cumulative risk or penetrance estimates, with accompanying Wald-type CIs. Cumulative lifetime risks and hazard ratio (HR) estimates for prostate cancer were calculated and compared with those of the general population. RESULTS Ninety-seven cases of prostate cancer were observed in 4,127 men. Median age at prostate cancer diagnosis was 65 years (range, 38 to 89 years), with 11.53% of affected individuals diagnosed before age 50 years. The cumulative risk of prostate cancer at ages 60 and 80 years was 6.30% (95% CI, 2.47 to 9.96) and 30.0% (95% CI, 16.54 to 41.30), as compared with the population risk of 2.59% and 17.84%, respectively. The overall prostate cancer HR among carriers was 1.99 (95% CI, 1.31 to 3.03). CONCLUSION The cumulative lifetime risk of prostate cancer in individuals with LS is two-fold higher than in the general population and is slightly higher in carriers diagnosed before age 60 years (HR, 2.48; 95% CI, 1.34 to 4.59). These estimates are clinically valuable to quantify risk for both patients and providers.