Is hypermethylation of SOX1 gene an independent prognostic marker in surgically resected non-small cell lung cancer?

Background: Promoter hypermethylation of tumor suppressor genes presents promising markers for lung cancer diagnosis and prognosis. The purpose of this study was to determine the association between the promoter hypermethylation of multiple genes and 5-year survival rate in patients with Non-small cell lung cancer (NSCLC). Materials and Methods: Primary tumor samples (n = 65), corresponding nonmalignant lung tissues (n = 65), and circulating blood were obtained from NSCLC patients who underwent curative surgery. Promoter methylation status in seven genes (RASSF1A, CDH13, MGMT, ESR1, DAPK, SOX1, and HOXA9) was quantified by using bisulfite pyrosequencing. Five-year survival data were obtained by a clinician. Cox proportional hazards models were used to analyze the associations between gene methylation status and overall patient survival. Results: The 5-year survival of the patients with SOX1 aberrant tumor methylation was found to be statistically significantly shorter than for those patients without aberrant tumor methylation (P = 0.01). This effect was independent of TNM stage. No significant survival differences were associated with aberrant methylation in other genes tested in either of the two tissue types. Conclusion: Our study shows that SOX1 promoter hypermethylation in NSCLC tumors is significantly associated with inferior survival, showing promise as a useful prognostic biomarker in patients with NSCLC.

Morphological findings in frozen non-neoplastic kidney tissues of patients with kidney cancer from large-scale multicentric studies on renal cancer.

There are unexplained geographical variations in the incidence of kidney cancer with the high rates reported in Baltic countries, as well as eastern and central Europe. Having access to a large and well-annotated collection of "tumor/non-tumor" pairs of kidney cancer patients from the Czech Republic, Romania, Serbia, UK, and Russia, we aimed to analyze the morphology of non-neoplastic renal tissue in nephrectomy specimens. By applying digital pathology, we performed a microscopic examination of 1012 frozen non-neoplastic kidney tissues from patients with renal cell carcinoma. Four components of renal parenchyma were evaluated and scored for the intensity of interstitial inflammation and fibrosis, tubular atrophy, glomerulosclerosis, and arterial wall thickening, globally called chronic renal parenchymal changes. Moderate or severe changes were observed in 54 (5.3%) of patients with predominance of occurrence in Romania (OR = 2.67, CI 1.07-6.67) and Serbia (OR = 4.37, CI 1.20-15.96) in reference to those from Russia. Further adjustment for comorbidities, tumor characteristics, and stage did not change risk estimates. In multinomial regression model, relative probability of non-glomerular changes was 5.22 times higher for Romania and Serbia compared to Russia. Our findings show that the frequency of chronic renal parenchymal changes, with the predominance of chronic interstitial nephritis pattern, in kidney cancer patients varies by country, significantly more frequent in countries located in central and southeastern Europe where the incidence of kidney cancer has been reported to be moderate to high. The observed association between these pathological features and living in certain geographic areas requires a larger population-based study to confirm this association on a large scale.

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development.

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity.

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population.

Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.

Acute Renal Failure in Different Malignant Tumors.

Acute renal failure (ARF) represents a severe complication of malignancies, that causes significant morbidity and mortality. ARF is a common part of multiple organ dysfunction in critically ill patients with cancer with reported mortality rates from 72% to 85% in patients who need renal replacement therapy. The pathways leading to ARF in cancer patients are common to the development of ARF in other conditions. However, certain factors leading to the development of ARF may be associated to the tumor or to the tumor therapy. The purpose of this review is to give specific aspects of renal disease in critically ill cancer patients (CICPs), to overview the causes of ARF in CICPs and to describe recent progress in the management of these complications, including treatment toxicity and bone marrow transplantation (BMT). The prevention of ARF is obligatory and therefore the possible treatments of ARF in CICPs are also discussed.

Parental military service, agent orange exposure, and the risk of rhabdomyosarcoma in offspring.

OBJECTIVE: To evaluate the role of parental military service-related exposures and rhabdomyosarcoma (RMS) risk in offspring using data from a large case-control study of childhood RMS. STUDY DESIGN: Cases (n = 319) were enrolled from the third trial run by the Intergroup Rhabdomyosarcoma Study Group. Population-based controls (n = 319) were pair-matched to cases on race, sex, and age. Conditional logistic regression was used to evaluate parental military service-related exposures and their associations with childhood RMS by generating aORs and 95% CIs. Statistical significance was defined as P < .05. RESULTS: There were no significant associations between parental military service and childhood RMS. The strongest association was with maternal military service; however, this association was attenuated and did not remain significant after adjusting for covariates (aOR = 2.75, 95% CI 0.71, 10.62). An elevated effect estimate was found when assessing paternal exposure to Agent Orange (AO) and childhood RMS but was not statistically significant (aOR = 1.72, 95% CI 0.55, 5.41). CONCLUSIONS: We found little evidence that parental military service of AO exposure influences the risk of RMS in offspring. These findings are notable in light of the continuing controversies surrounding the intergenerational effects of AO exposure.

Immunomodulatory effects of sex hormones: requirements for pregnancy and relevance in melanoma.

Similarities between the pathologic progression of cancer and the physiologic process of placentation (eg, proliferation, invasion, and local/systemic tolerance) have been recognized for many years. Sex hormones such as human chorionic gonadotropin, estrogens, progesterone, and others contribute to induction of immunologic tolerance at the beginning of gestation. Sex hormones have been shown to play contributory roles in the growth of cancers such as breast cancer, prostrate cancer, endometrial cancer, and ovarian cancer, but their involvement as putative mediators of the immunologic escape of cancer is still being elucidated. Herein, we compare the emerging mechanism by which sex hormones modulate systemic immunity in pregnancy and their potentially similar role in cancer. To do this, we conducted a PubMed search using combinations of the following keywords: "immune regulation," "sex hormones," "pregnancy," "melanoma," and "cancer." We did not limit our search to specific publication dates. Mimicking the maternal immune response to pregnancy, especially in late gestation, might aid in design of better therapies to reconstitute endogenous antitumor immunity and improve survival.

Early life factors and risk of childhood rhabdomyosarcoma.

Although little is known about etiology of childhood rhabdomyosarcoma (RMS), early life factors are suspected in the etiology. We explored this hypothesis using linked data from the California Cancer Registry and the California birth rolls. Incident cases were 359 children <6-year-old (218 embryonal, 81 alveolar, 60 others) diagnosed in 1988-2008. Controls (205, 173), frequency matched on birth year (1986-2007), were randomly selected from the birth rolls. We examined association of birth characteristics such as birth weight, size for gestational age, and timing of prenatal care with all-type RMS, embryonal, and alveolar subtypes. Crude and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. In contrast to a previous study, we observed statistically non-significant association for embryonal subtype among high birth weight (4000-5250 g) children for term births [OR (95% CI): 1.28 (0.85, 1.92)] and all births adjusted for gestational age [OR (95% CI): 1.21 (0.81, 1.81)]. On the other hand, statistically significant 1.7-fold increased risk of alveolar subtype (95% CI: 1.02, 2.87) was observed among children with late or no prenatal care and a 1.3-fold increased risk of all RMS subtypes among children of fathers ≥35 years old at child birth (95% CI: 1.00, 1.75), independent of all covariates. Our finding of positive association on male sex for all RMS types is consistent with previous studies. While we did not find a convincingly positive association between high birth weight and RMS, our findings on prenatal care supports the hypothesis that prenatal environment modifies risk for childhood RMS.

Association between TP53 R249S mutation and polymorphisms in TP53 intron 1 in hepatocellular carcinoma.

Over 100 single nucleotide polymorphisms (SNP) are validated in the TP53 tumor suppressor gene. They define haplotypes, which may differ in their activities. Therefore, mutation in cancer may occur at different rates depending upon haplotypes. However, these associations may be masked by differences in mutations types and causes of mutagenesis. We have analyzed the associations between 19 SNPs spanning the TP53 locus and a single specific aflatoxin-induced TP53 mutation (R249S) in 85 in hepatocellular carcinoma cases and 132 controls from Thailand. An association with R249S mutation (P = 0.007) was observed for a combination of two SNPs (rs17882227 and rs8064946) in a linkage disequilibrium block extending from upstream of exon 1 to the first half of intron 1. This domain contains two coding sequences overlapping with TP53 (WRAP53 and Hp53int1) suggesting that sequences in TP53 intron 1 encode transcripts that may modulate R249S mutation rate in HCC.

Expression of FGFR3 and FGFR4 and clinical risk factors associated with progression-free survival in synovial sarcoma.

Although rare, synovial sarcoma (SS) is one of the most common soft tissue sarcomas affecting young adults. To investigate potential tumor markers related to synovial sarcoma prognosis, we carried out a single-institution retrospective analysis of 103 patients diagnosed with SS between 1980 and 2009. Clinical outcome data were obtained from medical records, and archived tissue samples were used to evaluate the relationship between progression-free survival (PFS) and several prognostic factors, including tumor expression of FGFR3 and FGFR4. No associations were found between PFS and gender, body mass index, tumor site, SS18-SSX translocation, or FGFR4 expression. As seen in previous studies, age at diagnosis (<35, 63% versus ≥35 years, 31% 10-year PFS; P = .033), histologic subtype (biphasic, 75% versus monophasic 34% 10-year PFS; P = .034), and tumor size (≤5 cm, 70% versus >5 cm, 22% 10-year PFS; P < .0001) were associated with PFS in SS patients. In addition, in a subset of patients with available archived tumor samples taken prior to chemotherapy or radiation (n = 34), higher FGFR3 expression was associated with improved PFS (P = .030). To the best of our knowledge, this is the largest study of SS to date to suggest a potential clinical role for FGFR3. While small numbers make this investigation somewhat exploratory, the findings merit future investigation on a larger scale.

Genetic polymorphisms of epidermal growth factor in relation to risk of hepatocellular carcinoma: two case-control studies.

BACKGROUND: Earlier, we reported a highly statistically significant association between T-helper 1 (Th1) and Th2 cytokine genotypes and hepatocellular carcinoma (HCC) risk among natives of southern Guangxi, China, a hyperendemic region for HCC. Epidermal growth factor (EGF) plays a critical role in malignant transformation of hepatocytes and tumor progression. A polymorphism in the EGF gene (61A > G) results in elevation of EGF in liver tissues and blood. Epidemiological data are sparse on the possible association between EGF genetic polymorphism and HCC risk. METHODS: The EGF 61A > G polymorphism, multiple Th1 and Th2 genotypes, and environmental risk factors for HCC were determined on 117 HCC cases and 225 healthy control subjects among non-Asians of Los Angeles County, California, a low-risk population for HCC, and 250 HCC cases and 245 controls of southern Guangxi, China. RESULTS: Following adjustment for all known or suspected HCC risk factors, non-Asians in Los Angeles who possessed at least one copy of the high activity 61*G allele of the EGF gene showed a statistically non-significant, 78% increased risk of HCC compared with those possessing the EGF A/A genotype. This EGF-HCC risk association significantly strengthened among heavy users of alcohol [odds ratio (OR) = 3.44, 95% confidence interval (CI) = 0.93-12.76, P = 0.065)], and among individuals carrying the high-risk Th1/Th2 genotypes for HCC (OR = 3.34, 95% CI = 1.24-9.03, P = 0.017). No association between EGF genotype and HCC risk was observed among Chinese in southern Guangxi, China. CONCLUSION: Genetic polymorphism in the EGF gene resulting in elevated level of EGF, may contribute to HCC risk among low-risk non-Asians in Los Angeles.

Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium.

Li-Fraumeni syndrome (LFS) is a rare dominantly inherited cancer predisposition syndrome that was first described in 1969. In most families, it is caused by germline mutations in the TP53 gene and is characterized by early onset of multiple specific cancers and very high lifetime cumulative cancer risk. Despite significant progress in understanding the molecular biology of TP53, the optimal clinical management of this syndrome is poorly defined. We convened a workshop on November 2, 2010, at the National Institutes of Health in Bethesda, Maryland, bringing together clinicians and scientists, as well as individuals from families with LFS, to review the state of the science, address clinical management issues, stimulate collaborative research, and engage the LFS family community. This workshop also led to the creation of the Li-Fraumeni Exploration (LiFE) Research Consortium.

Low Prevalence of TP53 Mutations and MDM2 Amplifications in Pediatric Rhabdomyosarcoma.

The tumor suppressor gene TP53 is the most commonly mutated gene in human cancer. The reported prevalence of mutations in rhabdomyosarcoma (RMS) varies widely, with recent larger studies suggesting that TP53 mutations in pediatric RMS may be extremely rare. Overexpression of MDM2 also attenuates p53 function. We have performed TP53 mutation/MDM2 amplification analyses in the largest series analyzed thus far, including DNA isolated from 37 alveolar and 38 embryonal RMS tumor samples obtained from the Cooperative Human Tissue Network (CHTN). Available samples were frozen tumor tissues (N = 48) and histopathology slides. TP53 mutations in exons 4-9 were analyzed by direct sequencing in all samples, and MDM2 amplification analysis was performed by differential PCR on a subset of 22 samples. We found only one sample (1/75, 1.3%) carrying a TP53 mutation at codon 259 (p.D259Y) and no MDM2 amplification. Two SNPs in the TP53 pathway, associated with accelerated tumor onset in germline TP53 mutation carriers, (TP53 SNP72 (rs no. 1042522) and MDM2 SNP309 (rs no. 2279744)), were not found to confer earlier tumor onset. In conclusion, we confirm the extremely low prevalence of TP53 mutations/MDM2 amplifications in pediatric RMS (1.33% and 0%, respectively). The possible inactivation of p53 function by other mechanisms thus remains to be elucidated.

Aberrant promoter methylation of CDH13 and MGMT genes is associated with clinicopathologic characteristics of primary non-small-cell lung carcinoma.

UNLABELLED: Non­small-cell lung carcinoma (NSCLC) (n = 65) were analyzed for promoter methylation of RASSF1A, CDH13, MGMT, ESR1, and DAPK genes in matching lung tumors, normal lung tissue, and blood samples. Aberrant methylation in CDH13 and MGMT was associated with clinicopathologic features of NSCLC. Hypermethylation detected in primary tumors was not observed in corresponding blood samples, which rendered this an unsuitable blood-based test for NSCLC detection. INTRODUCTION: Systemic methylation changes may be a diagnostic marker for tumor development or prognosis. Here, we investigate the relationship between gene methylation in lung tumors relative to normal lung tissue and whether DNA methylation changes can be detected in paired blood samples. MATERIAL AND METHODS: Sixty-five patients were enrolled in a surgical case series of non-small-cell lung carcinoma at a single institution. By using bisulfite pyrosequencing, CpG methylation was quantified at 5 genes (RASSF1A, CDH13, MGMT, ESR1, and DAPK) in lung tumor, pathologically normal lung tissue, and circulating blood from enrolled cases. RESULTS: The analyses of methylation in tumors compared with normal lung tissue identified higher methylation of CDH13, RASSF1A, and DAPK genes, whereas ESR1 and MGMT methylation did not differ significantly between these tissue types. We then examined whether the 3 aberrantly methylated genes could be detected in blood. The difference in methylation observed in tumors was not reflected in methylation status of matching blood samples, which indicated a low feasibility of detecting lung cancer by analyzing these genes in a blood-based test. Lastly, we probed whether tumor methylation was associated with clinical and demographic characteristics. Histology and sex were associated with methylation at the CDH13 gene, whereas, stage was associated with methylation at MGMT. CONCLUSION: Our results showed higher methylation of RASSF1A, CDH13, and DAPK genes in lung tumors compared with normal lung. The lack of reflection of these methylation changes in blood samples from patients with non-small-cell lung carcinoma indicates their poor suitability for a screening test.

Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database.

BACKGROUND: Sarcoma is the index diagnosis of Li-Fraumeni syndrome (LFS), a familial predisposition to cancer that also includes brain cancer, breast cancer, and adrenal cortical carcinoma. Germline mutations in the TP53 gene are detected in approximately 80% of families that fulfill LFS criteria and in 15% to 25% of families that fulfill criteria for Li-Fraumeni-like syndrome (LFS), a group of related syndromes with broader clinical criteria. METHODS: The authors of this report used the International Agency for Research on Cancer TP53 database to analyze the types, age at onset and mutation patterns of sarcoma in TP53 mutation carriers. Those data were compared with sarcoma types in the general population of Caucasians using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. RESULTS: Overall, sarcomas represented 25% of tumors in TP53 mutation carriers, and 95.6% occurred before age 50 years compared with 38.3% before age 50 years in the SEER data set. Sarcomas were more likely to be rhabdomyosarcoma in carriers aged <5 years (odds ratio [OR], 11.6; 95% confidence interval [CI], 6.1-21.9) and osteosarcoma in carriers at any age (aged <20 years: OR, 1.41; 95% CI, 1.02-1.94; age >20 years: OR, 4.61; 95% CI, 2.72-7.83). Early sarcoma (at age <20 years) was associated with missense mutations in exons encoding the DNA-binding domain of p53 protein. Conversely, p53 null mutations (frameshift, splice sites, nonsense) and mutations outside the DNA-binding domain were associated with leiomyosarcoma (OR, 10.1; 95% CI, 3.4-29.9), a type of sarcoma that occurred after age 20 years. CONCLUSIONS: The current results further demonstrated genotype-phenotype correlations and age-dependent variations in sarcoma types in carriers of germline TP53 mutations.

Serum CRP and IL-6, genetic variants and risk of colorectal adenoma in a multiethnic population.

Chronic inflammation, which is suspected to play a role in the development of colorectal cancer (CRC), has rarely been studied in colorectal adenoma. We investigated the inter-relationships of serum levels of the inflammatory proteins CRP and in IL-6, single nucleotide polymorphisms (SNPs) in the CRP (rs1205, rs1130864, rs1800947) and IL6 (rs1800795) genes, and lifestyle factors with colorectal adenoma in a sigmoidoscopy-based case-control study of 271 adenoma cases and 539 age-, sex-, and race/ethnicity-matched controls in Hawaii. We found no association of serum CRP or IL-6 levels with the risk of adenoma. A multiple regression with stepwise selection identified elevated BMI, Caucasian and Native Hawaiian versus Japanese race/ethnicity, and current smoking as being associated with significantly higher serum CRP and IL-6 levels. Female versus male gender was also associated with higher CRP levels and older age with higher IL-6 levels. The C allele of rs1205 and the A allele of rs1130864 were significantly associated with higher serum CRP levels (p (trend): 0.0002 and 0.01, respectively), as well as with a decreased adenoma risk [rs1205: OR for CT and CC vs. TT = 0.69 (95% CI: 0.48-0.98) and 0.53 (0.34-0.83), respectively, p (trend) = 0.008; rs1130864: OR for GA and AA versus GG = 0.65 (0.45-0.93) and 0.74 (0.31-1.76), respectively, p (trend) = 0.04]. The findings of lower serum CRP and IL-6 levels in Japanese (a group with a high CRC risk) and of a decreased adenoma risk observed for alleles associated with higher circulating CRP levels suggest a protective effect for CRP in early colorectal neoplasia that warrants further study.