Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (Ptrend < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.
endometrial neoplasms; parity; reproductive history
Experimental and epidemiological evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis.
To investigate this hypothesis, a two-stage study was carried out to evaluate single nucleotide polymorphisms (SNPs) in inflammatory pathway genes in association with endometrial cancer risk. In stage 1, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage 1 SNPs significantly associated with endometrial cancer (P<0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage 2, which consisted of ten additional studies including 6,604 endometrial cancer cases and 8,511 controls.
Five of the 21 SNPs had significant allelic odds ratios and 95% confidence intervals as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples.
These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer.
This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.
endometrial cancer; inflammation; genetic risk variants; meta-analysis
Case-cohort studies have become common in epidemiological studies of rare disease, with Cox regression models the principal method used in their analysis. However, no appropriate procedures to assess the assumption of proportional hazards of case-cohort Cox models have been proposed.
We extended the correlation test based on Schoenfeld residuals, an approach used to evaluate the proportionality of hazards in standard Cox models. Specifically, pseudolikelihood functions were used to define “case-cohort Schoenfeld residuals”, and then the correlation of these residuals with each of three functions of event time (i.e., the event time itself, rank order, Kaplan-Meier estimates) was determined. The performances of the proposed tests were examined using simulation studies. We then applied these methods to data from a previously published case-cohort investigation of the insulin/IGF-axis and colorectal cancer.
Simulation studies showed that each of the three correlation tests accurately detected non-proportionality. Application of the proposed tests to the example case-cohort investigation dataset showed that the Cox proportional hazards assumption was not satisfied for certain exposure variables in that study, an issue we addressed through use of available, alternative analytical approaches.
The proposed correlation tests provide a simple and accurate approach for testing the proportional hazards assumption of Cox models in case-cohort analysis. Evaluation of the proportional hazards assumption is essential since its violation raises questions regarding the validity of Cox model results which, if unrecognized, could result in the publication of erroneous scientific findings.
Proportional hazards; Schoenfeld residuals; Case-cohort studies; Cox models
Germ-line variants in the 3′ untranslated region (3′UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3′UTR of the KRAS oncogene, referred to as the KRAS-variant, is associated with both cancer risk and altered tumor biology. Here we test the hypothesis that the KRAS-variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS-variant positive EOC patients. As this variant appears to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival.
EOC patients with complete clinical data were genotyped for the KRAS-variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125), and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were employed to confirm altered sensitivity to chemotherapy with the KRAS-variant. The KRAS-variant was directly targeted through siRNA/miRNA oligonucleotides in cell lines and survival was measured.
Post-menopausal EOC patients with the KRAS-variant were significantly more likely to die of ovarian cancer by multivariate analysis (HR=1.67, 95% CI=1.09–2.57, p=0.019, n=279). Possibly explaining this finding, EOC patients with the KRAS-variant were significantly more likely to be platinum resistant (OR=3.18, CI=1.31–7.72, p=0.0106, n=291). Additionally, direct targeting of the KRAS-variant led to a significant reduction in EOC cell growth and survival in vitro.
These findings confirm the importance of the KRAS-variant in EOC, and indicate that the KRAS-variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this work supports the hypothesis that these tumors have continued dependence on such 3′UTR lesions, and that direct targeting may be a viable future treatment approach.
Platinum resistance; KRAS-variant; ovarian cancer; outcome
Hepatocellular carcinoma (HCC) is one of the most common cancers and frequently presents with an advanced disease at diagnosis. There is only limited knowledge of genome-scale methylation changes in HCC.
Methods and Findings
We performed genome-wide methylation profiling in a total of 47 samples including 27 HCC and 20 adjacent normal liver tissues using the Illumina HumanMethylation450 BeadChip. We focused on differential methylation patterns in the promoter CpG islands as well as in various less studied genomic regions such as those surrounding the CpG islands, i.e. shores and shelves. Of the 485,577 loci studied, significant differential methylation (DM) was observed between HCC and adjacent normal tissues at 62,692 loci or 13% (p<1.03e-07). Of them, 61,058 loci (97%) were hypomethylated and most of these loci were located in the intergenic regions (43%) or gene bodies (33%). Our analysis also identified 10,775 differentially methylated (DM) loci (17% out of 62,692 loci) located in or surrounding the gene promoters, 4% of which reside in known Differentially Methylated Regions (DMRs) including reprogramming specific DMRs and cancer specific DMRs, while the rest (10,315) involving 4,106 genes could be potential new HCC DMR loci. Interestingly, the promoter-related DM loci occurred twice as frequently in the shores than in the actual CpG islands. We further characterized 982 DM loci in the promoter CpG islands to evaluate their potential biological function and found that the methylation changes could have effect on the signaling networks of Cellular development, Gene expression and Cell death (p = 1.0e-38), with BMP4, CDKN2A, GSTP1, and NFATC1 on the top of the gene list.
Substantial changes of DNA methylation at a genome-wide level were observed in HCC. Understanding epigenetic changes in HCC will help to elucidate the pathogenesis and may eventually lead to identification of molecular markers for liver cancer diagnosis, treatment and prognosis.
Stathmin is closely correlated with the progression and prognosis of a number of types of human cancer. The present study analyzed the associations between genetic variations in the stathmin gene and clinical outcomes of ovarian cancer. A total of 178 patients with epithelial ovarian cancer were treated with cytoreductive surgery followed by platinum-based chemotherapy. DNA was extracted from fresh tumor samples obtained during surgery. A total of 32 DNA samples were selected randomly for resequencing of the stathmin gene. Tag single nucleotide polymorphisms (SNPs) were identified based on the haplotype model as analyzed by PolyPhred software. Direct sequencing was employed in the genotyping of stathmin in 178 cases. A total of 10 nucleotide variations in stathmin were identified, of which 3 high-frequency variations were known SNPs from databases and 7 were new variations with low frequencies. The tag SNPs rs159531 and rs11376635 were selected from the linkage disequilibrium block of the gene to genotype stathmin in 178 cases. The distribution of the rs159531 genotype in ovarian cancer was 52.8% C/C, 35.4% C/T and 11.2% T/T. The distribution of the rs11376635 genotype in ovarian cancer was 32.0% G/G, 48.3% G/-, 18.5% -/-. The main haplotypes calculated by phase2.0 software were 55.6% CG, 27.8% T-, 15.4% C- and 1.2% TG. However, no associations between the stathmin genotype or haplotype and the outcomes in patients with ovarian cancer were observed. The stathmin genotype and haplotype were not associated with the phenotype of patients with ovarian cancer.
stathmin; genetic polymorphisms; ovarian cancer; genotype; haplotype
Genome-wide association studies (GWAS) have identified over 100 genetic loci for various cancers. However, only one is for endometrial cancer.
We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 SNPs in 832 cases and 2,682 controls (Stage 1) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (Stage 2). Nine SNPs showed results consistent in direction with Stage 1 with P<0.1. These 9 SNPs were investigated among 459 cases and 558 controls (Stage 3a) and 6 SNPs showed a direction of association consistent with Stages 1 and 2. These 6 SNPs, plus 2 additional SNPs selected based on linkage disequilibrium (LD) and P values in Stage 2, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (Stage 3b).
SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with odds ratios (OR) of 1.09 (95% CI: 1.03–1.16) for the A/G genotype and 1.17 (95% CI: 1.05–1.30) for the G/G genotype (P=1.6 × 10−4 in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04–1.18) and 1.21 (1.08–1.35), respectively (P=2.4 × 10−5).
Chromosome 1q42.2 may host an endometrial cancer susceptibility locus.
This study identified a potential genetic locus for endometrial cancer risk.
Insulin-like growth factor (IGF) I stimulates the proliferation of hepatic stellate cells (HSC), the primary source of extracellular matrix accumulation in liver fibrosis. In contrast, insulin-like growth factor binding protein (IGFBP) 3, the most abundant IGFBP in circulation, negatively modulates HSC mitogenesis. To investigate the role of the IGF axis in hepatitis C virus (HCV)-related liver disease among high-risk patients, we prospectively evaluated HCV-viremic/HIV-positive women.
A cohort investigation.
Total IGF-I and IGFBP-3 were measured in baseline serum specimens obtained from 472 HCV-viremic/HIV-positive subjects enrolled in the Women's Inter-agency HIV Study, a large multi-institutional cohort. The aspartate aminotransferase to platelet ratio index (APRI), a marker of liver fibrosis, was assessed annually.
Normal APRI levels (< 1.0) at baseline were detected in 374 of the 472 HCV-viremic/HIV-positive subjects tested, of whom 302 had complete liver function test data and were studied. IGF-I was positively associated [adjusted odds ratio comparing the highest and lowest quartiles (AORq4–q1), 5.83; 95% confidence interval (CI) 1.17–29.1; Ptrend = 0.03], and IGFBP-3 was inversely associated (AORq4–q1, 0.13; 95% CI 0.02–0.76; Ptrend = 0.04), with subsequent (incident) detection of an elevated APRI level(> 1.5), after adjustment for the CD4 T-cell count, alcohol consumption, and other risk factors.
High IGF-I may be associated with increased risk and high IGFBP-3 with reduced risk of liver disease among HCV-viremic/HIV-positive women.
aspartate aminotransferase to platelet ratio index; APRI; hepatitis C virus (HCV); HIV; IGFBP-3; IGF; liver disease
Meningioma, the most frequent tumor in the central nervous system, has few recognized risk factors. We explored the role of allergies in a population-based case-control consortium study of meningioma in five geographic areas. We also studied serum levels of a marker of atopic allergy (IgE) in a subset of study participants, a first for a study on meningioma. Participants (N = 1,065) with surgically resected, pathologically confirmed meningioma and controls (N = 634) selected via random-digit dialing were recruited and interviewed. Cases were less likely than controls to report history of physician-diagnosed allergy [odds ratio (OR) = 0.64; 95% confidence interval (95% CI): 0.51 – 0.80]. Also, cases (N = 295) had lower total serum IgE than controls [N = 192; OR = 0.85, 95% CI: 0.75–0.98 for each unit of Ln(IgE)]. Similar to glioma and cancers at several other sites, meningioma appears to have an inverse relationship with history of allergies and a biomarker of atopic allergy. Since some common opposing predisposition or developmental processes for allergy and meningioma may exist, further research into immune processes that can affect the incidence and natural history of meningioma is warranted.
Meningioma; epidemiology; risk factors; neurosurgery; brain tumor; genetics; immune factors
Long-term overweight and substantial weight gain over adulthood are known risk factors of endometrial cancer, but the timing of weight gain in relation to risk and the effect of weight change on age at diagnosis remain unclear. A population-based case–control study was conducted to evaluate the long-term effect of body weight on endometrial cancer risk. The study enrolled 668 incident cases and 674 population controls. Anthropometric features in each decade of adult life were ascertained through in-person interview and analyzed for their associations with endometrial cancer using unconditional logistic regression. As expected, high body mass index (BMI) was significantly associated with increased risk. Women who were overweight or obese at the time of interview had adjusted odds ratios of 1.54 (95%CI 1.13–2.10) and 4.76 (95%CI 3.50–6.49), respectively, compared to women of normal weight. Similar associations were observed for BMI assessed at each decade of adult life. More importantly, women who were overweight (BMI ≥ 25) in their 20s or 30s and maintained the overweight throughout life had significantly higher risk than those who became overweight at ages 40s or 50s. Women with substantial weight gain (≥35%) in early adulthood (age 20s) developed the disease 10 years earlier than those without such weight change in early life. These observations further confirm the critical link between body weight and development of endometrial cancer.
endometrial cancer; body mass index; risk factors; epidemiology; case–control study; early adulthood
Germline genetic variation may affect clinical outcomes of cancer patients. We applied a candidate-gene approach to evaluate the effect of putative markers on survival of patients with pancreatic cancer. We also examined gene-radiotherapy and gene-chemotherapy interactions, aiming to explain inter-individual differences in treatment outcomes.
In total, 211 patients with pancreatic cancer were recruited in a population-based study. Sixty-four candidate genes associated with cancer survival or treatment response were selected from existing publications. Genotype information was obtained from a previous GWAS dataset. The main effect of genetic variation and gene-specific treatment interactions on overall survival were examined by proportional hazards regression models.
Fourteen genes showed evidence of association with pancreatic cancer survival. Among these, rs1760217, located at the DPYD gene, rs17091162 at SERPINA3 and rs2231164 at ABCG2 had the lowest P-values of 10−4.60, 0.0013 and 0.0023, respectively. We also observed that two genes, RRM1 and IQGAP2, had significant interactions with radiotherapy in association with survival, and two others, TYMS and MET, showed evidence of interaction with 5-FU and erlotinib, respectively.
Our study suggested significant associations between germline genetic polymorphisms and overall survival in pancreatic cancer, as well as survival interactions between various genes and radiotherapy and chemotherapy.
Pancreatic neoplasms; Survival; Genetic heterogeneity; Polymorphism; single nucleotide; Prognosis
MicroRNA plays a vital role in gene expression, and microRNA dysregulation is involved in carcinogenesis. The miR-196a-2 polymorphism rs11614913 is reportedly associated with cancer susceptibility. This meta-analysis was performed to assess the overall association of miR-196a-2 with cancer risk.
A total of 27 independent case-control studies involving 10,435 cases and 12,075 controls were analyzed for the rs11614913 polymorphism.
A significant association was found between rs11614913 polymorphism and cancer risk in four genetic models (CT vs. TT, OR=1.15, 95%CI=1.05–1.27; CC vs. TT, OR=1.23, 95%CI=1.08–1.39; Dominant model, OR=1.17, 95%CI=1.06–1.30; Additive model, OR=1.08, 95%CI=1.01–1.14). In the subgroup analysis of different tumor types, the C allele was associated with increased risk of lung, breast, and colorectal cancer, but not with liver, gastric, or esophageal cancer. In the subgroup analysis by ethnicity, a significantly increased risk of cancer was found among Asians in all genetic models, but no associations were found in the Caucasian subgroup.
The meta-analysis demonstrated that the miR-196a-2 polymorphism is associated with cancer susceptibility, especially lung cancer, colorectal cancer, and breast cancer among Asian populations.
MIRN196 microRNA; human; polymorphism; neoplasms; meta-analysis
Programmed cell death 6 (PDCD6) beside its known proapoptotic functions may be a player in survival pathways in cancer. The purpose of this study is to further explore the roles of PDCD6 in epithelial ovarian cancer.
Lentiviral vector with shRNA for PDCD6 was used to investigate the effects of PDCD6 knockdown on cell growth, cell cycle, apoptosis and motility in ovarian cancer cells. Two hundred twelve epithelial ovarian cancer tissues were analyzed for mRNA expression of PDCD6 using RT-PCR. Associations of its expression with clinical pathological factors, progression free and overall survival were evaluated.
PDCD6 is highly expressed in metastatic ovarian cancer cells and positively regulates cell migration and invasion. Significantly, the level of PDCD6 expression in epithelial ovarian cancer correlates with clinical progression. Patients with medium or high levels of PDCD6 mRNA were at higher risk for disease progression, compared to those with low levels (HR, 1.29; P = 0.024 for medium levels; and HR, 1.57; P = 0.045 for high levels) after adjusting for age, disease stage, tumor grade, histologic type and residual tumor size. Kaplan-Meier survival analysis demonstrated similar results. However, no association was found between PDCD6 expression and overall survival.
PDCD6 seems to play an important role in ovarian cancer progression and it may be an independent predictor of progression free survival in epithelial ovarian cancer. Further studies are needed to more completely elucidate the molecular mechanisms of PDCD6 involve in ovarian cancer progression.
Published studies of physical activity, BMI, and endometrial cancer risk show conflicting results and many do not report on reliability or validity of physical activity questionnaires.
We collected physical activity data on 667 incident cases of endometrial cancer and 662 age-matched controls. Interview-administered questionnaires, collecting demographic and lifestyle information, including a validated questionnaire for physical activity. We performed unconditional logistic regression to examine the relationship between moderate- to vigorous-intensity sports/recreational physical activity (MV PA), sit time, and endometrial cancer risk.
Compared to women reporting 0 metabolic equivalent (MET) hours per week of MV PA, those who reported 7.5 MET h/wk or more had a 34% lower endometrial cancer risk (odds ratio (OR) = 0.66, 95% CI 0.50–0.87) after adjusting for risk factors including BMI. Those women sitting more than 8 h per day had a 52% increased odds (95% CI 1.07–2.16) of endometrial cancer compared to those sitting less than 4 h per day. We created a composite measure of physical activity and BMI and found that women with a BMI<25 and activity levels ≥7.5 MET h/wk had a 73% lower endometrial cancer risk (OR = 0.27, 95% CI 0.18–0.39) compared with the reference group of overweight (BMI ≥25) and sedentary (MET h/wk = 0).
Our data support an inverse, independent association between physical activity and endometrial cancer risk after adjusting for BMI and other risk factors.
Physical activity; Endometrial cancer; BMI
Telomere length plays important roles in maintaining genome stability and regulating cell replication and death. Telomerase has functions not only to extend telomere length but also to repair DNA damage. Studies have shown that telomerase may increase cancer cell resistance to DNA-damaging anticancer agents; tamoxifen may suppress telomerase expression in breast cancer cells. This study aimed to investigate the role of telomere length and telomerase activity in breast cancer prognosis.
qPCR and qRT-PCR were used to analyze telomere length and telomerase expression, respectively, in tumor samples of 348 breast cancer patients. Cox regression analysis was performed to examine telomere length and telomerase expression in association with disease-free survival and cause-specific mortality.
Telomere length had no relation to tumor features or disease outcomes. Telomerase expression was detected in 53% of tumors. Larger tumors or aggressive disease were more likely to have telomerase expression. Among patients treated with chemotherapy, high telomerase was found to be associated with increased risk of death (hazard ratio (HR) = 3.15; 95% CI: 1.34 to 7.40) and disease recurrence (HR = 2.04; 95% CI: 0.96 to 4.30) regardless of patient age, disease stage, tumor grade, histological type or hormone receptor status. Patients treated with endocrine therapy had different results regarding telomerase: high telomerase appeared to be associated with better survival outcomes. Telomerase expression made no survival difference in patients who received both chemotherapy and endocrine therapy.
Overall, telomerase expression was not associated with disease outcome, but this finding may be masked by adjuvant treatment. Patients with high telomerase expression responded poorly to chemotherapy in terms of disease-free and overall survival, but fared better if treated with endocrine therapy.
This paper presents a single-institution experience regarding the clinicopathologic features and treatment strategies used in uterine clear cell cancer (UCC), a rare, aggressive histologic subtype of uterine cancer with poor prognosis and discusses parameters associated with progression-free survival (PFS) and overall survival (OS). A retrospective chart review was performed on all patients (n = 80) diagnosed with UCC and treated between 1994 and 2009 at a single academic institution. Data on demographics, FIGO stage, treatment regimens, and recurrences were collected. Patients with early-stage UCC had an excellent survival regardless of adjuvant therapy. Advanced-stage patients had a worse survival. Vaginal apex brachytherapy was associated with an increased OS (P = 0.02) but not PFS (P = 0.10). The use of platinum-based chemotherapy in combination with vaginal apex brachytherapy did not significantly improve survival. Innovative therapies still need to be identified for this uncommon uterine cancer.
High expression of insulin-like growth factor-II (IGF-II) in epithelial ovarian cancer is associated with aggressive disease and poor prognosis. IGF-II transcription is initiated from multiple promoters. Promoter-specific expression is regulated by DNA methylation, which is often dys-regulated in cancer. Here, the effects of promoter-specific methylation on IGF-II expression are investigated in ovarian cancer. Fresh tumor samples were collected from 211 patients for analyses of IGF-II promoter methylation using methylation-specific PCR, and of promoter-specific expression of IGF-II mRNA with qRT-PCR, as well as tissue levels of IGF-II peptide with an ELISA. Cox regression analysis was performed to assess IGF-II methylation and expression in association with progression-free and overall survival. DNA methylation was high in IGF-II promoters 2 (P2, 64.2%) and 3 (P3, 52.1%) and low in promoter 4 (P4, 9.8%). High methylation was associated with low mRNA expression in a promoter-specific manner. P3 methylation and expression appeared to be critical in ovarian cancer compared to other promoters. While methylation in an individual promoter was not associated with the disease, a methylation pattern involving P2 and P3 was significantly different among patients with distinct tumor grade, debulking results, residual tumor size and treatment response. The methylation pattern was also associated with disease progression. The study suggests that DNA methylation regulates IGF-II promoter-specific expression in ovarian cancer and the regulation may play a role in disease progression. Assessing methylation patterns in IGF-II promoters may have clinical implications.
IGF-II; methylation; epithelial ovarian cancer; prognosis
Ovarian cancer is the single most deadly form of women’s cancer, typically presenting as an advanced disease at diagnosis in part due to a lack of known risk factors or genetic markers of risk. The KRAS oncogene and altered levels of the microRNA let-7 are associated with an increased risk of developing solid tumors. In this study, we investigated a hypothesized association between an increased risk of ovarian cancer and a variant allele of KRAS at rs61764370, referred to as the KRAS-variant, that disrupts a let-7 microRNA binding site in this oncogene. Specimens obtained were tested for the presence of the KRAS-variant from non-selected ovarian cancer patients in three independent cohorts, two independent ovarian case-control studies, and ovarian cancer patients with hereditary breast and ovarian cancer syndrome (HBOC) as well as in their family members. Our results indicate that the KRAS-variant is associated with greater than 25% of non-selected ovarian cancer cases. Further, we found that it is a marker for a significant increased risk of developing ovarian cancer, as confirmed by two independent case control analyses. Lastly, we determined that the KRAS-variant was present in 61% of HBOC patients without BRCA1 or BRCA2 mutations, previously considered uninformative, as well as in their family members with cancer. Our findings strongly support the hypothesis that the KRAS-variant is a genetic marker for increased risk of developing ovarian cancer, and they suggest that the KRAS-variant may be a new genetic marker of cancer risk for HBOC families without other known genetic abnormalities.
The insulin-like growth factor (IGF) axis has been hypothesized to influence the rate of human immunodeficiency virus (HIV) disease progression. This premise is based largely on laboratory models showing that IGF-I stimulates thymic growth and increases lymphocyte numbers and that IGF-binding protein (IGFBP)–3 has an opposing effect, inhibiting hematopoietic stem cell development.
We studied 1422 HIV-infected women enrolled in a large cohort that entailed semiannual follow-up (initiated in 1994). Baseline serum samples were tested for IGF-I and IGFBP-3 to determine their associations with incident clinical acquired immunodeficiency syndrome (AIDS) and CD4+ T cell count decline prior to April 1996 (before the era of highly active antiretroviral therapy [HAART]).
Low IGF-I levels (Ptrend = .02) and high IGFBP-3 levels (Ptrend = .02) were associated with rapid CD4+ T cell count decline. Only IGFBP-3, however, was significantly associated with AIDS incidence (hazard ratio for highest vs. lowest quartile, 2.65 [95% confidence interval, 1.30–5.42]; Ptrend = .02) in multivariable models.
These findings suggest that serum levels of IGFBP-3 (and possibly IGF-I) are associated with the rate of HIV disease progression in women and, more broadly, that interindividual heterogeneity in the IGF axis may influence HIV pathogenesis. If correct, the IGF axis could be a target for interventions to slow HIV disease progression and extend the time before use of HAART becomes necessary.
Mounting evidence suggests that neuronal PAS domain protein 2 (NPAS2) and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer. The current study further examined the prognostic significance of NPAS2 in breast cancer by genotyping the Ala394Thr polymorphism and measuring NPAS2 expression. DNA extracted from 348 breast cancer tissue samples was analyzed for NPAS2 genotype using the TaqMan allelic discrimination assay. Of these, 287 also had total RNA available for use in real-time PCR assays to determine NPAS2 expression. NPAS2 genotypes and expression levels were analyzed for associations with prognostic outcomes, as well as correlations with clinical characteristics. A high level of NPAS2 expression was strongly associated with improved disease free survival (AHR = 0.43, 95% CI: 0.21–0.86, P trend = 0.022) and overall survival (AHR = 0.42, 95% CI: 0.19–0.96, P trend = 0.036). In addition, there was a borderline, but nonsignificant association between the NPAS2 genotype corresponding to Thr394Thr and disease free survival (AHR = 1.82, 95% CI: 0.96–3.46). The Ala/Ala, Ala/Thr, and Thr/Thr genotypes were also differentially distributed by tumor severity, as measured by TNM classification (χ2 (6df, N = 344) = 14.96, P = 0.020). These findings provide the first evidence suggesting prognostic significance of the circadian gene NPAS2 in breast cancer.
Circadian gene; NPAS2; Breast caner; Survival
Dysregulation of the insulin-like growth factor (IGF) system, a common consequence of adiposity-induced insulin resistance, may be a key underlying mechanism linking excess body weight with colon cancer. Evidence has been derived from studies of cancer and polyps. Supporting data about aberrant crypt foci (ACF), putative pre-polyp changes, have been generated only from animal studies to date.
We randomly selected 26 patients with sex-specific elevated waist-hip-ratio (WHR) and 26 with normal values from a series of 150 patients seeking routine colonoscopy at the University of Connecticut Health Center. Cross-sectional analyses were performed of ACF number (<5, ≥5) in relation to total IGF1, IGF-binding protein-3 (IGFBP3), insulin, body mass index (BMI), WHR and waist circumference (WC). Visualized ACF in the 20 cm of the distal colon were counted using advanced endoscopic imaging.
Patients with ≥5 ACF had higher BMI, WHR, and WC compared with patients with >5 ACF (p = 0.04, p = 0.03, and p = 0.01, respectively). IGFBP3 was reduced (p = 0.02) and IGF1:IGFBP3 molar ratio was greater (p = 0.03) in patients with ≥5 ACF. We did not observe significant associations between ACF number and insulin or total IGF1.
Our study provides the first report in humans of a possible association of ACF prevalence and IGF1 bioavailability as characterized by IGF1:IGFBP3 molar ratio and IGFBP3 level. More research is needed to determine whether this relationship is varied by ACF features (e.g., size, dysplasia, molecular changes), synchronous cancer and polyps, and is modified by colon cancer risk factors.
Aberrant crypt foci; Obesity; Adiposity; Colon cancer; IGF1; IGFBP3; Insulin resistance; Metabolic syndrome
Obesity is a major risk factor for endometrial cancer, a relationship thought to be largely explained by the prevalence of high estrogen levels in obese women. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed whether insulin and/or insulin-like growth factor-I (IGF-I), a related hormone, are associated with endometrial cancer while accounting for estrogen levels. We therefore conducted a case-cohort study of incident endometrial cancer in the Women’s Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. The study involved all 250 incident cases and a random subcohort of 465 subjects for comparison. Insulin, total IGF-I, free IGF-I, IGF-binding protein-3, glucose, and estradiol levels were measured in fasting baseline serum specimens. Cox models were used to estimate associations with endometrial cancer, particularly endometrioid adenocarcinomas, the main histologic type (n = 205). Our data showed that insulin levels were positively associated with endometrioid adenocarcinoma [hazard ratio contrasting highest versus lowest quartile (HRq4-q1), 2.33; 95% confidence interval (95% CI), 1.13–4.82] among women not using hormone therapy after adjustment for age and estradiol. Free IGF-I was inversely associated with endometrioid adenocarcinoma (HRq4-q1, 0.53; 95% CI, 0.31–0.90) after adjustment for age, hormone therapy use, and estradiol. Both of these associations were stronger among overweight/obese women, especially the association between insulin and endometrioid adenocarcinoma (HRq4-q1, 4.30; 95% CI, 1.62–11.43). These data indicate that hyperinsulinemia may represent a risk factor for endometrioid adenocarcinoma that is independent of estradiol. Free IGF-I levels were inversely associated with endometrioid adenocarcinoma, consistent with prior cross-sectional data.
Myelodysplastic syndromes (MDS) are a group of hematological malignancies with poor survival. Although previous studies have identified the prognostic role of multiple demographic and clinical characteristics, the potential role of lifestyle factors has not been evaluated. In this study, we conducted an extensive assessment of the predictors of MDS survival, with a special focus on lifestyle factors. A total of 616 patients (median survival = 4.1 years) were included in the analysis, and multivariate Cox proportional hazard models were utilized to estimate hazard ratios. Compared with non-smokers, MDS patients who smoked at the initial clinical encounter had a significantly increased risk of death [hazard ratio (HR) = 1.46, 95% confidence intervals (CI): 1.07–2.00]. The elevated risk was restricted to men (HR = 1.76, 95% CI: 1.21–2.56) and not observed among women (HR = 0.98, 95% CI: 0.51–1.85). When patients were stratified by the IPSS categorization, a near three fold increased risk of death was associated with smoking among patients with low-risk MDS (HR = 2.83, 95% CI: 1.48–5.39), whereas smoking did not appear to influence the survival of patients with intermediate- or high-risk MDS. This study was the first to identify smoking as a significant and independent predictor of MDS survival, particularly among low-risk patients.
Myelodysplastic syndromes; Survival; Smoking
Carriage of a non–O ABO blood group and colonization by Helicobacter pylori are thought to be risk factors for pancreatic cancer. We examined these associations in a population-based case–control study of 373 case patients and 690 control subjects frequency matched on sex and age. Control subjects were selected by random-digit dialing. Seropositivity for H pylori and its virulence protein CagA was determined by enzyme-linked immunosorbent assay (ELISA). Increased risk of pancreatic cancer was associated with non–O blood group (adjusted odds ratio [OR] = 1.37, 95% confidence interval [CI] = 1.02 to 1.83, P = .034) and CagA-negative H pylori seropositivity (OR = 1.68, 95% CI = 1.07 to 2.66, P = .025), but no association was observed for CagA seropositivity (OR = 0.77, 95% CI = 0.52 to 1.16). An association between pancreatic cancer risk and CagA-negative H pylori seropositivity was found among individuals with non–O blood type but not among those with O blood type (OR = 2.78, 95% CI = 1.49 to 5.20, P = .0014; OR = 1.28, 95% CI = 0.62 to 2.64, P = .51, respectively). This study demonstrates an association between pancreatic cancer and H pylori colonization, particularly for individuals with non–O blood types.
African American (AA) race/ethnicity, lower body mass index (BMI), and higher insulin-like growth factor 1 (IGF-1) levels are associated with premenopausal breast cancer risk. This cross-sectional analysis investigated whether BMI or BMI at age 21 years contribute to racial differences in IGF-1, IGF-2, IGFBP-3, or free IGF-1. Participants included 816 white and 821 AA women between ages 40 and 79 years across a wide BMI range (18.5–40 kg/m2). Compared with white women, AA women had higher mean IGF-1 (146.3 vs. 134.4 ng/ml) and free IGF-1 (0.145 vs. 0.127) levels, and lower IGF-2 (1633.0 vs. 1769.3 ng/ml) and IGFBP-3 (3663.3 vs. 3842.5 ng/ml) levels (all p<0.01; adjusted for age, height, BMI, BMI at age 21, and menopause status). Regardless of race, IGF-1 and free IGF-1 levels sharply rose as BMI increased to 22–24 kg/m2, then declined thereafter, while IGF-2 and IGFBP-3 levels tended to rise with BMI. In contrast, BMI at age 21 was inversely associated with all IGF levels, but only among white women (p-interaction = 0.01). With the decline in IGF-1 with BMI at age 21 among whites, racial differences in IGF-1 significantly increased among women who were obese in early adulthood. In summary, BMI was associated with IGF-1 levels regardless of race/ethnicity, while obesity during childhood or young adulthood may have a greater impact on IGF-1 levels among white women. The effects of obesity throughout life on the IGF axis and racial differences in breast cancer risk require study.
Insulin-like growth factor; obesity; race; breast cancer