The development of second primary tumors (SPT) or recurrence alters prognosis for curatively-treated head and neck squamous cell carcinoma (HNSCC) patients. 13-cis-retnoic acid (13-cRA) has been tested as a chemoprevention agent in clinical trials with mixed results. Therefore, we investigated if genetic variants in the PI3K/PTEN/AKT/MTOR pathway could serve as biomarkers to identify which patients are at high risk of an SPT/recurrence while also predicting response to 13-cRA chemoprevention.
A total of 137 pathway SNPs were genotyped in 440 patients from the Retinoid Head and Neck Second Primary Trial and assessed for SPT/recurrence risk and response to 13-cRA. Risk models were created based on epidemiology, clinical, and genetic data.
Twenty-two genetic loci were associated with increased SPT/recurrence risk with six also being associated with a significant benefit following chemoprevention. Combined analysis of these high-risk/high-benefit loci identified a significant (P = 1.54×10−4) dose-response relationship for SPT/recurrence risk, with patients carrying 4–5 high-risk genotypes having a 3.76-fold (95%CI:1.87–7.57) increase in risk in the placebo group (n=215). Patients carrying 4–5 high-risk loci showed the most benefit from 13-cRA chemoprevention with a 73% reduction in SPT/recurrence (95%CI:0.13–0.58) compared to those with the same number of high-risk genotypes who were randomized to receive placebo. Incorporation of these loci into a risk model significantly improved the discriminatory ability over models with epidemiology, clinical, and previously identified genetic variables.
These results demonstrate that loci within this important pathway could identify individuals with a high-risk/high-benefit profile and are a step towards personalized chemoprevention for HNSCC patients.
Established psychosocial risk factors increase the risk for experimentation among Mexican-origin youth. Now we comprehensively investigate the added contribution of select polymorphisms in candidate genetic pathways associated with sensation seeking, risk taking, and smoking phenotypes to predict experimentation.
Participants, (N=1,118 Mexican origin youth) recruited from a large population-based cohort study in Houston, Texas, provided prospective data on cigarette experimentation over three years. Psychosocial data were elicited twice—baseline and final follow-up. Participants were genotyped for 672 functional and tagging variants in the dopamine, serotonin and opioid pathways.
After adjusting for gender and age, with a Bayesian False Discovery Probability set at 0.8 and prior probability of 0.05, six gene variants were significantly associated with risk of experimentation. After controlling for established risk factors, multivariable analyses revealed that participants with six or more risk alleles were 2.25 (95%CI: 1.62–3.13) times more likely to have experimented since baseline compared to participants with five or fewer. Among committed never smokers (N=872), three genes (OPRM1, SNAP25, HTR1B) were associated with experimentation as were all psychosocial factors. Among susceptible youth (N=246) older age at baseline, living with a smoker, and three different genes (HTR2A, DRD2, SLC6A3) predicted experimentation.
Our findings, which have implications for development of culturally-specific interventions, need to be validated in other ethnic groups.
These results suggest that variations in select genes interact with a cognitive predisposition toward smoking. In susceptible adolescents, the impact of the genetic variants appears to be larger compared to committed never smokers.
The purpose of this study was to examine the extent to which adolescent reports on mother’s smoking status and mother’s self-reports on smoking are concordant with one another.
Mothers self-reported on their smoking at two timepoints (first query and second query), while the adolescents reported on their mother’s smoking status at one timepoint. Kappa values and percent exact agreement as well as sensitivity and specificity were calculated to examine the degree of agreement between child and mother’s reports at the two timepoints.
Overall, the results indicated good concordance between mothers’ self-reports and adolescent reports on smoking. Specifically, higher concordance was observed for mother’s first query compared with mother’s second query (Κ = 0.69 vs. Κ = 0.51). Younger adolescents and girls provided more concordant reports than older adolescents and boys.
The results indicate that adolescent reports on mothers’ smoking behavior can be used as a proxy to obtain data if mothers’ self-report data are not available. Our results further suggest that when reports are not collected concurrently, self-report data obtained from the mothers prior to the proxy report obtained from her adolescent may be more reliable than the other way around.
Tobacco-induced lung cancer is characterized by a deregulated inflammatory microenvironment. Variants in multiple genes in inflammation pathways may contribute to risk of lung cancer.
We therefore conducted a three-stage comprehensive pathway analysis (discovery, replication and meta-analysis) of inflammation gene variants in ever smoking lung cancer cases and controls. A discovery set (1096 cases; 727 controls) and an independent and non-overlapping internal replication set (1154 cases; 1137 controls) were derived from an ongoing case-control study. For discovery, we used an iSelect BeadChip to interrogate a comprehensive panel of 11737 inflammation pathway SNPs and selected nominally significant (p<0.05) SNPs for internal replication.
There were 6 SNPs that achieved statistical significance (p<0.05) in the internal replication dataset with concordant risk estimates for former smokers and 5 concordant and replicated SNPs in current smokers. Replicated hits were further tested in a subsequent meta-analysis using external data derived from two published GWAS and a case-control study. Two of these variants (a BCL2L14 SNP in former smokers and a SNP in IL2RB in current smokers) were further validated. In risk score analyses, there was a 26% increase in risk with each additional adverse allele when we combined the genotyped SNP and the most significant imputed SNP in IL2RB in current smokers and a 36% similar increase in risk for former smokers associated with genotyped and imputed BCL2L14 SNPs.
Before they can be applied for risk prediction efforts, these SNPs should be subject to further external replication and more extensive fine mapping studies.
Inflammation SNPS; lung cancer; smokers
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.
Neurocognitive impairment occurs in 20%-40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion and homocysteine elevation following methotrexate treatment. We evaluated the relationship between folate pathway polymorphisms and neurocognitive impairment after childhood ALL chemotherapy.
Seventy-two childhood ALL survivors treated with chemotherapy alone underwent a neurocognitive battery consisting of: Trail Making Tests A (TMTA) and B (TMTB), Grooved Pegboard Test Dominant-Hand and Nondominant-Hand, Digit Span subtest, and Verbal Fluency Test. We performed genotyping for: 10-methylenetetrahydrofolate reductase (MTHFR 677C>T and MTHFR 1298A>C), serine hydroxymethyltransferase (SHMT 1420C>T), methionine synthase (MS 2756 A>G), methionine synthase reductase (MTRR 66A>G), and thymidylate synthase (TSER). Student's two sample t-test and analysis of covariance were used to compare test scores by genotype.
General impairment on the neurocognitive battery was related to MTHFR 1298A>C (p=0.03) and MS 2756A>G (p=0.05). Specifically, survivors with MTHFR 1298AC/CC genotypes scored, on average, 13 points lower on TMTB than those with MTHFR 1298AA genotype (p=0.001). The MS 2756AA genotype was associated with a 12.2 point lower mean TMTA score, compared to MS 2756 AG/GG genotypes (p=0.01). The TSER 2R/3R and 3R/3R genotypes were associated with an 11.4 point lower mean score on TMTB, compared to the TSER 2R/2R genotype (p=0.03). Survivors with >6 folate pathway risk alleles demonstrated a 9.5 point lower mean TMTA score (p=0.06) and 14.5 point lower TMTB score (p=0.002) than survivors with <6 risk alleles.
Folate pathway polymorphisms are associated with deficits in attention and processing speed after childhood ALL therapy.
folate; leukemia; neurocognitive; survivor
Understanding the factors that contribute to physical activity (PA) in Mexican-origin adolescents is essential to the design of effective efforts to enhance PA participation in this population.
Multivariable logistic regression was used to identify sociodemographic and behavioral correlates of self-reported PA in school and community settings in 1,154 Mexican-origin adolescents aged 12–17 years in Houston, TX.
The majority of adolescents were born in the US (74%), approximately half (51%) were overweight or obese, and nearly three-quarters (73%) watched more than 2 hours of weekday television. Similarities and differences by setting and gender were observed in the relationships between sociodemographic and behavioral characteristics and PA. In boys, parental education and attending physical education (PE) were positively associated with PA across multiple PA outcomes. Adolescent linguistic acculturation was inversely associated with participation in community sports, whereas parental linguistic acculturation was positively associated with PA at school. In girls, PA in school and community settings was inversely associated with TV viewing and positively associated with PE participation.
These findings highlight similarities and differences in correlates of PA among boys and girls, and point towards potential sources of opportunities as well as disparities for PA behaviors in Mexican-origin adolescents.
Mexican American; acculturation; physical education
For many decades, the standard of care radiotherapy regimen for medulloblastoma has been photon (megavoltage x-rays) craniospinal irradiation (CSI). The late effects associated with CSI are well-documented in the literature and are in-part attributed to unwanted dose to healthy tissue. Recently, there is growing interest in using proton therapy for CSI in pediatric and adolescent patients to reduce this undesirable dose. Previous comparisons of dose to target and non-target organs from conventional photon CSI and passively scattered proton CSI have been limited to small populations (n ≤ 3) and have not considered the use of age-dependent target volumes in proton CSI.
Standard of care treatment plans were developed for both photon and proton CSI for 18 patients. This cohort included both male and female medulloblastoma patients whose ages, heights, and weights spanned a clinically relevant and representative spectrum (age 2–16, BMI 16.4–37.9 kg/m2). Differences in plans were evaluated using Wilcoxon signed rank tests for various dosimetric parameters for the target volumes and normal tissue.
Proton CSI improved normal tissue sparing while also providing more homogeneous target coverage than photon CSI for patients across a wide age and BMI spectrum. Of the 24 parameters (V5, V10, V15, and V20 in the esophagus, heart, liver, thyroid, kidneys, and lungs) Wilcoxon signed rank test results indicated 20 were significantly higher for photon CSI compared to proton CSI (p ≤ 0.05) . Specifically, V15 and V20 in all six organs and V5, V10 in the esophagus, heart, liver, and thyroid were significantly higher with photon CSI.
Our patient cohort is the largest, to date, in which CSI with proton and photon therapies have been compared. This work adds to the body of literature that proton CSI reduces dose to normal tissue compared to photon CSI for pediatric patients who are at substantial risk for developing radiogenic late effects. Although the present study focused on medulloblastoma, our findings are generally applicable to other tumors that are treated with CSI.
Proton; Photon; Craniospinal irradiation; CSI; Medulloblastoma
Overall, Latinas are more likely to be diagnosed with a more advanced stage of breast cancer, and are 20% more likely to die of breast cancer than non-Hispanic white women. It is estimated that from 2003–2006, $82.0 billion in direct medical care expenditures, in addition to 100,000 lives annually, could be saved by eliminating health disparities experienced by Latinos and increasing the use of up to five preventive services in the U.S. An additional 3,700 lives could be saved if 90% of women ≥40 years were recently screened for breast cancer. We examined risk for breast cancer in a case-control population-based sample of Mexican-origin women in Harris County, TX (n=714), where rates of breast cancer mortality for Latina women have doubled since 1990. Half of breast cancer cases (n=119) were diagnosed before the age of 50. In a multivariable model, women with a family history of breast cancer (OR=4.3), born in Mexico and having high levels of language acculturation (OR=2.5), and without health insurance (OR=1.6) were found to have the highest risk of breast cancer. Because Mexican-origin women were found to be of high-risk for early onset pre-menopausal breast cancer, we recommend policies targeting screening, education and treatment to prevent increased disparities in mortality. The inclusion of community members and policymakers as partners in these endeavors would further safeguard against an increase in cancer health disparities, and aid in formulating a policy agenda congruent with scientifically-based, community-driven policy efforts addressing breast cancer screening, education and treatment in this vulnerable population.
Missing data often occur in cross-sectional surveys and longitudinal and experimental studies. The purpose of this study was to compare the prediction of self-rated health (SRH), a robust predictor of morbidity and mortality among diverse populations, before and after imputation of the missing variable “yearly household income.” We reviewed data from 4,162 participants of Mexican origin recruited from July 1, 2002, through December 31, 2005, and who were enrolled in a population-based cohort study. Missing yearly income data were imputed using three different single imputation methods and one multiple imputation under a Bayesian approach. Of 4,162 participants, 3,121 were randomly assigned to a training set (to derive the yearly income imputation methods and develop the health-outcome prediction models) and 1,041 to a testing set (to compare the areas under the curve (AUC) of the receiver-operating characteristic of the resulting health-outcome prediction models). The discriminatory powers of the SRH prediction models were good (range, 69–72%) and compared to the prediction model obtained after no imputation of missing yearly income, all other imputation methods improved the prediction of SRH (P<0.05 for all comparisons) with the AUC for the model after multiple imputation being the highest (AUC = 0.731). Furthermore, given that yearly income was imputed using multiple imputation, the odds of SRH as good or better increased by 11% for each $5,000 increment in yearly income. This study showed that although imputation of missing data for a key predictor variable can improve a risk health-outcome prediction model, further work is needed to illuminate the risk factors associated with SRH.
Self-rated health; Missing income data; Data imputation techniques; Mean substitution; Multiple imputation; Minority health
In genome-wide association studies, inherited risk of glioma has been demonstrated for rare familial syndromes and with common variants from 3–5 chromosomal regions. To assess the degree of familial aggregation of glioma, the authors performed a pooled analysis of data from 2 large glioma case-control studies in the United States (MD Anderson Cancer Center, Houston, Texas (1994–2006) and University of California, San Francisco (1991–2004)) and from the Swedish Cancer Registry (1958–2006) to measure excess cases of cancer among first-degree relatives of glioma probands. This analysis included 20,377 probands with glioma and 52,714 first-degree relatives. No overall increase was found in the expected number of cancers among family members; however, there were 77% more gliomas than expected. There were also significantly more sarcoma and melanoma cases than expected, which is supported by evidence in the literature, whereas there were significantly fewer-than-expected cases of leukemia, non-Hodgkin lymphoma, and bladder, lung, pancreatic, prostate, and uterine cancers. This large pooled analysis provided sufficient numbers of related family members to examine the genetic mechanisms involved in the aggregation of glioma with other cancers in these families. However, misclassification due to unvalidated cancers among family members could account for the differences seen by study site.
family; glioma; meta-analysis; neoplasms
Background: DNA strand breaks pose the greatest threat to genomic stability. Genetically determined mutagen sensitivity predisposes individuals to a variety of cancers, including glioma. However, polymorphisms in DNA strand break repair genes that may determine mutagen sensitivity are not well studied in cancer risk, especially in gliomas.
Methods: We correlated genotype data for tag single-nucleotide polymorphisms (tSNPs) of DNA strand break repair genes with a gamma-radiation-induced mutagen sensitivity phenotype [expressed as mean breaks per cell (B/C)] in samples from 426 glioma patients. We also conducted analysis to assess joint and haplotype effects of single-nucleotide polymorphisms (SNPs) on mutagen sensitivity. We further validate our results in an independent external control group totaling 662 subjects.
Results: Of the 392 tSNPs examined, we found that mutagen sensitivity was modified by one tSNP in the EME2 gene and six tSNPs in the RAD51L1 gene (P < 0.01). Among the six RAD51L1 SNPs tested in the validation set, one (RAD51L1 rs2180611) was significantly associated with mutagen sensitivity (P = 0.025). Moreover, we found a significant dose–response relationship between the mutagen sensitivity and the number of adverse tSNP genotypes. Furthermore, haplotype analysis revealed that RAD51L1 haplotypes F-A (zero adverse allele) and F-E (six adverse alleles) exhibited the lowest (0.42) and highest (0.93) mean B/C values, respectively. A similar dose–response relationship also existed between the mutagen sensitivity and the number of adverse haplotypes.
Conclusion: These results suggest that polymorphisms in and haplotypes of the RAD51L1 gene, which is involved in the double-strand break repair pathway, modulate gamma-radiation-induced mutagen sensitivity.
Glioblastoma (GBM) is the most common and aggressive type of glioma and has the poorest survival. However, a small percentage of patients with GBM survive well beyond the established median. Therefore, identifying the genetic variants that influence this small number of unusually long-term survivors may provide important insight into tumor biology and treatment.
Patients and Methods
Among 590 patients with primary GBM, we evaluated associations of survival with the 100 top-ranking glioma susceptibility single nucleotide polymorphisms from our previous genome-wide association study using Cox regression models. We also compared differences in genetic variation between short-term survivors (STS; ≤ 12 months) and long-term survivors (LTS; ≥ 36 months), and explored classification and regression tree analysis for survival data. We tested results using two independent series totaling 543 GBMs.
We identified LIG4 rs7325927 and BTBD2 rs11670188 as predictors of STS in GBM and CCDC26 rs10464870 and rs891835, HMGA2 rs1563834, and RTEL1 rs2297440 as predictors of LTS. Further survival tree analysis revealed that patients ≥ 50 years old with LIG4 rs7325927 (V) had the worst survival (median survival time, 1.2 years) and exhibited the highest risk of death (hazard ratio, 17.53; 95% CI, 4.27 to 71.97) compared with younger patients with combined RTEL1 rs2297440 (V) and HMGA2 rs1563834 (V) genotypes (median survival time, 7.8 years).
Polymorphisms in the LIG4, BTBD2, HMGA2, and RTEL1 genes, which are involved in the double-strand break repair pathway, are associated with GBM survival.
The impact of single-nucleotide polymorphisms (SNPs) of the DNA repair gene XPC on DNA repair capacity (DRC) and genotoxicity has not been comprehensively determined. We constructed a comprehensive haplotype map encompassing all common XPC SNPs and evaluated the effect of Bayesian-inferred haplotypes on DNA damage associated with tobacco smoking, using chromosome aberrations (CA) as a biomarker. We also used the mutagen-sensitivity assay, in which mutagen-induced CA in cultured lymphocytes are determined, to evaluate the haplotype effects on DRC. We hypothesized that if certain XPC haplotypes have functional effects, a correlation between these haplotypes and baseline and/or mutagen-induced CA would exist. Using HapMap and single nucleotide polymorphism (dbSNP) databases, we identified 92 SNPs, of which 35 had minor allele frequencies ≥ 0.05. Bayesian inference and subsequent phylogenetic analysis identified 21 unique haplotypes, which segregated into six distinct phylogenetically grouped haplotypes (PGHs A–F). A SNP tagging approach used identified 11 tagSNPs representing these 35 SNPs (r2 = 0.80). We utilized these tagSNPs to genotype a population of smokers matched to nonsmokers (n = 123). Haplotypes for each individual were reconstituted and PGH designations were assigned. Relationships between XPC haplotypes and baseline and/or mutagen-induced CA were then evaluated. We observed significant interaction among smoking and PGH-C (p = 0.046) for baseline CA where baseline CA was 3.5 times higher in smokers compared to nonsmokers. Significant interactions among smoking and PGH-D (p = 0.023) and PGH-F (p = 0.007) for mutagen-induced CA frequencies were also observed. These data indicate that certain XPC haplotypes significantly alter CA and DRC in smokers and, thus, can contribute to cancer risk.
DNA nucleotide excision repair; XPC gene; polymorphism; haplotypes; biomarkers; chromosome; smoking; cancer
In the current era of diet-gene analyses, large sample sizes are required to uncover the etiology of complex diseases. As such, consortia form and often combine available data. Food frequency questionnaires, which commonly use 2 different types of responses about the frequency of intake (predefined responses and open-ended responses), may be pooled to achieve the desired sample size. The common practice is to categorize open-ended responses into the predefined response categories. A problem arises when the predefined categories are noncontiguous: possible open-ended responses may fall in gaps between the predefined categories. Using simulated data modeled from frequency of intake among 1,664 controls in a lung cancer case-control study at The University of Texas M. D. Anderson Cancer Center (Houston, Texas, 2000–2005), the authors describe the effect of different categories of open-ended responses that fall in between noncontiguous, predefined response sets on estimates of the mean difference in intake and the odds ratios. A significant inflation of false positives appears when comparing mean differences of intake, while the bias in estimating odds ratios may be acceptably small. Therefore, if pooling data cannot be restricted to the same type of response, inferences should focus on odds ratio estimation to minimize bias.
computer simulation; data interpretation, statistical; diet surveys
Previous studies have been inconclusive in estimating the risk of different cancer sites among close relatives of glioma patients; however, malignant melanoma has been consistently described.
We obtained family history information from 1,476 glioma patients under age 75 who registered at M.D. Anderson Cancer Center between June 1992 and June 2006. The number of observed cancers (N=1,001) among 8,746 first-degree relatives (FDRs) were compared to the number expected from age-, sex-, and calendar-year specific rates from the Surveillance, Epidemiology, and End Results Program using standardized incidence ratios (SIRs).
The overall SIR for any cancer was 1.21 (95% CI; 1.14 – 1.29). Among FDRs under 45 years, the overall SIR was 5.08 and for relatives >45 the overall SIR was 0.95. The SIRs were significantly elevated for brain tumors (2.14), melanoma (2.02), and sarcoma (3.83). We observed an excess of pancreatic cancer which was significantly higher only among mothers.
We observed an overall 21% increase in cancer among the FDRs of glioma patients, including excess cases of brain tumors and melanoma which could point to similar genetic contributions to these two malignancies. A large international linkage study is underway to examine potential genomic regions important for familial glioma.
aggregation; cancer; glioma; first-degree relatives
DNA repair capacity is an important determinant of susceptibility to cancer. The hOGG1 enzyme is crucial for repairing the 8-oxoguanine lesion that occurs either as a byproduct of oxidative metabolism or as a result of exogenous sources such as exposure to cigarette smoke. It has been previously reported that smokers with low hOGG1 activity had significantly higher risk of developing lung cancer as compared to smokers with high hOGG1 activity.
In the current study we elucidate the association between plasma levels of 8-OHdG and the OGG1 repair capacity. We used the commercially available 8-OHdG ELISA (enzyme-linked immunosorbent assay), the Comet assay/FLARE hOGG1 (Fragment Length Analysis by Repair Enzymes) assay for quantification of the levels of 8-OHdG and measured the constitutive, induced and unrepaired residual damage, respectively. We compared the DNA repair capacity in peripheral blood lymphocytes following H2O2 exposure in 30 lung cancer patients, 30 non-, 30 former and 30 current smoker controls matched by age and gender.
Our results show that lung cancer cases and current smoker controls have similar levels of 8-OHdG lesions that are significantly higher compared to the non-smokers controls. However, lung cancer cases showed significantly poorer repair capacity compared to all controls tested, including the current smokers controls. After adjustment for age, gender and family history of smoking-related cancer using linear regression, we observed a 5-fold increase in risk of lung cancer associated with high levels of residual damage/reduced repair capacity. Reduced OGG1 activity could be expected to be a risk factor in other smoking-related cancers.
Our study shows that the Comet/FLARE assay is a relatively rapid and useful method for determination of DNA repair capacity. Using this assay we could identify individuals with high levels of residual damage and hence poor repair capacity who would be good candidates for intensive follow-up and screening.
HPV is important in a subset of HNSCC. Our meta-analysis determined the clinical characteristics of HPV-related HNSCC.
Pubmed search terms "HPV" and "HNSCC" were used to identify 34 studies since 1980. We obtained pooled adjusted odds ratio (OR) or hazard ratio (HR) using random or fixed-effects model and compared OS depicted in forest plot.
A total of 5681 patients were included. The prevalence of HPV+ tumors was 22%, with 86.7% of HPV16+ genotype. The OR for HNSCC in HPV16+ patients was 4.44 (95% CI = 2.87-6.02). HPV status was associated with p16 expression (adj OR = 3.00; 0.90-9.70), and HPV+ tumors were less likely to harbor p53 mutations (adj OR = 0.21; 0.04-0.38). The HR for death in HPV+ patients was 0.42 (0.27-0.57). HPV+ HNSCC also had a better response to therapy.
HPV+ HNSCC are established as a separate biologic entity. Prospective trials are needed to establish the optimal therapy for HPV+ HNSCC.
Although the pathogenesis of Hodgkin disease (HD) remains unknown, the results of epidemiologic studies suggest that heritable factors are important in terms of susceptibility. Polymorphisms in DNA repair genes may contribute to individual susceptibility for development of different cancers. However, to the authors’ knowledge, few studies to date have investigated the role of such polymorphisms as risk factors for development of HD.
The authors evaluated the relation between polymorphisms in 3 nucleotide excision repair pathway genes (XPD [Lys751Gln], XPC [Lys939Gln], and XPG [Asp1104His]), the base excision repair XRCC1 (Arg399Gln), and double-strand break repair XRCC3 (Thr241Met) in a population of 200 HD cases and 220 matched controls. Variants were investigated independently and in combination; odd ratios (OR) were calculated.
A positive association was found for XRCC1 gene polymorphism Arg399Gln (OR, 1.77; 95% confidence interval [95% CI], 1.16−2.71) and risk of HD. The combined analysis demonstrated that XRCC1/XRCC3 and XRCC1/XPC polymorphisms were associated with a significant increase in HD risk. XRCC1 Arg/Arg and XRCC3 Thr/Met genotypes combined were associated with an OR of 2.38 (95% CI, 1.24−4.55). The XRCC1 Arg/Gln and XRCC3 Thr/Thr, Thr/Met, and Met/Met genotypes had ORs of 1.88 (95% CI, 1.02−4.10), 1.97 (95% CI, 1.05−3.73), and 4.13 (95% CI, 1.50−11.33), respectively. XRCC1 Gln/Gln and XRCC3 Thr/Thr variant led to a significant increase in risk, with ORs of 3.00 (95% CI, 1.15−7.80). Similarly, XRCC1 Arg/Gln together with XPC Lys/Lys was found to significantly increase the risk of HD (OR, 2.14; 95% CI, 1.09−4.23).
These data suggest that genetic polymorphisms in DNA repair genes may modify the risk of HD, especially when interactions between the pathways are considered.
DNA repair; Hodgkin disease; susceptibility; genetic polymorphisms
The multi-endpoint cytokinesis-blocked micronucleus assay is used for assessing chromosome aberrations. We have recently reported that this assay is extremely sensitive to genetic damage caused by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyr-idyl)-1-butanone (NNK) and that the binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds in lymphocytes (chromosome damage endpoints measured by the assay) are strong predictors of lung cancer risk. In the current study, we refined our analysis to include toxicity endpoints (micronuclei in mononucleated cells, apoptosis, necrosis, and nuclear division index) to investigate the benefit of including these variables on improving the predictive value of the assay. Baseline and NNK-induced micronuclei in mononucleated cells were significantly higher in patients (n = 139) than controls (n = 130; P < 0.001). Baseline apoptosis was higher among cases; however, the controls showed a significant higher fold increase in NNK-induced apoptosis compared with baseline (P < 0.001). Principal components analysis was used to derive a summary measure for all endpoints and calculate the positive predictive value (PPV) and negative predictive value (NPV) for disease status. First principal component for NNK-induced chromosome damage endpoints (binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds) had an area under the curve = 97.9 (95% confidence interval, 95.9-99.0), PPV = 94.8, and NPV = 92.6. The discriminatory power improved when micronuclei in mononucleated cells were included: area under the curve = 99.1 (95% confidence interval, 97.9- 100.0), PPV = 98.7 and NPV = 95.6. The simplicity, rapidity, and sensitivity of the assay together with potential for automation make it a valuable tool for screening and prioritizing potential cases for intensive screening.
Risk prediction models are useful in clinical decision making. We have published an internally validated prediction tool for lung cancer based on easily obtainable epidemiologic and clinical data. Because the precision of the model was modest, we now estimate the improvement obtained by adding two markers of DNA repair capacity.
Assay data (host-cell reactivation and mutagen sensitivity) were available for 725 White lung cancer cases and 615 controls, all former or current smokers, a subset of cases and controls from the previous analysis. Multivariable models were constructed from the original variables with addition of the biomarkers separately and together. Pairwise comparisons of the area under the receiver operating characteristic curves (AUC) and 3-fold cross-validations were done.
For former smokers, the AUC and 95% confidence intervals were 0.67 (0.63–0.71) for the baseline model and 0.70 (0.66–0.74) for the expanded model. For current smokers, the comparable AUC values were 0.68 (0.64–0.72) and 0.73 (0.69–0.77). For both groups, the expanded models were statistically significantly better than the baseline models (P = 0.006 and P = 0.0048, respectively), although the increases in the concordance statistics were modest. We also recomputed 1-year absolute risks of lung cancer as described previously for two different risk profiles and showed that individuals who exhibited poor repair capacity or heightened mutagen sensitivity had increased absolute risks of lung cancer.
Addition of biomarker assays improved the sensitivity of the expanded models.
Because existing risk prediction models for lung cancer were developed in white populations, they may not be appropriate for predicting risk among African-Americans. Therefore, a need exists to construct and validate a risk prediction model for lung cancer that is specific to African-Americans. We analyzed data from 491 African-Americans with lung cancer and 497 matched African-American controls to identify specific risks and incorporate them into a multivariable risk model for lung cancer and estimate the 5-year absolute risk of lung cancer. We performed internal and external validations of the risk model using data on additional cases and controls from the same ongoing multiracial/ethnic lung cancer case-control study from which the model-building data were obtained as well as data from two different lung cancer studies in metropolitan Detroit, respectively. We also compared our African-American model with our previously developed risk prediction model for whites. The final risk model included smoking-related variables [smoking status, pack-years smoked, age at smoking cessation (former smokers), and number of years since smoking cessation (former smokers)], self- reported physician diagnoses of chronic obstructive pulmonary disease or hay fever, and exposures to asbestos or wood dusts. Our risk prediction model for African-Americans exhibited good discrimination [75% (95% confidence interval, 0.67−0.82)] for our internal data and moderate discrimination [63% (95% confidence interval, 0.57−0.69)] for the external data group, which is an improvement over the Spitz model for white subjects. Existing lung cancer prediction models may not be appropriate for predicting risk for African-Americans because (a) they were developed using white populations, (b) level of risk is different for risk factors that African-American share with whites, and (c) unique group-specific risk factors exist for African-Americans. This study developed and validated a risk prediction model for lung cancer that is specific to African-Americans and thus more precise in predicting their risks. These findings highlight the importance of conducting further ethnic-specific analyses of disease risk.
p73 can be inactivated by oncoprotein E6 of human papillomavirus (HPV). It is possible that p73 variation could alter the interaction between the E6 protein and p73, and thus alter the risk for HPV associated carcinogenesis. The p73 G4C14-to-A4T14 polymorphism is thought to affect p73 function by altering gene expression, but whether this also alters the risk of HPV16 associated squamous cell carcinoma of the oropharynx (SCCOP) is unknown.
This case-control study included 188 non-Hispanic white patients with newly diagnosed SCCOP and 349 healthy control subjects. Logistic regression analyses were used to calculate odds ratio (OR) and 95% confidence interval (CI) for cases and controls stratified by p73 genotype, age, sex, smoking, drinking and HPV16 status. The effects of p73 genotypes on risk of HPV16 associated SCCOP were explored with further stratification by smoking and drinking status.
HPV16 seropositivity was associated with an increased risk of SCCOP (adjusted OR, 5.98; 95% CI, 3.89-9.20), especially among never smokers (adjusted OR, 13.8; 95% CI, 5.91-32.1), never drinkers (adjusted OR, 14.9; 95% CI, 5.24-42.4), and subjects with p73 variant genotypes (GC/AT + AT/AT) (adjusted OR, 7.96; 95% CI, 3.83-16.5). Moreover, the risk of HPV16 associated SCCOP for those with p73 variant genotypes was particularly high in never smokers and never drinkers.
p73 G4C14-to-A4T14 polymorphism may modulate the risk of HPV16 associated SCCOP and the p73 variant genotypes may be a marker of genetic susceptibility to HPV16 associated SCCOP, particularly in never smokers and never drinkers.
p73 G4C14-to-A4T14 polymorphism may modulate the risk of HPV16 associated squamous cell carcinoma of the oropharynx and the p73 variant genotypes may be a marker of genetic susceptibility to HPV16 associated squamous cell carcinoma of the oropharynx, particularly in never smokers and never drinkers.
p73 polymorphism; cancer risk; genetic susceptibility; human papillomavirus (HPV); molecular epidemiology; oropharynx; squamous cell carcinoma
Magnesium (Mg) is required for maintenance of genomic stability; however, data on the relationship between dietary Mg intake and lung cancer are lacking. In an ongoing lung cancer case–control study, we identified 1139 cases and 1210 matched healthy controls with data on both diet and DNA repair capacity (DRC). Dietary intake was assessed using a modified Block-NCI food frequency questionnaire and DRC was measured using the host-cell reactivation assay to assess repair in lymphocyte cultures. After adjustment for potential confounding factors including DRC, the odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer with increasing quartiles of dietary Mg intake were 1.0, 0.83 (0.66–1.05), 0.64 (0.50–0.83) and 0.47 (0.36–0.61), respectively, for all subjects (P-trend < 0.0001). Similar results were observed by histology and clinical stage of lung cancer. Low dietary Mg intake was associated with poorer DRC and increased risk of lung cancer. In joint effects analyses, compared with those with high dietary Mg intake and proficient DRC, the OR (95% CI) for lung cancer in the presence of both low dietary Mg and suboptimal DRC was 2.36 (1.83–3.04). Similar results were observed for men and women. The effects were more pronounced among older subjects (>60 years), current or heavier smokers, drinkers, those with a family history of cancer in first-degree relatives, small cell lung cancer and late-stage disease. These intriguing results need to be confirmed in prospective studies.
p73 interacts with the HPV16 oncoproteins E6 and E7, and p73 variation may modify the interaction between p73 protein and HPV16 oncogenic proteins and contribute to cellular malignant transformation.
In this case-case comparison study, we analyzed HPV16 status in tumor specimens and genotyped the p73 G4C14-to-A4T14 polymorphism using genomic DNA from blood of 202 non-Hispanic white patients with squamous cell carcinoma of the Head and Neck (SCCHN). We calculated odds ratio (OR) and 95% confidence intervals (CIs) in univariate and multivariable logistic regression models to examine the association between the p73 polymorphism and HPV16 status in SCCHN.
Compared with the p73 GC/GC genotype, the AT/AT and combined GC/AT + AT/AT variant genotypes were significantly associated with tumor HPV16 positivity among SCCHN patients (adjusted OR = 5.32; 95% CI, 1.32-21.4 and adjusted OR = 1.91; 95% CI, 1.03-3.53, respectively). There was a significant dose-effect relationship between the AT allele and tumor HPV16-positive status in SCCHN patients (trend test: P = .014). Moreover, the stratified analyses showed that the association between tumor HPV16-positive status and the combined p73 GC/AT+AT/AT genotypes was more pronounced among several subgroups of patients who were older, male, ever drinkers, and those with oropharyngeal cancer.
The p73 polymorphism was associated with HPV16 status in SCCHN and may serve as a marker for tumor HPV16 positivity in patients with SCCHN, particularly those with oropharyngeal cancer.
p73 polymorphism; genetic susceptibility; HPV; squamous cell carcinoma of the head and neck; molecular epidemiology