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Genetic variation at insulin-like growth factor 1 (IGF1) has been linked to prostate cancer risk. However, the specific predisposing variants have not been identified. In this study, we fine-mapped the IGF1 locus for prostate cancer risk in African Americans. We conducted targeted Roche GS-Junior 454 resequencing of a 156-kb region of IGF1 in 80 African American aggressive prostate cancer cases. Three hundred and thirty-four IGF1 SNPs were examined for their association with prostate cancer risk in 1,000 African American prostate cancer cases and 991 controls. The top associated SNP in African Americans, rs148371593, was examined in an additional 3,465 prostate cancer cases and 3,425 controls of non-African American ancestry—European Americans, Japanese Americans, Latinos, and Native Hawaiians. The overall association of 334 IGF1 SNPs and prostate cancer risk was assessed using logistic kernel-machine methods. The association between each SNP and prostate cancer risk was evaluated through unconditional logistic regression. A false discovery rate threshold of q < 0.1 was used to determine statistical significance of associations. We identified 8 novel IGF1 SNPs. The cumulative effect of the 334 IGF1 SNPs was not associated with prostate cancer risk (P = 0.13) in African Americans. Twenty SNPs were nominally associated with prostate cancer at P < 0.05. The top associated SNP among African Americans, rs148371593 [minor allele frequency (MAF) = 0.03; P = 0.0014; q > 0.1], did not reach our criterion of statistical significance. This polymorphism was rare in non-African Americans (MAF < 0.003) and was not associated with prostate cancer risk (P = 0.98). Our findings do not support the role of IGF1 variants and prostate cancer risk among African Americans. Cancer Epidemiol Biomarkers Prev; 23(9); 1928–32. ©2014 AACR.

PDF file - 1238K, Supplemental Figure 1. Locus Zoom Plot for SNP rs148371593 in African Americans. Supplemental Table 1. Study subject characteristics. Supplemental Table 2. Association between 334 IGF1 variants and prostate cancer risk among African American. Supplemental Table 3. FASTA sequences of 8 novel IGF1 variants.

Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Background Extensive extracellular matrix (ECM) remodeling is a hallmark of metastatic pancreatic ductal adenocarcinoma (mPDA). We investigated fragments of collagen types III (C3M, PRO-C3), VI (PRO-C6), and VIII (C8-C), and versican (VCANM) in plasma as biomarkers for predicting progression-free survival (PFS) and overall survival (OS) in patients with mPDA treated with pegvorhyaluronidase alfa, a biologic that degrades the ECM component hyaluronan (HA), in a randomized phase 2 study (HALO109-202). Methods HALO109-202 comprised a discovery cohort (Stage 1, n = 94) and a validation cohort (Stage 2, n = 95). Plasma ECM biomarkers were analyzed by ELISAs. Univariate Cox regression analysis and Kaplan–Meier plots evaluated predictive associations between biomarkers, PFS and OS in patients treated with pegvorhyaluronidase alfa plus nab-paclitaxel/gemcitabine (PAG) versus nab-paclitaxel/gemcitabine (AG) alone. Results PFS was improved with PAG vs. AG in Stage 1 patients with high C3M/PRO-C3 ratio (median cut-off): median PFS (mPFS) 8.0 vs. 5.3 months, P = 0.031; HR = 0.40; 95% CI 0.17–0.92). High C3M/PRO-C3 ratio was validated in Stage 2 patients by predicting a PFS benefit of PAG vs. AG (mPFS: 8.8 vs. 3.4 months, P = 0.046; HR = 0.46; 95% CI 0.21–0.98). OS was also improved in patients with high C3M/PRO-C3 ratio treated with PAG vs. AG (mOS 13.8 vs 8.5 months, P = 0.009; HR = 0.35; 95% CI 0.16–0.77). Interestingly, high C3M/PRO-C3 ratio predicted for a PFS benefit to PAG vs. AG both in patients with HA-low tumors (HR = 0.36; 95% CI 0.17–0.79) and HA-high tumors (HR = 0.20; 95% CI 0.06–0.69). Conclusions The C3M/PRO-C3 ratio measuring type III collagen turnover in plasma has potential as a blood-based predictive biomarker in patients with mPDA and provides additional value to a HA biopsy when applied for patient selection. Trial registration: NCT01839487. Registered 25 April 2016

Purpose: The tumor microenvironment (TME) evolves to support tumor progression. One marker of more aggressive malignancy is hyaluronan (HA) accumulation. Here, we characterize biological and physical changes associated with HA-accumulating (HA-high) tumors. Experimental Design: We used immunohistochemistry, in vivo imaging of tumor pH, and microdialysis to characterize the TME of HA-high tumors, including tumor vascular structure, hypoxia, tumor perfusion by doxorubicin, pH, content of collagen. and smooth muscle actin (α-SMA). A novel method was developed to measure real-time tumor-associated soluble cytokines and growth factors. We also evaluated biopsies of murine and pancreatic cancer patients to investigate HA and collagen content, important contributors to drug resistance. Results: In immunodeficient and immunocompetent mice, increasing tumor HA content is accompanied by increasing collagen content, vascular collapse, hypoxia, and increased metastatic potential, as reflected by increased α-SMA. In vivo treatment of HA-high tumors with PEGylated recombinant human hyaluronidase (PEGPH20) dramatically reversed these changes and depleted stores of VEGF-A165, suggesting that PEGPH20 may also diminish the angiogenic potential of the TME. Finally, we observed in xenografts and in pancreatic cancer patients a coordinated increase in HA and collagen tumor content. Conclusions: The accumulation of HA in tumors is associated with high tIP, vascular collapse, hypoxia, and drug resistance. These findings may partially explain why more aggressive malignancy is observed in the HA-high phenotype. We have shown that degradation of HA by PEGPH20 partially reverses this phenotype and leads to depletion of tumor-associated VEGF-A165. These results encourage further clinical investigation of PEGPH20. Clin Cancer Res; 24(19); 4798–807. ©2018 AACR.

Introduction Subcutaneous (SC) formulations of therapeutics with recombinant human hyaluronidase PH20 (rHuPH20) are currently approved across various disease indications. The rHuPH20-mediated enzymatic degradation of SC hyaluronan (HA) facilitates bulk fluid flow and dispersion of co-administered therapeutics. However, current methods of quantifying dispersion in the SC space are limited. Here, a novel method is outlined to quantify and follow rapid SC volumetric dispersion of a representative therapeutic fluid in the presence of rHuPH20 using computed tomography (CT). Methods Ten Yucatan miniature swine were randomized to three groups. Animals received simultaneous infusions of contrast agent (CA) alone (left side of the animal) or in combination with rHuPH20 (right side) at infusion rates of 2.5, 5, or 10 mL/min. Spiral CT scans (1.5 mm thickness) were conducted before and after the infusion and at regular time intervals throughout. Scans were used to create three-dimensional (3D) reconstructions of the fluid pockets and analyze surface area, volume, and sphericity. Results 3D reconstruction showed increased dispersion of CA with rHuPH20 compared with CA alone, with fenestration and increased dispersion in the craniocaudal and lateromedial directions. The CA with rHuPH20 fluid pockets showed an average increase of 46% in surface area (p = 0.001), a 35% increase in volume (p = 0.001) and a 17% decrease in sphericity post-infusion compared with CA alone at 30 min post-infusion. Discussion This exploratory study confirms the value of CT imaging as a non-invasive method of assessing real-time spatial and temporal behavior of SC-administered fluids. This technique could help to assess the dispersion pattern of novel rHuPH20 SC co-formulations.

Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E-05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89-0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn's-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn's-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.

Genetic variation at insulin-like growth factor 1 (IGF1) has been linked to prostate cancer risk. However, the specific predisposing variants have not been identified. In this study, we fine-mapped the IGF1 locus for prostate cancer risk in African Americans. We conducted targeted Roche GS-Junior 454 resequencing of a 156-kb region of IGF1 in 80 African American aggressive prostate cancer cases. Three hundred and thirty-four IGF1 SNPs were examined for their association with prostate cancer risk in 1,000 African American prostate cancer cases and 991 controls. The top associated SNP in African Americans, rs148371593, was examined in an additional 3,465 prostate cancer cases and 3,425 controls of non-African American ancestry—European Americans, Japanese Americans, Latinos, and Native Hawaiians. The overall association of 334 IGF1 SNPs and prostate cancer risk was assessed using logistic kernel-machine methods. The association between each SNP and prostate cancer risk was evaluated through unconditional logistic regression. A false discovery rate threshold of q < 0.1 was used to determine statistical significance of associations. We identified 8 novel IGF1 SNPs. The cumulative effect of the 334 IGF1 SNPs was not associated with prostate cancer risk (P = 0.13) in African Americans. Twenty SNPs were nominally associated with prostate cancer at P < 0.05. The top associated SNP among African Americans, rs148371593 [minor allele frequency (MAF) = 0.03; P = 0.0014; q > 0.1], did not reach our criterion of statistical significance. This polymorphism was rare in non-African Americans (MAF < 0.003) and was not associated with prostate cancer risk (P = 0.98). Our findings do not support the role of IGF1 variants and prostate cancer risk among African Americans. Cancer Epidemiol Biomarkers Prev; 23(9); 1928–32. ©2014 AACR.

Introduction Hyaluronan (HA) is a naturally occurring glycosaminoglycan that can accumulate in the tumour microenvironment (TME). In pancreatic and other cancers, high levels of HA are associated with poor clinical outcome. In mouse models, high levels of HA in the TME can increase interstitial fluid pressure and compress tumour vasculature, thereby impairing delivery of anti-cancer therapeutics. Here, a novel, first-in-class biologic that enzymatically degrades HA, PEGPH20, increased tumour vascular volume (VV) and improved anti-tumour efficacy when combined with chemotherapy or checkpoint inhibitor antibodies in multiple HA-accumulating tumour models. Material and methods Various human and mouse cancer cell lines were transduced with hyaluronan synthase 3 (HAS3) to increase HA production, and implanted in the mammary fat pat (4 T1/HAS3) or adjacent to the tibial periosteum (all other cell lines). Tumour VV was measured by high resolution ultrasound coupled with micro-bubbles (A549/HAS3 and WT-CLS1/HAS3), or IHC (CT26/HAS3), following PEGPH20 treatment (0.0375 mg/kg or 1 mg/kg, IV, 2qw). For BxPC3/HAS3 studies, mice were dosed with vehicle or PEGPH20 (4.5 mg/kg, IV, 2qw)±nab paclitaxel (NAB, 10 mg/kg, IV, 2qw)±gemcitabine (GEM, 180 mg/kg, IP; 24 hour after PEGPH20 ±NAB, qw). For AsPC1/HAS3 studies, mice were dosed with vehicle or PEGPH20 (0.0375 mg/kg, IV, 2qw)±NAB (10 mg/kg, IV, qw)±GEM (180 mg/kg, IP; 24 hour after PEGPH20 ±NAB, qw). For checkpoint inhibitor studies (CT26/HAS3, 4 T1/HAS3, Pan02/HAS3), mice were dosed with PEGPH20 (0.0375 mg/kg, IV) 24 hour prior to anti-CTLA4 (clone 9D9, 4 mg/kg, IP) or anti-PD-L1 (clone 10F.9G2, 5 mg/kg, IP). Results and discussions PEGPH20 administration resulted in degradation of HA in all tumour models tested, and resulted in increased VV in the 3 models tested. PEGPH20 +GEM + NAB led to enhanced tumour growth inhibition (TGI) compared to GEM+NAB in the BxPC3/HAS3 (104% v 70%, respectively, p Conclusion These studies demonstrate that the use of PEGPH20 to enzymatically remodel the TME in HA-high tumours may represent a novel approach for enhancing the efficacy of cancer therapeutics. A Phase 3 study of GEM and NAB ±PEGPH20 in patients with prospectively selected HA-high PDA is ongoing (NCT02715804).

Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9. Electronic supplementary material The online version of this article (doi:10.1007/s10689-010-9408-8) contains supplementary material, which is available to authorized users.

Colorectal cancer is the third most common cancer, and the third most common cause of cancer-related death, among both men and women in the United States. To address this unmet clinical need, ongoing efforts have focused on classifying different subtypes of colorectal cancer, with the goal of identifying therapies with the highest likelihood of success for a given tumor subtype. One marker that has been associated with poor clinical outcome in multiple solid tumor types, including colorectal cancer, is the accumulation of the glycosaminoglycan hyaluronan (HA), which, in preclinical tumor models, increases interstitial fluid pressure, compresses tumor vasculature, and restricts the access of therapeutics. PEGylated recombinant human hyaluronidase PH20 (pegvorhyaluronidase alfa; PEGPH20), which enzymatically degrades HA, is currently being evaluated in combination with existing therapies in clinical trials for HA-accumulating pancreatic, gastric, non-small cell lung, and bile duct cancers. Here, we review the available data for PEGPH20 as published by the authors to evaluate the potential utility of PEGPH20 in treating colorectal cancer. We first studied PEGPH20 in two HA-accumulating murine colon tumor models: CT26 transduced with hyaluronan synthase-3 (HAS3) and MC38 (Charles River Laboratories). In CT26-HAS3 tumors, PEGPH20 monotherapy induced 43% tumor growth inhibition and was associated with tumor blood vessel decompression. In combination with anti-CTLA4 treatment, PEGPH20 further enhanced tumor growth inhibition (79%, p≤0.002 vs anti-CTLA4 alone and PEGPH20 alone). In MC38 tumors, combination of PEGPH20 with anti-PD-L1 treatment significantly increased infiltration of CD8+ T cells (2.8-fold, p Citation Format: Renee Clift, Benjamin J. Thompson, Darin Taverna, Barbara Blouw, Jisook Lee, Curtis B. Thompson, Daniel C. Maneval. Rationale for evaluating PEGylated recombinant human hyaluronidase PH20 (pegvorhyaluronidase alfa; PEGPH20) in patients with hyaluronan (HA)-accumulating colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1743.

Introduction Hyaluronan (HA), a primary component of the extracellular matrix, can accumulate in a variety of solid malignancies, where histological analyses of patient tumour tissues demonstrated that HA levels may correlate with patient outcomes. HA accumulation in the TME may be associated with poor prognosis. Preclinical studies demonstrated elevated TME HA levels increased tumour interstitial pressure, reduced tumour blood flow, and resulted in poor penetration of anticancer agents and immune cells. A PEGylated recombinant human hyaluronidase, pegvorhyaluronidase alfa (PEGPH20), depolymerizes HA, increases tumour vascular perfusion, and may increase access and anti-tumour efficacy of cytotoxic and immunotherapies. Material and methods Pegvorhyaluronidase alfa is being evaluated in clinical studies for pancreatic, breast, lung, cholangiocarcinoma, and gastric cancers. To broaden the spectrum of possible tumour types that may benefit from pegvyorhyaluronidase alfa, we assessed the prevalence and accumulation of HA in 3633 human histological samples in 22 solid tumour types. HA levels were measured using tissue microarrays (TMAs) stained with a proprietary HA probe, HTI–601, a recombinant immunoadhesin containing a modified HA–specific link domain from TNF-Stimulated Gene 6 protein (TSG–6) and the Fc portion of human IgG1. The resulting HA probe was biotinylated for use in an affinity-based histochemistry method. HA staining was evaluated with research-grade histological image analysis software. HA levels associated with distinct tumour compartments (stroma or tumour cells) were assessed. HA accumulation associated with immune infiltrates present in the TMA cores was also evaluated. Results and discussions Distribution of HA accumulation across compartments fell into 4 main arrangements: - For desmoplastic tumour indications (pancreatic ductal adenocarcinoma, cholangiocarcinoma), the stroma was associated with high percentage of surface area stained with HTI-601 relative to the tumour cells; - Comparable distribution of HA staining in both tumour cells and stroma (gall bladder and glioblastoma); - Sub-clusters of HA staining within a specific tumour type (NSCLC non-squamous); - Distribution bias towards increased or decreased HA intensity staining (head and neck excluding nasopharyngeal cavities and renal cell carcinoma, respectively). Conclusion Understanding HA prevalence and accumulation in solid tumours may potentially identify malignancies that may benefit from pegvorhyaluronidase alfa therapy targeting HA.

Corrigendum: Genome-wide association study of colorectal cancer identifies six new susceptibility loci

El document inclou una pàgina final amb una correcció (corrigendum). Aquesta, per si sola, té el següent DOI: 10.1038/ncomms9739 i es va publicar al mateix vol. 6., Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P

Proteins exhibit a nonuniform distribution of structures. A number of models have been advanced to explain this observation by considering the distribution of designabilities, that is, the fraction of all sequences that could successfully fold into any particular structure. It has been postulated that more designable structures should be more common, although the exact nature of this relationship has not been addressed. We find that the nonuniform distribution of protein structures found in nature can be explained by the interplay of evolution and population dynamics with the designability distribution. The relative frequency of different structures has a greater-than-linear dependence on designability, making the distribution of observed protein structures more uneven than the distribution of designabilities. The distribution of structures is also affected by additional factors such as the topology of the sequence space and the similarity of other structures.

Arachidonate lipoxygenase (ALOX) enzymes metabolize arachidonic acid to generate potent inflammatory mediators and play an important role in inflammation-associated diseases. We investigated associations between colorectal cancer risk and polymorphisms in ALOX5, FLAP, ALOX12, and ALOX15, and their interactions with non-steroidal anti-inflammatory drug (NSAID) use. We genotyped fifty tagSNPs, one candidate SNP, and two functional promoter variable nucleotide tandem repeat (VNTR) polymorphisms in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). Individuals with variant genotypes of the ALOX5 VNTR had decreased risk of rectal cancer, with the strongest association seen for individuals with one or more alleles of >5 repeats (wildtype=5, OR>5/≥5=0.42, 95% CI 0.20-0.92; p=0.01). Four SNPs in FLAP (rs17239025), ALOX 12 (rs2073438), and ALOX15 (rs4796535 and rs2619112) were associated with rectal cancer risk at p≤0.05. One SNP in FLAP (rs12429692) was associated with adenoma risk. A false discovery rate (FDR) was applied to account for false positives due to multiple testing; the ALOX15 associations were noteworthy at 25% FDR. Colorectal neoplasia risk appeared to be modified by NSAID use in individuals with variant alleles in FLAP and ALOX15. One noteworthy interaction (25% FDR) was observed for rectal cancer. Genetic variability in arachidonate lipoxygenases may affect risk of colorectal neoplasia, particularly for rectal cancer. Additionally, genetic variability in FLAP and ALOX15 may modify the protective effect of NSAID use against colorectal neoplasia.

Background: It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways. Methods: In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for more than 600 tagSNPs and 99 single-nucleotide polymorphisms (SNP) were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls). Results: The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (OR per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the “effective” number of markers in stage II (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency < 0.03) in whites, Japanese Americans, Latinos, and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, body mass index (BMI) levels, regular aspirin use, or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822. Conclusions: Our results provide new evidence of association between PPARG variants and colorectal cancer risk. Impact: Further replication in independent samples is warranted. Cancer Epidemiol Biomarkers Prev; 22(11); 2094–101. ©2013 AACR.

Background: The current study explores T-cell (TC) clonality and molecular factors associated with this metric. Tumors employ multiple mechanisms to evade antitumor immune responses. One process involves TC inhibition via upregulation of immune checkpoint (IC) ligands in the tumor microenvironment (TME). Gradual upregulation of inhibitory receptor at their cellular surface results in a decreased capacity to proliferate and activate cytotoxic pathways against tumor cells presenting antigenic peptides.1 In melanoma, this subset of exhausted TCs has been described as highly clonal, where the majority of PD-1-expressing TC population shares the same TCR sequence specific against the same antigenic fragment.2 Previous studies have demonstrated that a clonal TCR repertoire appears to be associated in part with therapeutic responses during IC blockade.3 Methods: We performed TCR sequencing on 82 blood and 73 archival tumor tissue samples collected from ED SCLC patients (pts) in an ongoing longitudinal cohort study in US community oncology practices. Of these, 82 blood and 48 tissue samples had sufficient material available to quantify a clonality metric. To quantify TC abundance as a fraction of total nucleated cells, 82 blood and 58 tissue samples had sufficient material available. Results: Within the subset of 48 tumor samples, a more clonal (ie, less diverse) TCR repertoire was associated with less necrosis (P≤0.012) and lower levels of inflammatory cell infiltration in the local TME (P≤0.021). When pts were divided into 2 equal groups according to the median clonality level, pts with a less clonal TCR repertoire (n = 24/48) who were treated with non-immune-targeted therapy trended toward a longer overall survival (OS; 446 vs 301 days; P≤0.039). In contrast, the percentage of TCs in the TME did not correlate with improved survival (P≤0.412), necrosis (P≤0.131), and inflammation (P≤0.615). This observation differs from results in melanoma describing the impact of IC blockade where pts responding to therapy were associated with a more clonal TME TC population and increased CD8 TCs in the tumor compartment and at the invasive margin.3 In blood, while a less clonal TCR repertoire was associated with a similar but non-significant trend toward longer survival (P≤0.148), pts with increased TC abundance had longer OS (P≤0.025). No association was observed between clonality in TME and clonality (P≤0.571) or TC abundance (P≤0.965) in blood. Conclusion: We hypothesize that a diverse TCR repertoire in the TME and increased peripheral TC abundance are 2 predictors of longer OS in ED SCLC. To further explore factors that may influence TC responses in ED SCLC, the current TCR sequencing results will be integrated with transcriptome and whole genome sequencing analyses. References 1. Wherry EJ. Nat Immunol. 2011;12:492-99. 2. Gros A, et al. J Clin Invest. 2014;124:2246-59. 3. Tumeh PC, et al. Nature. 2014;515:568-71. Citation Format: Maen Hussein, Sharon Wilks, Marc Monte, Donald A. Richards, Jerome H. Goldschmidt, David Waterhouse, Lisu Wang, Saumya Pant, Erik Yusko, Ryan O. Emerson, Darin M. Taverna, Kaushal Desai, Spyro Mousses, Zhenhao Qi, Jason D. Hipp, Harlan Robins, Kimary Kulig, Cory Batenchuk. Characterization of the T-cell receptor (TCR) repertoire in extensive disease small cell lung cancer (ED SCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4159.

Background & Aims Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. Methods We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. Results Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10 −8 : an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10 −8 ). We also found evidence for 3 additional loci with P values less than 5.0 × 10 −7 : a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10 −8 ), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10 −8 ), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10 −7 ). Conclusions In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

Background— Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts. Methods and Results— The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P =4.7×10 −41 ), 16q23.1 (rs2549513; P =0.0004), 6p24.1 (rs499818; P =0.0002), 2q36.3 (rs2943634; P =6.7×10 −6 ), MTHFD1L (rs6922269, P =5.1×10 −10 ), APOE (rs429358; P =2.7×10 −18 ), ZNF627 (rs4804611; P =5.0×10 −8 ), CXCL12 (rs501120; P =1.4×10 −6 ) and LPL (rs268; P =2.7×10 −17 ). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities. Conclusions— Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

Most globular proteins are marginally stable regardless of size or activity. The most common interpretation is that proteins must be marginally stable in order to function, and so marginal stability represents the results of positive selection. We consider the issue of marginal stability directly using model proteins and the dynamical aspects of protein evolution in populations. We find that the marginal stability of proteins is an inherent property of proteins due to the high dimensionality of the sequence space, without regard to protein function. In this way, marginal stability can result from neutral, non-adaptive evolution. By allowing evolving protein sub-populations with different stability requirements for functionality to complete, we find that marginally stable populations of proteins tend to dominate. Our results show that functionalities consistent with marginal stability have a strong evolutionary advantage, and might arise because of the natural tendency of proteins towards marginal stability.

We model the evolution of duplicated genes by assuming that the gene's protein message, if transcribed and translated, must form a stable, folded structure. We observe the change in protein structure over time in an evolving population of lattice model proteins. We find that selection of stable proteins conserves the original structure if the structure is highly designable, that is, if a large fraction of all foldable sequences form that structure. This effect implies the relative number of pseudogenes can be less than previously predicted with neutral evolution models. The data also suggests a reason for lower than expected ratios of non-synonymous to synonymous substitutions in pseudogenes.

senting 54 different chromosome regions, were suggestively associated with knee OA at a threshold of P < 10 -4 . We then tested these SNPs for association with knee OA in cases and controls from the JoCo Study. Of the 87 SNPs available for replication in JoCo, none were significantly associated with knee OA at a nominal P < 0.01. At our tested levels of significance (i.e., P < 10

Introduction: 5-Lipoxygenase-activating protein (FLAP) binds to arachidonic acid (AA) and activates arachidonate 5-lipoxygenase (ALOX5). ALOX5 is upregulated in colon cancer and is involved in the synthesis of leukotriene A4, which plays an important role in immunity and inflammation. ALOX5 also competes with the prostaglandin H synthases PTGS1 and PTGS2, which convert AA into prostaglandins. NSAIDs reduce the risk of colorectal neoplasia and inhibit PTGS1 and PTGS2. We investigated associations between ALOX5 and FLAP and risk of colorectal neoplasia, as well as potential NSAID interactions in three independent study populations that capture the range of colorectal carcinogenesis by including both adenoma and cancer cases. Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 32 tagSNPs in FLAP, representing common genetic variation in Europeans. ALOX5 lacked resequencing data, and we were only able to look at candidate polymorphisms. We used an identical Illumina platform to investigate FLAP SNPs and 1 ALOX5 candidate SNP in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). VNTR polymorphisms in both genes were also genotyped. Multiple logistic regression analysis was used, adjusting for age, sex, center and restricted to Caucasians (>90% of all study participants). A p value < 0.05 without multiple comparison adjustment was considered statistically significant. Results: The variant ALOX5 allele of rs4986832 G>A showed a significant trend towards decreased risk of rectal cancer (ORhzv=0.65; 95% CI 0.43-0.98; p-trend=0.04). For FLAP, several SNPs showed increased risk of colorectal neoplasia across all three studies, with the strongest associations for: rs12429692 A>T ORhzv=2.05, 95% CI 1.20-3.53 in adenoma (global p=0.01); rs17239025 G>C ORhet/hzv=1.43, 95% CI 1.01-2.04 in rectal cancer (global p=0.05, p-trend=0.04); rs17222919 A>C ORhzv=1.55, 95% CI 1.00-2.42 in rectal cancer (p-trend=0.05). The inverse association with NSAID use was stronger among those with the wildtype genotype for rs9551960 A>G (rectal cancer p-interaction=0.05) and rs17239025 G>C (colon cancer p-int=0.02), whereas those with variant genotypes had greater NSAID risk reduction of rectal cancer for rs9315053 A>C (p-int=0.03), rs9508832 G>A (p-int=0.02), and rs9506352 G>A (p-int=0.04). Conclusion: We show evidence that genetic variability in ALOX5 and FLAP may affect risk of colorectal neoplasia. These results suggest that, in ALOX5, rs4986832 is associated with a decreased risk of rectal cancer, whereas FLAP SNPs rs12429692, rs17239025 and rs17222919 increase colorectal neoplasia risk. Additionally, we provide evidence that genetic variability in FLAP may modify the protective association of NSAID use against colorectal neoplasia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3761. doi:10.1158/1538-7445.AM2011-3761

Introduction: Arachidonate lipoxygenase (ALOX) enzymes generate potent inflammatory mediators via the metabolism of arachidonic acid. Genetic polymorphisms in the lipoxygenase gene family have been implicated in cancer and inflammatory diseases such as asthma, bone loss, and atherosclerosis. NSAIDs, which reduce colorectal cancer risk, induce apoptosis in colon cancer cells via upregulation of ALOX15. We hypothesize that polymorphisms in lipoxygenases ALOX12 and ALOX15 may influence colorectal neoplasia risk and protective NSAIDs effects. Methods: A linkage-disequilibrium (LD)-based tagSNP-selection algorithm (r2=0.90, MAF=4%) identified tagSNPs in ALOX12 and ALOX15 representing common genetic variation in Europeans. We genotyped 17 SNPs in ALOX12 and 21 SNPs in ALOX15 in three independent study populations that capture the range of colorectal carcinogenesis by including adenoma, colon, and rectal cancer cases. We investigated these SNPs in relation to colorectal neoplasia risk and potential interactions with NSAID use in three US population-based case-control studies of colon cancer (n=1424/1780 cases/controls), rectal cancer (n=583/775), and colorectal adenoma (n=485/578). Multiple logistic regression analysis was used, adjusting for age, sex, and study site, and restricted to Caucasians (>90% of all study participants). A p value < 0.05 without multiple comparison adjustment was considered statistically significant. Results: In ALOX12, rs11571364 was associated with a modestly increased risk of colon cancer among variant allele carriers (OR: 1.23, 95% CI: 1.01-1.51). A risk increase was also seen in rectal cancer, but was not statistically significant (OR: 1.26, 95% CI: 0.92-1.71). The homozygous variant genotype of another SNP in ALOX12 showed a possible reduced risk of rectal cancer (rs2073438, OR: 0.66, 95% CI: 0.42-1.04), but not colon cancer or adenomas. No significant interactions between SNPs in ALOX12 and NSAID use were observed in any of the three studies. In ALOX15, rs2619112 showed a suggested increase in rectal cancer risk. However, the risk was more elevated among those with a heterozygous genotype (OR: 1.37; 95% CI: 1.06-1.77) than among those with a homozygous variant genotype (OR: 1.13, 95% CI: 0.83-1.55). We detected a significant interaction between this SNP and NSAID use. Among NSAID non-users, the homozygous genotype was associated with increased rectal cancer risk (OR: 1.24). Among NSAID users, the homozygous wildtype and homozygous variant genotypes were associated with decreased risk, but there was no association among heterozygous NSAID users (p-interaction=0.04). Conclusion: Polymorphisms in ALOX12 and ALOX15 are associated with risk of rectal and colon cancer, but not colorectal adenomas. An ALOX15 SNP previously associated with bone mineral density levels and coronary artery disease risk was associated with rectal cancer risk and showed possible interaction with NSAID use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3756. doi:10.1158/1538-7445.AM2011-3756

Introduction: Glutathione peroxidases (GPXs) are selenium-dependent enzymes that scavenge hydroperoxides linked to oxidative stress, prostaglandin synthesis, inflammation and proliferation. Because these processes are important in carcinogenesis, we hypothesized that genetic variability in the GPXs may influence colorectal neoplasia risk. We investigated candidate polymorphisms and tagSNPs in GPX1-4 in relation to colorectal neoplasia in three independent study populations capturing the range of colorectal carcinogenesis. Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 24 tagSNPs, including the candidates (GPX1 P200L and GPX4 2573 C>T), representing common genetic variation in Europeans. We used an identical Illumina platform to investigate GPX SNPs in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). For gene-level associations, we conducted principal components analysis (PCA). Multiple logistic regression was used for single SNPs, adjusting for age, sex, and study center, restricted to Caucasians (>90% of all study populations). Results: In PCA, GPX3 was significant for rectal cancer at p=0.03. Without correction for multiple testing, five polymorphisms in GPX2 and GPX3 were associated with significant differences in rectal cancer risk at α=0.05 (see Table). GPX3 rs8177406 also reduced risk in rectal polyps. The candidate GPX1 P200L showed a marginally increased risk for LP/LL vs. PP (1.22, 0.98-1.52, p=0.06). No other SNPs in GPX1-4 showed significant associations for rectal cancer or adenomas. No associations were observed for colon cancer. Conclusion: These data provide evidence that genetic variability in GPX2 and GPX3 contributes to risk of rectal cancer but not of colon cancer and thus provide additional support for unique etiological mechanisms for colon and rectal cancer.Table.Selected tagSNPs in GPX1, GPX2 and GPX3 and risk of rectal cancer, adjusted for age, sex, and study center*SNPGenotypeCasesControlsOR95%CIp (2df)p-trendGPX1rs105045**CC252367 2834 C>T, P200LCT or TT3013601.220.981.520.06NAGPX2rs2277502**GG4595741.00.. 2834 G>AGA or AA1141890.770.600.990.04NA rs4902347**GG4565741.00.. 1756 G>AGA or AA1141880.780.601.000.05NAGPX3rs3828599CC3404091.00.. 1580 C->TCT2142980.850.681.07 TT29660.520.330.830.010.01 rs736775CC2372821.00 9133 C->TCT2753540.910.721.15 TT701380.590.420.830.010.01 rs8177447CC4135001.00 7241 C->TCT1552350.790.621.01 TT14350.480.260.910.020.01* r2 < 0.70, except rs2277502 and rs4902347 (r2 > 0.90)** Dominant model is shown because there were 10 or fewer subjects with the homozygous variant model Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 933.

Introduction: Pancreatic phospholipase A2 (also known as PLA2G1B or PLA2A) catalyzes the release of fatty acids from dietary phospholipids for adsorption in the small intestine. Some of the polyunsaturated fatty acids removed from the intestinal lumen are precursors to eicosanoids, which are linked to inflammation, cell proliferation and colorectal carcinogenesis. We suspect that genetic variation at the PLA2A locus might affect colorectal neoplasia and thus we evaluated the association of PLA2A tagSNPs with colorectal neoplasia risk in three independent study populations capturing the range of colorectal carcinogenesis. Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 3 tagSNPs in PLA2A. We genotyped these SNPs on the same Illumina platform in 3 US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). LD was calculated among Caucasian controls for each study. For gene-level associations, we conducted principal components analysis (PCA) and haplotype analysis. Multiple logistic regression was used for single SNPs, adjusting for age, sex, and study center, restricted to Caucasians (>90% of all study populations). Results: Two PLA2A variants were statistically significantly associated with reduced risk of rectal cancer (rs5637, 3702G>A Ser98Ser, p-trend = 0.03 and rs9657930, 1593C>T p-trend = 0.01, see table). Linkage disequilibrium between the SNPs was modest (r2 Conclusion: The results suggest that genetic variability in PLA2A affects susceptibility to rectal but not colon cancer. Additional observational and functional follow-up studies are needed.Table.Selected tagSNPs in PLA2A and risk of rectal cancer, adjusted for age, sex, and study centerSNPGenotypeCasesControlsOR95%CIp (2df)p-trendrs56373702 G>AGG4285361.00.. Ser98SerGA1472150.850.661.08 AA8230.430.190.980.060.03 rs9657930CC4886141.00.. 1593 C>TCT891480.750.561.00 TT3100.390.111.430.050.01 rs2070873GG4365741.00.. 3027 G>TGT1391811.000.781.29 TT6190.420.171.060.150.36Principal component analysis p= 0.02 Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 934.

First results from genome-wide association studies (GWAS) have demonstrated considerable success in identifying genetic variants associated with colorectal cancer (CRC). To date, 10 CRC susceptibility loci have been identified. However, these marginal single nucleotide polymorphism (SNP) associations explain only ∼6% of the heritable variation underlying CRC risk. We employed a pathway-based approach using our recently developed Gene-set Ridge Regression in Association Studies (GRASS) method to assess whether sets of functionally related genes are enriched for SNPs associated with colon cancer risk. We used GWAS data from three studies: The Women's Health Initiative (WHI; 483 cases and 530 controls); the Prostate, Lung, Colon and Ovarian Cancer Screening Trial (PLCO; 546 cases and 1177 controls); and the Diet, Activity and Lifestyle population-based case-control study (DALS; 698 cases and 719 controls). Samples were genotyped on Illumina HumanHap 300K + 240K, 550K or 610K platforms. After applying stringent quality control criteria, our final analysis included 392,361 SNPs. We used genomic partition to assign SNPs to nearby genes and defined pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We restricted our analysis to 170 pathways with 10 or more genes (range 10-253 genes). Our GRASS method uses eigenSNPs derived from principal components analysis within each gene. Regularized regression is performed for each pathway, using a novel group ridge penalty function. The penalty function results in selection of the most representative eigenSNPs within genes while assessing the association of all the genes, within a pathway, with disease risk. Permutations are used to standardize the test statistics and obtain p-values. The false discovery rate (FDR) was calculated using the Benjamini-Hochberg method. We analyzed WHI, PLCO and DALS separately, adjusting for age, sex, and genetic ancestry derived from principal components analysis, and performed a meta-analysis to combine the results. Five pathways were significant at a p-value cutoff of 0.05. The top pathway, the transforming growth factor beta (TGF-beta) signaling pathway (p-value=0.009), also met a FDR cutoff of 20%. This pathway remained significant (p=0.014) after excluding the known CRC susceptibility loci and all SNPs with linkage disequilibrium r2>0.2 with those 10 loci. The top genes in the pathway were TFGB1, SMAD4, FST, TFGB2, INHBA, PITX2, BMPR2 and PP2R2B (all p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4733.

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce risk of colorectal adenomas and cancer. NSAIDs, including aspirin, target the prostaglandin H synthases, COX-1 and COX-2, which convert arachidonic acid into prostaglandins. We examined tagSNPs and candidate polymorphisms in COX-1 and COX-2 in relation to colorectal neoplasia risk and potential interactions with NSAID use. Methods: A linkage-disequilibrium (LD)-based tagSNP-selection algorithm (r2=0.90, MAF=4%) identified tagSNPs in PTGS1 (COX-1) and PTGS2 (COX-2) representative of common genetic variation in Europeans. Including candidate polymorphisms, we genotyped 18 SNPs in PTGS1 and 17 SNPs in PTGS2. SNPs were genotyped on the same Illumina platform in three independent study populations that capture the range of colorectal carcinogenesis by including adenoma and cancer cases. We investigated these SNPs in relation to the risk of colorectal neoplasia and potential interactions with NSAID use in three US population-based case-control studies of colon cancer (n=1424) vs. controls (n=1780), rectal cancer (n=583) vs. controls (n=775), and colorectal adenoma (n=485) vs. controls (n=578). For single SNP associations, multiple logistic regression analysis was used, adjusting for age, sex, center and restricted to Caucasians (>90% of all study populations). No correction was made for multiple testing. Results: There were no main associations with PTGS1 tagSNPs or candidate polymorphisms (R8W, P17L and L237M) and colorectal neoplasia risk. Although not statistically significant, the L15-L16 deletion allele showed a trend towards increased risk for both colon and rectal cancer, consistent with the previously reported increased adenoma risk. In PTGS2, a rare 5′ tagSNP (rs4648250, −1877A>G, MAF=1%) was associated with a marginally decreased risk of both rectal (OR: 0.24, 95% CI: 0.05-1.08) and colon cancer (OR: 0.63, 95% CI: 0.36-1.10). NSAID use is known to reduce the risk of colorectal neoplasia and all three studies have shown the same protective effect in previous analyses. Interactions between genotypes and NSAID use essentially fell into one of two general categories: a) Individuals with the variant allele lost the protective effect of NSAID use (PTGS1 rs10306110-G, rectal p-interaction=0.02, adenoma p-int=0.08; PTGS2 [rs689466][1]-G, rectal p-int=0.03, colon p-int=0.18; rs20424-G, colon p-int=0.05; [rs689469][2]-A, colon p-int=0.03, rectal p-int=0.09).); and b) Individuals with the variant allele showed stronger protection with by NSAIDs than individuals with the wildtype genotype (PTGS1 rs6478565-G, rs10306135-T, rs10306164-G, rectal p-int=0.01-0.02). Conclusion: These data suggest that a rare 5′ SNP in PTGS2 may predict risk of colorectal cancer and provide further evidence that genetic variability in PTGS1 and PTGS2 may modify the protective association between NSAID and colorectal neoplasia risk, especially for rectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5710. [1]: /lookup/external-ref?link_type=GEN&access_num=rs689466&atom=%2Fcanres%2F70%2F8_Supplement%2F5710.atom [2]: /lookup/external-ref?link_type=GEN&access_num=rs689469&atom=%2Fcanres%2F70%2F8_Supplement%2F5710.atom

Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8×10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p&nbsp