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Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

BACKGROUND: Acute myeloid leukemia (AML) is comprised of several bone marrow-based cancers and is the most common type of leukemia in the United States. The etiology of AML is not well understood. A case-control study was conducted at The University of Texas M. D. Anderson Cancer Center to investigate associations between lifestyle characteristics and the risk of AML in Texas. METHODS: This study included 638 adult patients with de novo AML (cases) and a group of 636 matched controls. Interviewer-administered questionnaires were used to collect demographic and occupational data. The distribution of cases by World Health Organization (WHO) subtype was 71 patients (11%) with recurrent cytogenetic abnormalities (AML-RCA), 134 patients (21%) with multilineage dysplasia (AML-MD), and 389 patients (61%) with AML not otherwise categorized (AML-NOC). Multivariate logistic regression analyses were performed among all AML cases and among both sexes and each WHO subgroup. RESULTS: Among men, heavy smoking (≥30 pack-years; odds ratio [OR], 1.86) and occupational solvent exposure at low levels (OR, 2.87) or moderate/high levels (OR, 4.13) statistically significantly increased the risk of AML. Among women, obesity (OR, 1.62) and solvent exposure to low levels (OR, 2.73) or moderate/high levels (OR, 3.90) increased the risk of AML. Across WHO subtypes, obesity was associated with a statistically significantly increased risk of AML-RCA (OR, 3.15), whereas solvent exposure increased the risk in all subtypes at low levels (AML-RCA: OR, 4.11; AML-MD: OR, 2.54) and moderate/high levels (AML-RCA: OR, 5.13; AML-MD: OR, 3.02). A joint effect between smoking and solvent exposure was observed, and the highest risk was observed among smokers who had solvent exposure (OR, 4.51). CONCLUSIONS: The current results suggested that several factors play a role in AML predisposition with possible joint effects. Risk profiles for AML differed by sex and WHO subtype. Cancer 2012. © 2012 American Cancer Society.

DNA repair variants may play a potentially important role in an individual's susceptibility to developing cancer. Numerous studies have reported the association between genetic single nucleotide polymorphisms (SNPs) in DNA repair genes and different types of hematologic cancers. However, to date, the effects of such SNPs on modulating Hodgkin lymphoma (HL) risk have not yet been investigated. We hypothesized that gene-gene interaction between candidate genes in direct reversal, nucleotide excision repair (NER), base excision repair (BER) and double strand break (DSB) pathways may contribute to susceptibility to HL. To test this hypothesis, we conducted a study on 200 HL cases and 220 controls to assess associations between HL risk and 21 functional SNPs in DNA repair genes. We evaluated potential gene-gene interactions and the association of multiple polymorphisms in a chromosome region using a multi-analytic strategy combining logistic regression, multi-factor dimensionality reduction and classification and regression tree approaches. We observed that, in combination, allelic variants in the XPC Ala499Val, NBN Glu185Gln, XRCC3 Thr241Me, XRCC1 Arg194Trp, and XRCC1 399Gln polymorphisms modify the risk for developing HL. Moreover, the cumulative genetic risk score revealed a significant trend where the risk for developing HL increases as the number of adverse alleles in BER and DSB genes increase. These findings suggest that DNA repair variants in BER and DSB pathways may play an important role in the development of HL.

Androgen levels during critical periods of testicular development may be involved in the aetiology of testicular germ cell tumours (TGCT). We evaluated the roles of adolescent and early adult life correlates of androgen exposure and TGCT in a hospital-based case-control study. TGCT cases (n=187) and controls (n=148), matched on age, race and state of residence, participated in the study. Unconditional logistic regression was used to estimate associations between TGCT and male pattern baldness, severe acne, markers of puberty onset and body size. Cases were significantly less likely to report hair loss than controls [odds ratio (OR): 0.6; 95% confidence interval (CI): 0.4, 1.0]. Amount of hair loss, increasing age at onset and increasing rate of loss were all inversely associated with TGCT (rate of hair loss: p-trend=0.03; age at onset: p-trend=0.03; amount of hair loss: p-trend=0.01). History of severe acne was inversely associated with TGCT (OR: 0.5; 95% CI: 0.3, 0.9) and height was positively associated with TGCT (p-trend=0.02). Increased endogenous androgen levels during puberty and early adulthood may be associated with a decreased risk of TGCT. Additional studies of endogenous hormone levels during puberty and early adult life are warranted, especially studies evaluating the role of androgen synthesis, metabolism and uptake.

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B-cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5-9% in individuals over age 60 years. It has been reported to be higher among first-degree relatives from CLL families. We report results of multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (P = 0·04). MBL patients had significantly higher mean absolute lymphocyte counts (2·4 × 10(9) /l) and B-cell counts (0·53 × 10(9) /l) than those with a normal B-cell immuno-phenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk.

We assessed the expression of Matrix Metalloproteinase (MMP) to E-cadherin (M/E ratio) to determine the correlation of gene expression with pathologic variables and outcome in a cohort of African American (AA) prostate cancer patients.Tumors from formalin-fixed, paraffin embedded RP specimens were examined. Gleason scores were 6, 7, andor=8 in 7, 16, 13 tumors, respectively. Pathologic stage was organ confined (pT2) in 18 and advanced (pT2) in 18 tumors. A colorimetric mRNA in situ hybridization (ISH) assay was performed using biotinylated anti-sense oligonucleotide probes for MMP 2 and 9, as well as for E-cadherin gene transcripts. Immunohistochemistry (IHC) was performed utilizing specific monoclonal antibodies to detect the above genes. Image analysis was performed to determine the intensity of both mRNA and protein expression. Two reviewers analyzed ISH gene expression independently.The M/E expression ratio was significantly increased at the invasive edge (but not the center) of tumors of higher Gleason score (P = 0.02 and 0.0008) and pathologic stage (P = 0.0001 and0.0001) when examined by both ISH and IHC. Significant variability in ISH staining interpretation was noted within and among the two study reviewers. An M/E ratio2.5 was associated with biochemical recurrence after radical prostatectomy in addition to tumor pathologic stage subsequent to univariate statistical analysis.The M/E ratio characterizes an important aspect of the molecular phenotype associated with the histologic progression of prostate cancer among African American prostate cancer patients. A larger comparative study is required to determine potential racial variation and prognostic significance of gene expression.

BACKGROUND There is a paucity of information regarding prostate cancer (PCa) risk factors among Hispanics, the fastest-growing ethnic group in the United States. METHODS This population-based case-control study included 176 Texas men of Mexican descent with PCa and 174 age- and ethnicity-matched controls. Demographic, lifetime occupational history, family history of cancer, lifestyle (e.g., smoking, alcohol, diet, and recreational physical activity) and anthropometric information were collected by personal interviews. Chemical exposure and physical activity were determined using job-exposure matrices for each reported job. RESULTS Logistic regression models adjusted for relevant covariates were used to evaluate their independent effects. Compared to controls, cases were three times more likely to work in jobs with high agrichemical exposure (OR = 3.44, 95% CI 1.84–6.44), and 54% less likely to work in jobs with moderate/high occupational physical activity (OR = 0.46, 95% CI 0.28–0.77). In analyses stratified by stage, cases with organ-confined PCa were three times more likely to have high agrichemical exposure (OR = 3.39, 9%CI 1.68–6.84), and 56% less likely to have moderate/high levels of occupational physical activity (OR = 0.44, 95% CI 0.26–0.76). Increased risk of being diagnosed with advanced PCa was associated with obesity at time of diagnosis (OR = 2.50, 95% CI 1.20–5.20) and high levels of agrichemical exposure (OR = 4.65, 95% CI 1.97–10.97), but not with occupational physical activity. CONCLUSIONS This case-control study, the first conducted in a homogeneous Hispanic population, identified modifiable PCa risk factors, such as physical activity and agrichemical exposure, which may be useful in developing interventions for this understudied population. Prostate 68: 563–570, 2008. © 2008 Wiley-Liss, Inc.

Previous reports show that obesity predicts biochemical failure after treatment for localized prostate cancer. Since obesity is associated with increased fat consumption, we investigated the role that dietary fat intake plays in modulating obesity-related risk of biochemical failure. We evaluated the association between saturated fat intake and biochemical failure among 390 men from a previously described prostatectomy cohort. Participants completed a food frequency questionnaire collecting nutrient information for the year prior to diagnosis. Because fat and energy intake are highly correlated, the residual method was used to adjust fat (total and saturated) intakes for energy. Biochemical-failure-free-survival rates were calculated using the Kaplan–Meier method. Crude and adjusted effects were estimated using Cox proportional hazards models. During a mean follow-up of 70.6 months, 78 men experienced biochemical failure. Men who consumed high- saturated fat (HSF) diets were more likely to experience biochemical failure (p = 0.006) and had significantly shorter biochemical-failure-free-survival than men with low saturated fat (LSF) diets (26.6 vs. 44.7 months, respectively, p = 0.002). After adjusting for obesity and clinical variables, HSF-diet patients were almost twice as likely to experience biochemical failure (hazard ratio = 1.95, p = 0.008) compared to LSF diet patients. Men who were both obese and consumed HSF diets had the shortest biochemical-failure-free-survival (19 months), and nonobese men who consumed LSF diets had the longest biochemical-failure-free-survival (46 months, p < 0.001). Understanding the interplay between modifiable factors, such as diet and obesity, and disease characteristics may lead to the development of behavioral and/or targeted interventions for patients at increased risk of progression. © 2008 Wiley-Liss, Inc.

BACKGROUND. Several reports have shown that obesity is associated with increased risk of biochemical failure after radical prostatectomy. However, limited information is available regarding the impact of obesity on prostate cancer progression after radiotherapy. The current study sought to determine whether obesity was an independent predictor of biochemical failure (BF) and clinical recurrence (CF) among patients treated with external-beam radiotherapy (EBRT). METHODS. A retrospective analysis was performed on 873 patients receiving EBRT as the sole treatment for localized prostate cancer between 1988 and 2001. The Kaplan–Meier method, log-rank test, and Cox proportional hazards analyses were performed. RESULTS. Of the 873 patients, 18% were mildly obese and 5% were moderately to severely obese. Obesity was related to younger age at diagnosis (P < .001), more recent year of diagnosis (P = .03), and race (P = .03), with African-American men having the highest obesity rates. During a mean follow-up of 96 months, 295 patients experienced BF and 127 had CF. On multivariate analysis, controlling for clinical and treatment characteristics, increased body mass index (BMI) significantly predicted BF (hazards ratio [HR] = 1.04; 95% confidence interval [95% CI], 1.02–1.07) with a positive trend by BMI category (P = .001). Similar results were found when the outcome was CF; BMI remained an independent predictor of progression (HR = 1.05; 95% CI, 1.01–1.09), with a statistically significant trend by increased BMI category (P = .03). CONCLUSIONS. The current findings validate the important role of obesity, not only on BF but also on CF, and suggest a link to the biologic basis of tumor progression that can be therapeutically exploited. Cancer 2006. © 2006 American Cancer Society.

Background Little is known about the role of inherited genotypes in prostate cancer (PC) progression. This prospective study evaluated the predictive value of androgen receptor (AR) polymorphisms (CAG and GGC repeats) among prostatectomy patients. Methods We studied 354 patients registered at M. D. Anderson Cancer Center from 1991 to 2001. Kaplan–Meier and Cox proportional hazard analyses were used. Results During an average follow-up of 56 months, 66 (19%) post-prostatectomy patients experienced biochemical failure (BF). Patients with higher CAG repeats (CAG ≥ 24) had significantly longer BF-free survival (BFFS) than those with fewer repeats (CAG ≤ 23) (P = 0.04). Higher CAG repeats were significantly associated with lower BF risk among Whites and African Americans. Among Whites, longer CAG repeats (relative risk (RR) = 0.45, P = 0.03) and Gleason score ≥8 (RR = 19.33, P = 0.005) remained significant BFFS predictors in multivariate analysis. GGC repeats were not associated with BF. Conclusions Our data showed that an inherited polymorphism (CAG repeats) in the AR is related to differences in genetic susceptibility to BF, supporting the hypothesis that increased AR activity may play a role in PC progression. © 2004 Wiley-Liss, Inc.

Oxidative damage is an important factor in prostate carcinogenesis, and overexpression of human MutT homolog (hMTH), a repair gene that removes oxidative damage, is a molecular marker of cellular oxidative stress. Therefore, we tested the hypothesis that overexpression of hMTH in unaffected (normal) surrogate tissue is associated with risk of prostate cancer in a pilot study of 51 patients with diagnosed prostate cancer and 50 age- and ethnicity-matched controls. Total RNA was extracted from phytohemagglutinin-stimulated peripheral blood lymphocytes of these subjects. We performed the real-time reverse transcription–polymerase chain reaction assay to evaluate the relative mRNA expression of three oxidative-damage-repair genes, human MutM homolog (hMMH), hMTH, and human MutY homolog (hMYH), with β-actin and human O6-methylguanine DNA methyltransferase (hMGMT) as the internal controls. The relative gene expression levels of hMMH and hMTH were borderline higher in the cases than in controls (15.3% and 28.8% higher, respectively; P = 0.046 and P = 0.035, respectively), whereas no increase was observed for hMYH and hMGMT. With the median of the controls' values as the cutoff point, we observed that a high expression level of hMTH, but not of other genes, was associated with a significantly increased risk of prostate cancer (odds ratio = 2.62; 95% confidence interval = 1.13–6.75) after adjustment for age and ethnicity. These results suggested that increased expression of hMTH in peripheral lymphocytes may be a risk factor for prostate cancer and support our priori hypothesis. Although our findings were biologically plausible and consistent with the literature, they were preliminary and need to be confirmed in larger studies. In addition, a correlation between the expression level of hMTH and the level of oxidative DNA damage in the target tissues needs to be established as well. © 2003 Wiley-Liss, Inc.

Background Higher prostate cancer mortality rates among US immigrants from countries with lower rates suggest environmental influences on prostate carcinogenesis (e.g., diet, body composition). Methods In a study identifying determinants of clinically relevant prostate cancer, we compared plasma concentrations of leptin, an adiposity-related hormone, in 48 men with tumors ≤ 0.5 cc measured after radical prostatectomy and 151 men with tumors > 0.5 cc in volume or with histologic evidence of extraprostatic extension but without metastases (“high-volume disease”), matched by age (± 5 years) and year at diagnosis (± 1 year). Results Men with high-volume disease exhibited higher leptin concentrations overall and after stratification by age, testosterone level, height, and body mass index (BMI). Analysis revealed that men with elevated leptin concentrations had an increased risk of diagnosis with high-volume disease (odds ratio (OR) = 2.35, 95% confidence interval (CI) = 1.01–5.44), as did men with high leptin and high testosterone (OR = 9.73, 95% CI = 2.05–46.24) and men ≥5′8″ with high leptin (OR = 3.67, 95% CI = 1.40–9.63). Conclusions Leptin may affect the risk of clinically relevant prostate cancer through testosterone and factors related to stature and obesity. Prostate 46:62–67, 2001. © 2001 Wiley-Liss, Inc.

While tumor volume and Gleason scores are the best available prognostic indicators for prostate cancer, contemporary predictive methods are unable to identify which men with Gleason scores of 7 have clinically insignificant tumors that will not progress and which men will develop highly aggressive prostate cancer. Our objective was to evaluate potential environmental determinants of significant prostate cancer. Subjects were patients identified from a universitybased hospital and tertiary cancer center who had undergone radical prostatectomy for prostate cancer. Cases were 103 patients whose tumor volumes were

BACKGROUND Chemotherapy is known to cure a small minority of patients with acute myeloid leukemia (AML). Less is known about the risk of such patients developing subsequent cancers or about their ability to return to work. METHODS The authors analyzed outcomes among 1892 patients who received treatment for newly diagnosed AML at the University of Texas M. D. Anderson Cancer Center from 1965 to May 1995. RESULTS Because failure rates declined to relatively low levels after a first or later complete remission of ≥3 years' duration, such patients comprised a "potentially cured" cohort. The criterion for entry into this cohort was fulfilled by 215 patients (10.7%; 203 in first complete remission and 12 in second remission). At a median of 6.2 years after entry into the cohort (i.e., 9.2 years from complete remission), 163 patients (76%) remain alive and in complete remission. Approximately 9% and 5% of the 1892 patients have been in complete remission for >5 years and >10 years, respectively. The pretreatment prognostic importance of cytogenetics is still apparent even after 5 years in complete remission. On average, members of the potentially cured cohort were not observed to be at increased risk of subsequent invasive malignancies compared with a normal population. Furthermore, two-thirds of those in the potentially cured cohort who were working full time before diagnosis of AML claimed to have returned to full-time work. Of those not working, only 10% cited physical limitation as the reason. CONCLUSIONS The major threat to the life and well-being of the patient with AML is clearly the disease and not its treatment. Cancer 1997; 80:2176-80. © 1997 American Cancer Society.

In this study we compared parameter estimates and model hypotheses in pedigree data collected by fixed sampling with estimates and hypotheses derived by sequential sampling. Employing a fixed sampling scheme, we previously analyzed data on relatives of 159 childhood sarcoma patients. We have now extracted from that data set individuals who would have been included in a sequentially sampled study. We applied segregation analysis to the truncated data, to determine the mode of inheritance and major locus parameter estimates. With data from both sampling schemes we made a family-by-family comparison to determine each family's contribution to a major gene model. The two sampling schemes yielded similar results: we detected segregation of a dominant major gene and obtained similar major locus parameter estimates. However, the sequential sampling scheme derived these conclusions from data on 982 relatives rather than the 2,451 ascertained in the fixed sampling scheme. The sequential sampling scheme failed to identify only one of the kindreds likely to be segregating the gene. For this data set, the sequential sampling scheme would have provided an efficient mechanism to discriminate genetic hypotheses and would have permitted focus of resources on the specific kindreds likely to segregate a major gene. © 1992 Wiley-Liss, Inc.