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1.  Reproductive, lifestyle and anthropometric risk factors for cancer in elderly women 
Background
With an increasing elderly population, the United States will experience an increased cancer burden in the coming years. We evaluated associations between anthropometric, lifestyle and reproductive factors and risk of breast, ovarian, and colorectal cancer in a prospective study of postmenopausal women with a focus on diagnoses occurring among very elderly women (≥75 years).
Methods
For each cancer type, we estimated associations with relevant exposures in two age bands (< vs. ≥75 years of age). During 22 years of follow-up, 322 ovarian, 1,311 colon, 315 rectal, and 2,664 breast cancers occurred among 37,459 postmenopausal women (mean age at baseline 62 years, range 55–71 years).
Results
For ovarian cancer, we identified few significant associations in either age band. Colon cancer cases had a higher body mass index and were less likely to report estrogen or aspirin use than non-cases, yet these associations were consistent in both age bands. Few risk factors were identified for rectal cancer in women ≥75 years of age. For breast cancer, notably different patterns were revealed, with alcohol consumption associated with risk in the younger group and previous hysterectomy associated with risk only in the older group.
Conclusion
These analyses suggest some important differences in risk factors for cancer depending on age at diagnosis.
Impact
This study suggests that etiologic differences may exist in cancers occurring in the very elderly. The ongoing demographic shift in the United States provides a strong rationale for studies evaluating cancer etiology in the elderly.
doi:10.1158/1055-9965.EPI-12-0966
PMCID: PMC3617066  PMID: 23429062
cancer risk; elderly; ovarian; colorectal; breast
2.  Trends in Incidence and Survival of Pediatric and Adolescent Germ Cell Tumors in the United States, 1975-2006 
Cancer  2010;116(20):4882-4891.
Background
Pediatric germ cell tumors (GCTs) are rare and heterogeneous tumors with uncertain etiology. We used data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program to evaluate trends in incidence and survival of GCTs in boys and girls ≤ 19 years of age. Few studies have evaluated trends in pediatric GCTs. Results from these analyses may provide clues to the etiology of GCTs.
Methods
Frequencies, incidence rates and five-year relative survival rates stratified by sex were evaluated overall and for demographic subgroups based on age (0-9 and 10-19 years), race (white, black, and other), and ethnicity (non-Hispanic and Hispanic) as sample size permitted.
Results
In whites, the incidence of GCTs was lower for females than males in the 10-19 year age group (RR=0.47, 95% CI 0.42—0.53) while the rates were similar in the 0-9 year age group. In contrast, incidence rates were higher in black females than in black males in both age groups (RR=2.01, 95%CI 1.08—3.84 in 0-9 year olds; RR=3.30, 95% CI 2.13—5.28 in 10-19 year olds). The incidence of ovarian GCT was significantly higher in Hispanic than non-Hispanic girls in the 10—19 year age group. Incidence rates increased during the study period in boys ages 10-19 (APC 1.2, 95% CI 0.4—2.1) and girls ages 0-9 (APC 1.9, 95% CI 0.3-2.5).
Conclusions
The incidence of pediatric GCTs in the United States is increasing only in certain subgroups, suggesting that the etiology is not completely overlapping in all age groups. Differences in incidence patterns by race and ethnicity merit further investigation.
doi:10.1002/cncr.25454
PMCID: PMC3931133  PMID: 20597129
pediatric cancer; germ cell tumors; SEER; incidence
3.  Genetic variation in the vitamin D receptor (VDR) and the vitamin D binding protein (GC) and risk of colorectal cancer: Results from the Colon Cancer Family Registry 
Epidemiologic evidence supports a role for vitamin D in colorectal cancer (CRC) risk. Variants in vitamin D-related genes might modify the association between vitamin D levels and CRC risk. In this analysis, we performed a comprehensive evaluation of common variants in the vitamin D receptor (VDR) and the vitamin D binding protein (GC, group-specific component) genes using a population-based case-unaffected sibling control design that included 1,750 sibships recruited into the Colon Cancer Family Registry (Colon CFR). We also evaluated whether any associations differed by calcium supplement use, family history of CRC, or tumor characteristics. Heterogeneity by calcium and vitamin D intake was evaluated for a subset of 585 cases and 837 sibling controls who completed a detailed food frequency questionnaire (FFQ). Age- and sex-adjusted associations were estimated using conditional logistic regression. Overall, we did not find evidence for an association between any SNP in VDR or GC and risk of CRC (range of unadjusted p-values 0.01—0.98 for VDR and 0.07—0.95 for GC). None of these associations was significant after adjustment for multiple comparisons. We also found no evidence that calcium or vitamin D intake (food and supplement) from the FFQ modified the association estimates between VDR and GC SNPs and CRC. We did observe associations between SNPs in GC and microsatellite unstable CRC, although these results should be confirmed in additional studies. Overall, our results do not provide evidence for a role of common genetic variants in VDR or GC in susceptibility to CRC.
doi:10.1158/1055-9965.EPI-09-0662
PMCID: PMC2819604  PMID: 20086113
vitamin D; vitamin D receptor (VDR); vitamin D binding protein (GC; DBP); colorectal cancer
4.  Associations between smoking, alcohol consumption and colorectal cancer, overall and by tumor microsatellite instability status 
Introduction
Both smoking and alcohol consumption have been associated with modestly increased risks of colorectal cancer (CRC). Reports have suggested that these associations may differ by tumor molecular subtype, with stronger associations for microsatellite unstable (MSI-H) tumors.
Methods
We used a population-based case-unaffected sibling design including 2,248 sibships (2,253 cases; 4,486 siblings) recruited to the Colon Cancer Family Registry to evaluate the association between smoking, alcohol consumption and CRC. Associations were assessed using conditional logistic regression, treating sibship as the matching factor.
Results
Although there were no statistically significant associations between any smoking variable and CRC overall, smoking did confer an increased risk of certain types of CRC. We observed an association between pack years of smoking and rectal cancer (OR=1.85, 95% CI 1.23—2.79 for > 40 pack years vs. non-smokers, p for trend = 0.03), and there was an increased risk of MSI-H CRC with increasing duration of smoking (OR=1.94, 95% CI 1.09—3.46 for >30 years of smoking vs. non-smokers). Alcohol intake was associated with a modest increase in risk for CRC overall (OR=1.21, 95% CI 1.03—1.44 for 12+ drinks per week vs. non-drinkers), with more marked increases in risk for MSI-L CRC (OR=1.85, 95% CI 1.06—3.24) and rectal cancer (OR=1.48, 95% CI 1.08—2.02).
Conclusions
We found associations between cigarette smoking and increased risks of rectal cancer and MSI-H CRC. Alcohol intake was associated with increased risks of rectal cancer and MSI-L CRC. These results highlight the importance of considering tumor phenotype in studies of risk factors for CRC.
doi:10.1158/1055-9965.EPI-09-0517
PMCID: PMC2759847  PMID: 19755657
colorectal cancer; cigarette smoking; alcohol consumption; microsatellite instability
5.  Predictors of mother and child DNA yields in buccal cell samples collected in pediatric cancer epidemiologic studies: a report from the Children’s Oncology group 
BMC Genetics  2013;14:69.
Background
Collection of high-quality DNA is essential for molecular epidemiology studies. Methods have been evaluated for optimal DNA collection in studies of adults; however, DNA collection in young children poses additional challenges. Here, we have evaluated predictors of DNA quantity in buccal cells collected for population-based studies of infant leukemia (N = 489 mothers and 392 children) and hepatoblastoma (HB; N = 446 mothers and 412 children) conducted through the Children’s Oncology Group. DNA samples were collected by mail using mouthwash (for mothers and some children) and buccal brush (for children) collection kits and quantified using quantitative real-time PCR. Multivariable linear regression models were used to identify predictors of DNA yield.
Results
Median DNA yield was higher for mothers in both studies compared with their children (14 μg vs. <1 μg). Significant predictors of DNA yield in children included case–control status (β = −0.69, 50% reduction, P = 0.01 for case vs. control children), brush collection type, and season of sample collection. Demographic factors were not strong predictors of DNA yield in mothers or children in this analysis.
Conclusions
The association with seasonality suggests that conditions during transport may influence DNA yield. The low yields observed in most children in these studies highlight the importance of developing alternative methods for DNA collection in younger age groups.
doi:10.1186/1471-2156-14-69
PMCID: PMC3751424  PMID: 23937514
DNA collection; Buccal cells; Pediatric epidemiology
6.  DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors 
BMC Cancer  2013;13:313.
Background
Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development.
Methods
We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing.
Results
Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q < 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location.
Conclusion
Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy.
doi:10.1186/1471-2407-13-313
PMCID: PMC3701494  PMID: 23806198
Germ Cell Tumor; Teratoma; DNA Methylation; Imprinting
7.  Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: Potential modifying effect of BRCA1/BRCA2 mutation carrier status 
Rare deleterious mutations in BRCA1 and BRCA2 are associated with an elevated risk of breast and ovarian cancer. Whether or not common variants in these genes are independently associated with risk of breast cancer remains unclear. In this study, we included 632 Caucasian women with asynchronous contralateral breast cancer (CBC, cases) and 1,221 women with unilateral breast cancer (controls) from the WECARE (Women’s Environment, Cancer And Radiation Epidemiology) Study. BRCA1 and BRCA2 deleterious mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing, yielding including 88 BRCA1 and 60 BRCA2 deleterious mutation carriers. We also genotyped samples on the Illumina Omni1-Quad platform. We assessed the association between CBC risk and common (minor allele frequency>0.05) single nucleotide polymorphisms (SNPs) in BRCA1 (n SNPs=22) and BRCA2 (n SNPs=30) and haplotypes using conditional logistic regression accounting for BRCA1/BRCA2 mutation status. We found no significant associations between any single-SNPs or haplotypes of BRCA1 or BRCA2 and risk of CBC among all women. When we stratified by BRCA1 and BRCA2 mutation carrier status, we found suggestive evidence that risk estimates for selected SNPs in BRCA1 (rs8176318, rs1060915 and rs16940) and BRCA2 (rs11571686, rs206115 and rs206117) may differ in non-carriers and carriers of deleterious mutations in BRCA1 and BRCA2. One common haplotype on BRCA1 was inversely significantly associated with risk only among non-BRCA1 and BRCA2 carriers. The association between common variants in BRCA1 and BRCA2 and risk of CBC may differ depending on BRCA1 and BRCA2 mutation carrier status.
doi:10.1007/s10549-010-1285-1
PMCID: PMC3234998  PMID: 21161372
BRCA1; BRCA2; haplotype; polymorphism; breast cancer; contralateral
8.  Genetic variation in the retinoid X receptor and calcium-sensing receptor and risk of colorectal cancer in the Colon Cancer Family Registry 
Carcinogenesis  2010;31(8):1412-1416.
Genetic variants in the calcium/vitamin D metabolic pathway may be related to risk for colorectal cancer. While several investigations of vitamin D receptor (VDR) polymorphisms and colorectal cancer have been conducted, no studies to date have evaluated the association of genetic variation in the heterodimer partner for VDR, the retinoid X receptor (RXR). Another important gene in this pathway is the calcium-sensing receptor (CASR). Employing a discordant-sibship case–control design, we examined the association between single nucleotide polymorphisms (SNPs) in RXRA and CASR and risk for colorectal cancer overall and by colorectal subsite and microsatellite instability (MSI) status using data from the Colon Cancer Family Registry. No gene-level relationships between RXRA or CASR and colorectal cancer overall were observed. However, for RXRA SNP rs7861779, a high-interest SNP selected for study a priori, there was a statistically significantly increased risk for proximal colorectal cancer among those with at least one A allele [odds ratio (OR) = 1.42; 95% confidence interval (CI) = 1.03–1.97]. Another selected RXRA SNP, rs12004589, was significantly associated with risk of MSI-high cancers (OR = 2.27; 95% CI = 1.13–4.56). Additionally, CASR SNP rs1801726 was significantly associated with a reduced risk for rectal cancer (OR = 0.53; 95% CI = 0.29–0.96). These results provide support that RXRA SNPs rs7861779 and rs12004589 and CASR SNP rs1801726 may be important markers for colorectal neoplasia. Further work is needed to elucidate their role in the carcinogenic pathway.
doi:10.1093/carcin/bgq127
PMCID: PMC2915636  PMID: 20558521
9.  A Candidate Gene Study of Folate-Associated One Carbon Metabolism Genes and Colorectal Cancer Risk 
Background
Folate-associated one carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer.
Methods
This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry (C-CFR). We used a comprehensive tagSNP approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B12 metabolism. Genotyping was performed using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. MSI status was determined using standard techniques and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or co-dominant model.
Results
In the log additive model, two linked (r2=0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in CRC risk after correction for multiple testing (OR=0.87; 95% CI=0.71 – 0.94; P=0.029 and OR=0.87 95% CI=0.71 – 0.95, P=0.034 for rs1677693 and rs1643659 respectively. These two linked (r2=0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced CRC risk only among individuals not using multivitamin supplements.
Conclusions
Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect CRC risk except in non multivitamin users.
Impact
This study suggests that multivitamin supplement use may modify the association between folate pathway genes and CRC risk in a post folic acid supplemented population.
doi:10.1158/1055-9965.EPI-10-0151
PMCID: PMC2950115  PMID: 20615890
Colorectal Cancer; TagSNP; Folate Supplementation; Multivitamins; Microsatellite Instability; Colon subsite; ADA; ADH1C; AHCY; AMD1; CBS; DHFR; GIF; CUBN; MAT2A; MTHFD1; MTR; MTRR; SHMT1; TCN2; TYMS
10.  Reproductive factors and risk of contralateral breast cancer by BRCA1 and BRCA2 mutation status: results from the WECARE study 
Cancer causes & control : CCC  2010;21(6):839-846.
Objective
Reproductive factors, such as early age at menarche, late age at menopause, and nulliparity are known risk factors for breast cancer. Previously, we reported these factors to be associated with risk of developing contralateral breast cancer (CBC). In this study, we evaluated the association between these factors and CBC risk among BRCA1 and BRCA2 (BRCA1/2) mutation carriers and non-carriers.
Methods
The WECARE Study is a population-based multi-center case–control study of 705 women with CBC (cases) and 1,397 women with unilateral breast cancer (controls). All participants were screened for BRCA1/2 mutations and 181 carriers were identified. Conditional logistic regression models were used to evaluate associations between reproductive factors and CBC for mutation carriers and non-carriers.
Results
None of the associations between reproductive factors and CBC risk differed between mutation carriers and non-carriers. The increase in risk with younger age at menarche and decrease in risk in women with more than two full-term pregnancies seen in non-carriers were not significantly different in carriers (adjusted RRs = 1.31, 95% CI 0.65–2.65 and 0.53, 95% CI 0.19–1.51, respectively). No significant associations between the other reproductive factors and CBC risk were observed in mutation carriers or non-carriers.
Conclusion
For two reproductive factors previously shown to be associated with CBC risk, we observed similar associations for BRCA1/2 carriers. This suggests that reproductive variables that affect CBC risk may have similar effects in mutation carriers and non-carriers.
doi:10.1007/s10552-010-9510-0
PMCID: PMC2873079  PMID: 20130978
Contralateral breast cancer; BRCA1; BRCA2; Reproductive factors
11.  Genes involved with folate uptake and distribution and their association with colorectal cancer risk 
Cancer causes & control : CCC  2009;21(4):597-608.
Folate status is an important predictor of colorectal cancer risk. Common genetic variants in genes involved in regulating cellular folate levels might also predict risk, but there are limited data on this issue. We conducted a family-based case-control association study of variants in four genes involved in folate uptake and distribution: FOLR1, FPGS, GGH, and SLC19A1, using 1,750 population-based and 245 clinic-based cases of pathologically-confirmed colorectal cancer and their unaffected relatives participating in the Colon Cancer Family Registries. Standardized questionnaires, administered to all participants, collected information on risk factors and diet. Standard molecular techniques were used to determine microsatellite instability (MSI) status on cases. tagSNPs (n=29) were selected based on coverage as assessed by pairwise r2. We found no evidence that tagSNPs in these genes were associated with risk of colorectal cancer. For the SLC19A1- rs1051266 (G80A, Arg27His) missense polymorphism, the A/A genotype was not associated with risk of colorectal cancer using population-based (OR=1.00; 95% CI=0.81–1.23) or clinic-based (OR=0.75; 95% CI=0.44–1.29) families compared to the G/A and G/G genotypes. We found no evidence that the association between any tagSNP and CRC risk was modified by multivitamin use, folic acid use and dietary folate intake and total folate intake. The odds ratios were similar, irrespective of MSI status, tumor subsite and family history of colorectal cancer. In conclusion, we found no significant evidence that genetic variants in FOLR1, GGH, FPGS and SLC19A1 are associated with the risk of colorectal cancer.
doi:10.1007/s10552-009-9489-6
PMCID: PMC2904058  PMID: 20037791
Folate; folate receptor 1 (FOLR1); solute carrier family 19 (SLC19A1); reduced folate carrier (RFC); folylpolyglutamate synthase (FPGS); gamma-glutamyl hydrolase (GGH); family-based; population-based; clinic-based; polymorphisms; colorectal cancer; case-control
12.  Case–Control Study of Overweight, Obesity, and Colorectal Cancer Risk, Overall and by Tumor Microsatellite Instability Status 
Background
Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%–20% of colorectal tumors display microsatellite instability (MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status.
Methods
The study included 1794 case subjects with incident colorectal cancer who were identified through population-based cancer registries and 2684 of their unaffected sex-matched siblings as control subjects. Recent body mass index (BMI), BMI at age 20 years, and adult weight change were derived from self-reports of height and weight. Tumor MSI status, assessed at as many as 10 markers, was obtained for 69.7% of the case subjects and classified as microsatellite (MS)-stable (0% of markers unstable; n = 913), MSI-low (>0% but <30% of markers unstable; n = 149), or MSI-high (≥30% of markers unstable; n = 188). Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided.
Results
Recent BMI, modeled in 5 kg/m2 increments, was positively associated with risk of colorectal cancer for men and women combined (OR = 1.24; 95% CI = 1.15 to 1.34), for women only (OR = 1.20; 95% CI = 1.10 to 1.32), and for men only (OR = 1.30; 95% CI = 1.15 to 1.47). There was no interaction with sex (P = .22). Recent BMI, per 5 kg/m2, was positively associated with the risk of MS-stable (OR = 1.38; 95% CI = 1.24 to 1.54) and MSI-low (OR = 1.33; 95% CI = 1.04 to 1.72) colorectal tumors, but not with the risk of MSI-high tumors (OR = 1.05; 95% CI = 0.84 to 1.31).
Conclusion
The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status.
doi:10.1093/jnci/djq011
PMCID: PMC2841037  PMID: 20208017
13.  Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers 
Background
Germline mutations in MSH6 account for 10%–20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain.
Methods
We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment.
Results
For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7).
Conclusion
We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.
doi:10.1093/jnci/djp473
PMCID: PMC2815724  PMID: 20028993
14.  Family history of cancer and malignant germ cell tumors in children: A report from the Children's Oncology Group 
Cancer causes & control : CCC  2009;21(2):181-189.
Family history of testicular cancer is an established risk factor for adult testicular germ cell tumors (GCT). We evaluated the association between family history of cancer and pediatric GCT in a Children's Oncology Group case–control study that included 274 GCT cases (195 female and 79 male) diagnosed
doi:10.1007/s10552-009-9448-2
PMCID: PMC2861351  PMID: 19842050
Germ cell tumor; Family history; Children
Background
The MTHFR C677T TT genotype is associated with a 15%–18% reduction in colorectal cancer (CRC) risk but it is not clear if other variants of the gene are associated with CRC risk.
Methods
We used a tagSNP approach to comprehensively evaluate associations between variation in the MTHFR gene and CRC risk using a large family-based case control study of 1,750 population-based and 245 clinic-based families from the Colon Cancer Family Registry (CCFR).We assessed 22 TagSNPs, selected based on pairwise r2>95%, using Haploview Tagger and genotyped on the Illumina GoldenGate or Sequenom platforms. The association between SNPs and colorectal cancer was assessed using log additive, co-dominant, and recessive models.
Results
From studying the population-based families, the C677T (rs1801133) and A1298C (rs1801131) polymorphisms were associated with a decreased CRC risk overall (OR=0.81, 95% CI=0.63–1.04 and OR=0.82, 95% CI=0.64–1.07, respectively). The 677 TT genotype was associated with a decreased risk of microsatellite stable/microsatellite low tumors (OR=0.69, 95% CI=0.49–0.97) and an increased risk of microsatellite high tumors (OR= 2.22, 95% CI=0.91–5.43) (interaction p-value = 0.01), as well as an increased risk of proximal cancers and a decreased risk of distal and rectal cancers (interaction p-value = 0.02). No other SNP was associated with risk overall or within subgroups.
Conclusion
The 677 TT and 1298 CC genotypes may each be associated with a decrease in CRC risk. We observed little evidence of additional genetic variability in the MTHFR gene relevant to CRC risk.
doi:10.1158/1055-9965.EPI-09-0727
PMCID: PMC2805460  PMID: 20056627
MTHFR; Colorectal Cancer; TagSNP; Folate Supplementation; Multivitamins; Microsatellite Instability; Colon subsite
Maternal vitamin supplementation has been linked to a reduced risk of several pediatric malignancies. We examined this relationship in a study of childhood germ cell tumors (GCTs). Subjects included 278 GCT cases diagnosed <15 years during 1993-2001 at a United States or Canadian Children's Oncology Group Institution and 423 controls that were ascertained through random digit dialing matched to cases on sex, and age within one year. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% Confidence Intervals (CIs) for the association between GCTs and maternal vitamin use at several time points during and around pregnancy. In models controlling for the child's age, sex, household income, and maternal education, any maternal vitamin use during the 6 months prior to conception through nursing was associated with a non-significant reduced risk of GCTs (OR=0.7; 95% CI 0.0.4-1.2). Inverse associations were observed for both extragonadal (OR=0.8; 95% CI 0.4-1.6) and gonadal (OR=0.6; 95% CI 0.3-1.1) tumors and for dysgerminoma/seminoma (OR=0.6; 95% CI 0.2-1.3) and teratoma (OR=0.5; 95% CI 0.2-0.9) but not yolk sac tumors (OR=1.1; 95% CI 0.5-2.3). No consistent patterns were found with respect to vitamin use during the periconceptional period (6 months before pregnancy and first trimester) or first trimester specifically. In conclusion, while our study suggests that maternal vitamin supplementation may reduce the risk or pediatric GCTs in the offspring, the small study size and limitations inherent to observational studies must be considered when interpreting these results.
doi:10.1158/1055-9965.EPI-09-0462
PMCID: PMC2759848  PMID: 19755653
germ cell tumors; pediatrics; prenatal vitamins; folic acid; risk factors
Microsatellite instability (MSI) occurs in 10−20% of colorectal cancers (CRC), and has been attributed to both MLH1 promoter hypermethylation and germline mutation in the mismatch repair (MMR) genes. We present results from a large population- and clinic-based study of MLH1 methylation, immunohistochemistry, and MMR germline mutations that enabled us to: 1) estimate the prevalence of MMR germline mutations and MLH1 methylation among MSI-H cases and help us understand if all MSI-H CRC is explained by these mechanisms; and 2) estimate the associations between MLH1 methylation and sex, age, and tumor location within the colon. MLH1 methylation was measured in 1,061 population- and 172 clinic-based cases of CRC. Overall, we observed MLH1 methylation in 60% of population-based MSI-H cases and in 13% of clinic-based MSI-H cases. Within the population-based cases with MMR mutation screening and conclusive IHC results, we identified a molecular event in MMR in 91% of MSI-H cases: 54% had MLH1 methylation, 14% had a germline mutation in a MMR gene, and 23% had IHC evidence for loss of a MMR protein. We observed a striking age difference, with the prevalence of a MMR germline mutation more than four-fold lower and the prevalence of MLH1 methylation more than four-fold higher in cases diagnosed after age 50 than in cases diagnosed before age 50. We also determined that female sex is an independent predictor of MLH1 methylation within the MSI-H subgroup. These results reinforce the importance of distinguishing between the underlying causes of MSI in studies of etiology and prognosis.
doi:10.1158/1055-9965.EPI-08-0512
PMCID: PMC2628332  PMID: 18990764
MLH1 methylation; MMR mutation; colorectal cancer

Results 1-17 (17)