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• W2026349620 abstract "Tissue hypoxia commonly occurs in tumors. Hypoxia-inducible factor (HIF)-1 and HIF-2, which are essential mediators of cellular response to hypoxia, regulate gene expression for tumor angiogenesis, glucose metabolism, and resistance to oxidative stress. Their key regulatory subunits, HIF1A (HIF-1α) and endothelial PAS domain protein 1 (EPAS1; HIF-2α), are overexpressed and associated with patient prognosis in a variety of cancers. However, prognostic or molecular features of colon cancer with HIF expression remain uncertain. Among 731 colorectal cancers in two prospective cohort studies, 142 (19%) tumors showed HIF1A overexpression, and 322 (46%) showed EPAS1 overexpression by immunohistochemistry. HIF1A overexpression was significantly associated with higher colorectal cancer-specific mortality in Kaplan-Meier analysis (log-rank test, P < 0.0001), univariate Cox regression (hazard ratio = 1.84; 95% confidence interval, 1.37 to 2.47; P < 0.0001) and multivariate analysis (adjusted hazard ratio = 1.72; 95% confidence interval, 1.26 to 2.36; P = 0.0007) that adjusted for clinical and tumoral features, including microsatellite instability, TP53 (p53), PTGS2 (cyclooxygenase-2), CpG island methylator phenotype, and KRAS, BRAF, PIK3CA, and LINE-1 methylation. In contrast, EPAS1 expression was not significantly associated with patient survival. In addition, HIF1A expression was independently associated with PTGS2 expression (P = 0.0035), CpG island methylator phenotype-high (P = 0.013), and LINE-1 hypomethylation (P = 0.017). EPAS1 expression was inversely associated with high tumor grade (P = 0.0017) and obesity (body mass index ≥ 30 kg/m2) (P = 0.039). In conclusion, HIF1A expression is independently associated with poor prognosis in colorectal cancer, suggesting HIF1A as a biomarker with potentially important therapeutic implications. Tissue hypoxia commonly occurs in tumors. Hypoxia-inducible factor (HIF)-1 and HIF-2, which are essential mediators of cellular response to hypoxia, regulate gene expression for tumor angiogenesis, glucose metabolism, and resistance to oxidative stress. Their key regulatory subunits, HIF1A (HIF-1α) and endothelial PAS domain protein 1 (EPAS1; HIF-2α), are overexpressed and associated with patient prognosis in a variety of cancers. However, prognostic or molecular features of colon cancer with HIF expression remain uncertain. Among 731 colorectal cancers in two prospective cohort studies, 142 (19%) tumors showed HIF1A overexpression, and 322 (46%) showed EPAS1 overexpression by immunohistochemistry. HIF1A overexpression was significantly associated with higher colorectal cancer-specific mortality in Kaplan-Meier analysis (log-rank test, P < 0.0001), univariate Cox regression (hazard ratio = 1.84; 95% confidence interval, 1.37 to 2.47; P < 0.0001) and multivariate analysis (adjusted hazard ratio = 1.72; 95% confidence interval, 1.26 to 2.36; P = 0.0007) that adjusted for clinical and tumoral features, including microsatellite instability, TP53 (p53), PTGS2 (cyclooxygenase-2), CpG island methylator phenotype, and KRAS, BRAF, PIK3CA, and LINE-1 methylation. In contrast, EPAS1 expression was not significantly associated with patient survival. In addition, HIF1A expression was independently associated with PTGS2 expression (P = 0.0035), CpG island methylator phenotype-high (P = 0.013), and LINE-1 hypomethylation (P = 0.017). EPAS1 expression was inversely associated with high tumor grade (P = 0.0017) and obesity (body mass index ≥ 30 kg/m2) (P = 0.039). In conclusion, HIF1A expression is independently associated with poor prognosis in colorectal cancer, suggesting HIF1A as a biomarker with potentially important therapeutic implications. Tissue hypoxia commonly occurs in tumor, and adaptation to tissue hypoxia appears to be one of important characteristics of malignant cells.1Bertout JA Patel SA Simon MC The impact of O2 availability on human cancer.Nat Rev Cancer. 2008; 8: 967-975Crossref PubMed Scopus (1046) Google Scholar, 2Wouters BG Koritzinsky M Hypoxia signalling through mTOR and the unfolded protein response in cancer.Nat Rev Cancer. 2008; 8: 851-864Crossref PubMed Scopus (699) Google Scholar Hypoxia-inducible factor (HIF)-1 and HIF-2 play a key role in cellular adaptation to hypoxia and regulate the expression of genes responsible for glucose metabolism, angiogenesis, and cell survival.1Bertout JA Patel SA Simon MC The impact of O2 availability on human cancer.Nat Rev Cancer. 2008; 8: 967-975Crossref PubMed Scopus (1046) Google Scholar, 2Wouters BG Koritzinsky M Hypoxia signalling through mTOR and the unfolded protein response in cancer.Nat Rev Cancer. 2008; 8: 851-864Crossref PubMed Scopus (699) Google Scholar, 3Erler JT Bennewith KL Nicolau M Dornhofer N Kong C Le QT Chi JT Jeffrey SS Giaccia AJ Lysyl oxidase is essential for hypoxia-induced metastasis.Nature. 2006; 440: 1222-1226Crossref PubMed Scopus (1147) Google Scholar Thus, HIF and related pathways are potential therapeutic targets.4Narita T Yin S Gelin CF Moreno CS Yepes M Nicolaou KC Van Meir EG Identification of a novel small molecule HIF-1α translation inhibitor.Clin Cancer Res. 2009; 15: 6128-6136Crossref PubMed Scopus (94) Google Scholar, 5Koh MY Spivak-Kroizman TR Powis G Inhibiting the hypoxia response for cancer therapy: the new kid on the block.Clin Cancer Res. 2009; 15: 5945-5946Crossref PubMed Scopus (23) Google Scholar Cellular HIF levels are regulated not only by the oxygen-dependent pathway (eg, VHL and prolyl hydroxylase, EGLN) but also by the oxygen-independent pathway (eg, glycogen synthase kinase 3, the phosphatidylinositol 3-kinase pathway, the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway).6Kaelin Jr, WG The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer.Nat Rev Cancer. 2008; 8: 865-873Crossref PubMed Scopus (539) Google Scholar, 7Yee Koh M Spivak-Kroizman TR Powis G HIF-1 regulation: not so easy come, easy go.Trends Biochem Sci. 2008; 33: 526-534Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar HIF and hypoxia signaling influence a wide variety of pathways including those related to vascular endothelial growth factor (VEGF), cyclins, and MTOR.1Bertout JA Patel SA Simon MC The impact of O2 availability on human cancer.Nat Rev Cancer. 2008; 8: 967-975Crossref PubMed Scopus (1046) Google Scholar, 2Wouters BG Koritzinsky M Hypoxia signalling through mTOR and the unfolded protein response in cancer.Nat Rev Cancer. 2008; 8: 851-864Crossref PubMed Scopus (699) Google Scholar Thus, cellular HIF levels may modify responsiveness to drugs targeting those pathways or hypoxia signaling, and it is of particular interest to examine HIF expression in human cancers. Key regulatory subunits of HIF, HIF1A (the official symbol for HIF-1α), and endothelial PAS domain protein 1 (EPAS1; the official symbol for HIF-2α) are differentially overexpressed8Zhong H De Marzo AM Laughner E Lim M Hilton DA Zagzag D Buechler P Isaacs WB Semenza GL Simons JW Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases.Cancer Res. 1999; 59: 5830-5835PubMed Google Scholar, 9Talks KL Turley H Gatter KC Maxwell PH Pugh CW Ratcliffe PJ Harris AL The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages.Am J Pathol. 2000; 157: 411-421Abstract Full Text Full Text PDF PubMed Scopus (1100) Google Scholar and have distinct functions in human cancers.9Talks KL Turley H Gatter KC Maxwell PH Pugh CW Ratcliffe PJ Harris AL The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages.Am J Pathol. 2000; 157: 411-421Abstract Full Text Full Text PDF PubMed Scopus (1100) Google Scholar, 10Wang V Davis DA Haque M Huang LE Yarchoan R Differential gene up-regulation by hypoxia-inducible factor-1α and hypoxia-inducible factor-2α in HEK293T cells.Cancer Res. 2005; 65: 3299-3306Crossref PubMed Scopus (67) Google Scholar, 11Aprelikova O Wood M Tackett S Chandramouli GV Barrett JC Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection.Cancer Res. 2006; 66: 5641-5647Crossref PubMed Scopus (126) Google Scholar HIF1A expression leads to increased tumor growth and metastasis in some studies,12Krishnamachary B Berg-Dixon S Kelly B Agani F Feldser D Ferreira G Iyer N LaRusch J Pak B Taghavi P Semenza GL Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1.Cancer Res. 2003; 63: 1138-1143PubMed Google Scholar, 13Kaidi A Qualtrough D Williams AC Paraskeva C Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia.Cancer Res. 2006; 66: 6683-6691Crossref PubMed Scopus (254) Google Scholar, 14Dang DT Chen F Gardner LB Cummins JM Rago C Bunz F Kantsevoy SV Dang LH Hypoxia-inducible factor-1α promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts.Cancer Res. 2006; 66: 1684-1693Crossref PubMed Scopus (104) Google Scholar, 15Ryan HE Poloni M McNulty W Elson D Gassmann M Arbeit JM Johnson RS Hypoxia-inducible factor-1α is a positive factor in solid tumor growth.Cancer Res. 2000; 60: 4010-4015PubMed Google Scholar whereas HIF1A inhibits tumor growth by cell cycle arrest or apoptosis induction in other studies.16Carmeliet P Dor Y Herbert JM Fukumura D Brusselmans K Dewerchin M Neeman M Bono F Abramovitch R Maxwell P Koch CJ Ratcliffe P Moons L Jain RK Collen D Keshert E Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis.Nature. 1998; 394: 485-490Crossref PubMed Scopus (2215) Google Scholar, 17Scortegagna M Martin RJ Kladney RD Neumann RG Arbeit JM Hypoxia-inducible factor-1α suppresses squamous carcinogenic progression and epithelial-mesenchymal transition.Cancer Res. 2009; 69: 2638-2646Crossref PubMed Scopus (57) Google Scholar, 18Sowter HM Ratcliffe PJ Watson P Greenberg AH Harris AL HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors.Cancer Res. 2001; 61: 6669-6673PubMed Google Scholar, 19Goda N Ryan HE Khadivi B McNulty W Rickert RC Johnson RS Hypoxia-inducible factor 1α is essential for cell cycle arrest during hypoxia.Mol Cell Biol. 2003; 23: 359-369Crossref PubMed Scopus (435) Google Scholar Similar paradoxical effects of EPAS1 have also been reported; EPAS1 appears to promote cancer development and progression in neuroblastoma and renal carcinoma,20Holmquist-Mengelbier L Fredlund E Lofstedt T Noguera R Navarro S Nilsson H Pietras A Vallon-Christersson J Borg A Gradin K Poellinger L Pahlman S Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: hIF-2α promotes an aggressive phenotype.Cancer Cell. 2006; 10: 413-423Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar, 21Kondo K Kim WY Lechpammer M Kaelin Jr, WG Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth.PLoS Biol. 2003; 1: E83Crossref PubMed Scopus (21) Google Scholar, 22Raval RR Lau KW Tran MG Sowter HM Mandriota SJ Li JL Pugh CW Maxwell PH Harris AL Ratcliffe PJ Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.Mol Cell Biol. 2005; 25: 5675-5686Crossref PubMed Scopus (757) Google Scholar whereas it appears to inhibit tumor growth in other cancers including colon cancer.23Imamura T Kikuchi H Herraiz MT Park DY Mizukami Y Mino-Kenduson M Lynch MP Rueda BR Benita Y Xavier RJ Chung DC HIF-1α and HIF-2α have divergent roles in colon cancer.Int J Cancer. 2009; 124: 763-771Crossref PubMed Scopus (132) Google Scholar, 24Acker T Diez-Juan A Aragones J Tjwa M Brusselmans K Moons L Fukumura D Moreno-Murciano MP Herbert JM Burger A Riedel J Elvert G Flamme I Maxwell PH Collen D Dewerchin M Jain RK Plate KH Carmeliet P Genetic evidence for a tumor suppressor role of HIF-2α.Cancer Cell. 2005; 8: 131-141Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 25Favier J Lapointe S Maliba R Sirois MG HIF2α reduces growth rate but promotes angiogenesis in a mouse model of neuroblastoma.BMC Cancer. 2007; 7: 139Crossref PubMed Scopus (28) Google Scholar Previous data on HIF1A, EPAS1, and clinical outcome in colorectal cancer have been inconclusive. A study of 90 rectal cancer patients showed poor prognosis associated with HIF1A but not with EPAS1.26Rasheed S Harris AL Tekkis PP Turley H Silver A McDonald PJ Talbot IC Glynne-Jones R Northover JM Guenther T Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis.Br J Cancer. 2009; 100: 1666-1673Crossref PubMed Scopus (66) Google Scholar In contrast, another study of 87 colorectal cancer patients reported poor prognosis associated with EPAS1 but not with HIF1A.27Yoshimura H Dhar DK Kohno H Kubota H Fujii T Ueda S Kinugasa S Tachibana M Nagasue N Prognostic impact of hypoxia-inducible factors 1α and 2α in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression.Clin Cancer Res. 2004; 10: 8554-8560Crossref PubMed Scopus (156) Google Scholar Among studies assessing only HIF1A, some reported its independent prognostic effect28Schmitz KJ Muller CI Reis H Alakus H Winde G Baba HA Wohlschlaeger J Jasani B Fandrey J Schmid KW Combined analysis of hypoxia-inducible factor 1α and metallothionein indicates an aggressive subtype of colorectal carcinoma.Int J Colorectal Dis. 2009; 24: 1287-1296Crossref PubMed Scopus (22) Google Scholar, 29Rajaganeshan R Prasad R Guillou PJ Scott N Poston G Jayne DG Expression patterns of hypoxic markers at the invasive margin of colorectal cancers and liver metastases.Eur J Surg Oncol. 2009; 35: 1286-1294Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar whereas others did not.30Kuwai T Kitadai Y Tanaka S Onogawa S Matsutani N Kaio E Ito M Chayama K Expression of hypoxia-inducible factor-1α is associated with tumor vascularization in human colorectal carcinoma.Int J Cancer. 2003; 105: 176-181Crossref PubMed Scopus (154) Google Scholar, 31Furlan D Sahnane N Carnevali I Cerutti R Bertoni F Kwee I Uccella S Bertolini V Chiaravalli AM Capella C Up-regulation of the hypoxia-inducible factor-1 transcriptional pathway in colorectal carcinomas.Hum Pathol. 2008; 39: 1483-1494Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar However, all previous studies26Rasheed S Harris AL Tekkis PP Turley H Silver A McDonald PJ Talbot IC Glynne-Jones R Northover JM Guenther T Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis.Br J Cancer. 2009; 100: 1666-1673Crossref PubMed Scopus (66) Google Scholar, 27Yoshimura H Dhar DK Kohno H Kubota H Fujii T Ueda S Kinugasa S Tachibana M Nagasue N Prognostic impact of hypoxia-inducible factors 1α and 2α in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression.Clin Cancer Res. 2004; 10: 8554-8560Crossref PubMed Scopus (156) Google Scholar, 28Schmitz KJ Muller CI Reis H Alakus H Winde G Baba HA Wohlschlaeger J Jasani B Fandrey J Schmid KW Combined analysis of hypoxia-inducible factor 1α and metallothionein indicates an aggressive subtype of colorectal carcinoma.Int J Colorectal Dis. 2009; 24: 1287-1296Crossref PubMed Scopus (22) Google Scholar, 29Rajaganeshan R Prasad R Guillou PJ Scott N Poston G Jayne DG Expression patterns of hypoxic markers at the invasive margin of colorectal cancers and liver metastases.Eur J Surg Oncol. 2009; 35: 1286-1294Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 30Kuwai T Kitadai Y Tanaka S Onogawa S Matsutani N Kaio E Ito M Chayama K Expression of hypoxia-inducible factor-1α is associated with tumor vascularization in human colorectal carcinoma.Int J Cancer. 2003; 105: 176-181Crossref PubMed Scopus (154) Google Scholar, 31Furlan D Sahnane N Carnevali I Cerutti R Bertoni F Kwee I Uccella S Bertolini V Chiaravalli AM Capella C Up-regulation of the hypoxia-inducible factor-1 transcriptional pathway in colorectal carcinomas.Hum Pathol. 2008; 39: 1483-1494Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar were limited by small sample sizes (N <136). Considering the increasing importance of the HIF pathway as a potential target for cancer treatment,1Bertout JA Patel SA Simon MC The impact of O2 availability on human cancer.Nat Rev Cancer. 2008; 8: 967-975Crossref PubMed Scopus (1046) Google Scholar, 2Wouters BG Koritzinsky M Hypoxia signalling through mTOR and the unfolded protein response in cancer.Nat Rev Cancer. 2008; 8: 851-864Crossref PubMed Scopus (699) Google Scholar, 6Kaelin Jr, WG The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer.Nat Rev Cancer. 2008; 8: 865-873Crossref PubMed Scopus (539) Google Scholar the assessment of HIF1A and EPAS1 expression and clinical outcome using a large number of colorectal cancers is needed. We therefore examined prognostic effects of HIF1A and EPAS1 expression among 731 colorectal cancer patients identified in two prospective cohort studies. Moreover, because we concurrently assessed other important molecular events including mutations in KRAS, BRAF, and PIK3CA, LINE-1 hypomethylation, microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP), we could evaluate the effect of HIF1A or EPAS1 expression after controlling for these potential confounders. We used the databases of two independent, prospective cohort studies: the Nurses' Health Study (N = 121,701 women followed since 1976)32Chan AT Ogino S Fuchs CS Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.N Engl J Med. 2007; 356: 2131-2142Crossref PubMed Scopus (621) Google Scholar and the Health Professionals Follow-Up Study (N = 51,529 men followed since 1986).32Chan AT Ogino S Fuchs CS Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.N Engl J Med. 2007; 356: 2131-2142Crossref PubMed Scopus (621) Google Scholar We collected paraffin-embedded tissue blocks from hospitals where patients with incident colorectal cancers underwent tumor resections.32Chan AT Ogino S Fuchs CS Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.N Engl J Med. 2007; 356: 2131-2142Crossref PubMed Scopus (621) Google Scholar We excluded cases preoperatively treated with radiation and/or chemotherapy. On the basis of availability of adequate tissue specimens and follow-up data, a total of 731 colorectal cancers (diagnosed up to 2004) were included (Table 1). Patients were observed until death or June 2008, whichever came first. Among our cohort studies, there was no significant difference in demographic features between cases with tissue available and those without available tissue.32Chan AT Ogino S Fuchs CS Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.N Engl J Med. 2007; 356: 2131-2142Crossref PubMed Scopus (621) Google Scholar Tissue sections from all cases were reviewed by a pathologist (S.O.) unaware of other data. The tumor grade was categorized as low versus high (≥50 versus <50% gland formation). This current analysis represents a new analysis of HIF1A and EPAS1 on the existing colorectal cancer database that has been previously characterized for CIMP, MSI, LINE-1 methylation, and clinical outcome,32Chan AT Ogino S Fuchs CS Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.N Engl J Med. 2007; 356: 2131-2142Crossref PubMed Scopus (621) Google Scholar, 33Ogino S Nosho K Kirkner GJ Kawasaki T Meyerhardt JA Loda M Giovannucci EL Fuchs CS CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer.Gut. 2009; 58: 90-96Crossref PubMed Scopus (635) Google Scholar, 34Ogino S Nosho K Kirkner GJ Kawasaki T Chan AT Schernhammer ES Giovannucci EL Fuchs CS A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer.J Natl Cancer Inst. 2008; 100: 1734-1738Crossref PubMed Scopus (303) Google Scholar, 35Ogino S Kawasaki T Kirkner GJ Kraft P Loda M Fuchs CS Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample.J Mol Diagn. 2007; 9: 305-314Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar which is analogous to novel studies using the well-described cell lines or animal models. We have not examined HIF1A or EPAS1 expression in any of our previous studies. Written informed consent was obtained from all study subjects. Tissue collection and analyses were approved by the Harvard School of Public Health and Brigham and Women's Hospital Institutional Review Boards.Table 1Clinical and Pathologic Features according to HIF1A Expression or EPAS1 (HIF-2α) Expression StatusHIF1A expressionEPAS1 expressionClinical or pathologic featureTotal (N)(−)(+)P value(−)(+)P valueAll cases731589142373322Sex0.0580.0043 Male (HPFS)261220 (37%)41 (29%)112 (30%)130 (40%) Female (NHS)470369 (63%)101 (71%)261 (70%)192 (60%)Age (yr) ≤59148116 (20%)32 (23%)0.7480 (21%)56 (17%)0.40 60–69307250 (42%)57 (40%)152 (41%)139 (43%) ≥70276223 (38%)53 (37%)141 (38%)127 (40%)BMI0.900.021 <30 kg/m2604487 (83%)117 (82%)297 (80%)277 (86%) ≥30 kg/m2126101 (17%)25 (18%)76 (20%)44 (14%)Family history of colorectal cancer0.400.48 (−)560455 (77%)105 (74%)290 (78%)243 (75%) (+)171134 (23%)37 (26%)83 (22%)79 (25%)Tumor location0.800.21 Proximal colon (cecum to transverse)361294 (51%)67 (48%)184 (50%)159 (50%) Distal colon (splenic flexure to sigmoid)214172 (30%)42 (30%)100 (27%)100 (32%) Rectum142112 (19%)30 (22%)83 (23%)56 (18%)Stage0.0690.28 I160140 (24%)20 (14%)74 (20%)82 (26%) II222180 (31%)42 (30%)110 (29%)101 (31%) III200157 (27%)43 (30%)110 (29%)77 (24%) IV10877 (13%)31 (22%)58 (16%)44 (14%) Unknown4135 (5.9%)6 (4.2%)21 (5.6%)18 (5.6%)Tumor grade0.360.0016 Low660535 (91%)125 (89%)325 (88%)305 (95%) High6852 (8.9%)16 (11%)45 (12%)17 (5.3%)Mucinous component0.260.11 0%373297 (57%)76 (62%)196 (60%)157 (54%) >0%272226 (43%)46 (38%)128 (40%)133 (46%)Signet ring cell component0.240.16 0%549443 (89%)106 (93%)272 (88%)250 (92%) >0%6153 (11%)8 (7.0%)37 (12%)23 (8.4%)Percentage indicates the proportion of tumors with a specific clinical or pathologic feature in all patients or patients with a specific category of HIF1A or EPAS1 expression status. HPFS, Health Professionals Follow-Up Study; NHS, Nurses' Health Study. Open table in a new tab Percentage indicates the proportion of tumors with a specific clinical or pathologic feature in all patients or patients with a specific category of HIF1A or EPAS1 expression status. HPFS, Health Professionals Follow-Up Study; NHS, Nurses' Health Study. Genomic DNA was extracted from tumor and PCR and Pyrosequencing targeted for KRAS (codons 12 and 13),36Ogino S Kawasaki T Brahmandam M Yan L Cantor M Namgyal C Mino-Kenudson M Lauwers GY Loda M Fuchs CS Sensitive sequencing method for KRAS mutation detection by Pyrosequencing.J Mol Diagn. 2005; 7: 413-421Abstract Full Text Full Text PDF PubMed Scopus (446) Google ScholarBRAF (codon 600),37Ogino S Kawasaki T Kirkner GJ Loda M Fuchs CS CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations.J Mol Diagn. 2006; 8: 582-588Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar and PIK3CA (exons 9 and 20)38Nosho K Kawasaki T Ohnishi M Suemoto Y Kirkner GJ Zepf D Yan L Longtine JA Fuchs CS Ogino S PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations.Neoplasia. 2008; 10: 534-541Abstract Full Text PDF PubMed Scopus (205) Google Scholar were performed. MSI status was determined using D2S123, D5S346, D17S250, BAT25, BAT26, BAT40, D18S55, D18S56, D18S67, and D18S487.39Ogino S Brahmandam M Cantor M Namgyal C Kawasaki T Kirkner G Meyerhardt JA Loda M Fuchs CS Distinct molecular features of colorectal carcinoma with signet ring cell component and colorectal carcinoma with mucinous component.Mod Pathol. 2006; 19: 59-68Crossref PubMed Scopus (203) Google Scholar MSI-high was defined as the presence of instability in ≥30% of the markers, MSI-low as instability in 1 to 29% of the markers, and microsatellite stability (MSS) as the absence of unstable markers.35Ogino S Kawasaki T Kirkner GJ Kraft P Loda M Fuchs CS Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample.J Mol Diagn. 2007; 9: 305-314Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar Bisulfite DNA treatment and real-time PCR (MethyLight) were validated and performed.40Ogino S Kawasaki T Brahmandam M Cantor M Kirkner GJ Spiegelman D Makrigiorgos GM Weisenberger DJ Laird PW Loda M Fuchs CS Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis.J Mol Diagn. 2006; 8: 209-217Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar We quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1].35Ogino S Kawasaki T Kirkner GJ Kraft P Loda M Fuchs CS Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample.J Mol Diagn. 2007; 9: 305-314Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 41Ogino S Cantor M Kawasaki T Brahmandam M Kirkner GJ Weisenberger DJ Campan M Laird PW Loda M Fuchs CS CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies.Gut. 2006; 55: 1000-1006Crossref PubMed Scopus (298) Google Scholar, 42Weisenberger DJ Siegmund KD Campan M Young J Long TI Faasse MA Kang GH Widschwendter M Weener D Buchanan D Koh H Simms L Barker M Leggett B Levine J Kim M French AJ Thibodeau SN Jass J Haile R Laird PW CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.Nat Genet. 2006; 38: 787-793Crossref PubMed Scopus (1525) Google Scholar CIMP-high was defined as the presence of ≥6/8 methylated promoters, CIMP-low as 1/8 to 5/8 methylated promoters, and CIMP-0 as the absence (0/8) of methylated promoters, according to the previously established criteria.35Ogino S Kawasaki T Kirkner GJ Kraft P Loda M Fuchs CS Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample.J Mol Diagn. 2007; 9: 305-314Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar To accurately quantify relatively high methylation levels in LINE-1 repetitive elements, we used Pyrosequencing as described previously.43Ogino S Kawasaki T Nosho K Ohnishi M Suemoto Y Kirkner GJ Fuchs CS LINE-1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer.Int J Cancer. 2008; 122: 2767-2773Crossref PubMed Scopus (207) Google Scholar Tissue microarray blocks were constructed.44Ogino S Brahmandam M Kawasaki T Kirkner GJ Loda M Fuchs CS Combined analysis of COX-2 and p53 expressions reveals synergistic inverse correlations with microsatellite instability and CpG island methylator phenotype in colorectal cancer.Neoplasia. 2006; 8: 458-464Abstract Full Text PDF PubMed Scopus (74) Google Scholar Methods of immunohistochemistry for TP53 and PTGS2 (cyclooxygenase-2, COX-2) were described previously.32Chan AT Ogino S Fuchs CS Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.N Engl J Med. 2007; 356: 2131-2142Crossref PubMed Scopus (621) Google Scholar, 39Ogino S Brahmandam M Cantor M Namgyal C Kawasaki T Kirkner G Meyerhardt JA Loda M Fuchs CS Distinct molecular features of colorectal carcinoma with signet ring cell component and colorectal carcinoma with mucinous component.Mod Pathol. 2006; 19: 59-68Crossref PubMed Scopus (203) Google Scholar, 45Ogino S Kawasaki T Kirkner GJ Yamaji T Loda M Fuchs CS Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP.Mod Pathol. 2007; 20: 15-22Crossref PubMed Scopus (52) Google Scholar Appropriate positive and negative controls were included in every run of immunohistochemistry. For HIF1A staining (Figure 1), deparaffinized tissue sections in Antigen Retrieval Citra Solution (Biogenex Laboratories, San Ramon, CA) were treated with microwave (15 minutes). Tissue sections were incubated with 5% normal goat serum (Vector Laboratories, Burlingame, CA) in PBS (30 minutes). Primary antibody [rabbit polyclonal anti-HIF-1α (H-206), 1/500 dilution; Santa Cruz Biotechnology, Santa Cruz, CA] was applied at 4°C for overnight, followed by rabbit secondary antibody (Vector Laboratories) (30 minutes), an avidin–biotin complex conjugate (Vector Laboratories) (30 minutes), diaminobenzidine (5 minutes), and methyl-green counterstain. Cytoplasmic HIF1A expression was recorded as no, weak, moderate, or strong expression with the percentage of positive tumor cells (Figure 1). Among the 731 tumors, 200 tumors showed no HIF1A expression, 345 showed weak expression, 176 showed moderate expression, and 10 showed strong expression. The percentage of HIF1A-positive tumor cells ranged from 0 to 90% (median, 30%). In our initial exploratory analysis, we randomly selected 366 tumors as a training set and classified the training set tumors according to the intensity and extent of HIF1A expression. In the train" @default.
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