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• W2892008658 abstract "Evidence indicates a complex link between microbiota, tumor characteristics, and host immunity in the tumor microenvironment. In experimental studies, bifidobacteria appear to modulate intestinal epithelial cell differentiation. Accumulating evidence suggests that bifidobacteria may enhance the antitumor immunity and efficacy of immunotherapy. We hypothesized that the amount of bifidobacteria in colorectal carcinoma tissue might be associated with tumor differentiation and higher immune response to colorectal cancer. Using a molecular pathologic epidemiology database of 1313 rectal and colon cancers, we measured the amount of Bifidobacterium DNA in carcinoma tissue by a quantitative PCR assay. The multivariable regression model was used to adjust for potential confounders, including microsatellite instability status, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Intratumor bifidobacteria were detected in 393 cases (30%). The amount of bifidobacteria was associated with the extent of signet ring cells (P = 0.002). Compared with Bifidobacterium-negative cases, multivariable odd ratios for the extent of signet ring cells were 1.29 (95% CI, 0.74–2.24) for Bifidobacterium-low cases and 1.87 (95% CI, 1.16–3.02) for Bifidobacterium-high cases (Ptrend = 0.01). The association between intratumor bifidobacteria and signet ring cells suggests a possible role of bifidobacteria in determining distinct tumor characteristics or as an indicator of dysfunctional mucosal barrier in colorectal cancer. Evidence indicates a complex link between microbiota, tumor characteristics, and host immunity in the tumor microenvironment. In experimental studies, bifidobacteria appear to modulate intestinal epithelial cell differentiation. Accumulating evidence suggests that bifidobacteria may enhance the antitumor immunity and efficacy of immunotherapy. We hypothesized that the amount of bifidobacteria in colorectal carcinoma tissue might be associated with tumor differentiation and higher immune response to colorectal cancer. Using a molecular pathologic epidemiology database of 1313 rectal and colon cancers, we measured the amount of Bifidobacterium DNA in carcinoma tissue by a quantitative PCR assay. The multivariable regression model was used to adjust for potential confounders, including microsatellite instability status, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Intratumor bifidobacteria were detected in 393 cases (30%). The amount of bifidobacteria was associated with the extent of signet ring cells (P = 0.002). Compared with Bifidobacterium-negative cases, multivariable odd ratios for the extent of signet ring cells were 1.29 (95% CI, 0.74–2.24) for Bifidobacterium-low cases and 1.87 (95% CI, 1.16–3.02) for Bifidobacterium-high cases (Ptrend = 0.01). The association between intratumor bifidobacteria and signet ring cells suggests a possible role of bifidobacteria in determining distinct tumor characteristics or as an indicator of dysfunctional mucosal barrier in colorectal cancer. The human gut microbiome is composed of >30 trillion microorganisms, and it is under intense investigation because of its substantial role in intestinal tumorigenesis as well as immune modulation of the tumor microenvironment and response to immunotherapy.1Dzutsev A. Badger J.H. Perez-Chanona E. Roy S. Salcedo R. Smith C.K. Trinchieri G. Microbes and cancer.Annu Rev Immunol. 2017; 35: 199-228Crossref PubMed Scopus (157) Google Scholar, 2Honda K. Littman D.R. 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Nishihara R. Qian Z.R. Cao Y. Sukawa Y. Nowak J.A. Yang J. Dou R. Masugi Y. Song M. Kostic A.D. Giannakis M. Bullman S. Milner D.A. Baba H. Giovannucci E.L. Garraway L.A. Freeman G.J. Dranoff G. Garrett W.S. Huttenhower C. Meyerson M. Meyerhardt J.A. Chan A.T. Fuchs C.S. Ogino S. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.Gut. 2016; 65: 1973-1980Crossref PubMed Scopus (494) Google Scholar, 11Mima K. Sukawa Y. Nishihara R. Qian Z.R. Yamauchi M. Inamura K. Kim S.A. Masuda A. Nowak J.A. Nosho K. Kostic A.D. Giannakis M. Watanabe H. Bullman S. Milner D.A. Harris C.C. Giovannucci E. Garraway L.A. Freeman G.J. Dranoff G. Chan A.T. Garrett W.S. Huttenhower C. Fuchs C.S. Ogino S. Fusobacterium nucleatum and T cells in colorectal carcinoma.JAMA Oncol. 2015; 1: 653-661Crossref PubMed Scopus (367) Google Scholar Our incomplete knowledge of the interactions between microbes, distinctive tumor features, and the host immune system highlights the critical need for transdisciplinary integrated analyses of microorganisms and cancer.12Rajpoot M. Sharma A.K. Sharma A. Gupta G.K. Understanding the microbiome: emerging biomarkers for exploiting the microbiota for personalized medicine against cancer.Semin Cancer Biol. 2018; 52: 1-8Crossref PubMed Scopus (62) Google Scholar, 13Ogino S. Galon J. Fuchs C.S. Dranoff G. Cancer immunology: analysis of host and tumor factors for personalized medicine.Nat Rev Clin Oncol. 2011; 8: 711-719Crossref PubMed Scopus (230) Google Scholar, 14Ogino S. Nowak J.A. Hamada T. Phipps A.I. Peters U. Milner Jr., D.A. Giovannucci E.L. Nishihara R. Giannakis M. Garrett W.S. Song M. Integrative analysis of exogenous, endogenous, tumour and immune factors for precision medicine.Gut. 2018; 67: 1168-1180Crossref PubMed Scopus (126) Google Scholar Colon and rectal cancers represent heterogeneous sets of neoplasms with differing combinations of genetic and epigenetic alterations, the accrual of which is influenced by complicated interplay between tumor cells, host cells, and microorganisms.14Ogino S. Nowak J.A. Hamada T. Phipps A.I. Peters U. Milner Jr., D.A. Giovannucci E.L. Nishihara R. Giannakis M. Garrett W.S. Song M. Integrative analysis of exogenous, endogenous, tumour and immune factors for precision medicine.Gut. 2018; 67: 1168-1180Crossref PubMed Scopus (126) Google Scholar, 15Ogino S. Nishihara R. VanderWeele T.J. Wang M. Nishi A. Lochhead P. Qian Z.R. Zhang X. Wu K. Nan H. Yoshida K. Milner Jr., D.A. Chan A.T. Field A.E. Camargo Jr., C.A. Williams M.A. Giovannucci E.L. Review article: the role of molecular pathological epidemiology in the study of neoplastic and non-neoplastic diseases in the era of precision medicine.Epidemiology. 2016; 27: 602-611Crossref PubMed Scopus (142) Google Scholar, 16Masugi Y. Nishihara R. Yang J. Mima K. da Silva A. Shi Y. Inamura K. Cao Y. Song M. Nowak J.A. Liao X. Nosho K. Chan A.T. Giannakis M. Bass A.J. Hodi F.S. Freeman G.J. Rodig S. Fuchs C.S. Qian Z.R. Ogino S. Tumour CD274 (PD-L1) expression and T cells in colorectal cancer.Gut. 2017; 66: 1463-1473Crossref PubMed Scopus (135) Google Scholar, 17Bijlsma M.F. Sadanandam A. Tan P. Vermeulen L. Molecular subtypes in cancers of the gastrointestinal tract.Nat Rev Gastroenterol Hepatol. 2017; 14: 333-342Crossref PubMed Scopus (79) Google Scholar, 18Naxerova K. Reiter J.G. Brachtel E. Lennerz J.K. van de Wetering M. Rowan A. Cai T. Clevers H. Swanton C. Nowak M.A. Elledge S.J. Jain R.K. Origins of lymphatic and distant metastases in human colorectal cancer.Science. 2017; 357: 55-60Crossref PubMed Scopus (267) Google Scholar, 19Li H. Courtois E.T. Sengupta D. Tan Y. Chen K.H. Goh J.J.L. Kong S.L. Chua C. Hon L.K. Tan W.S. Wong M. Choi P.J. Wee L.J.K. Hillmer A.M. Tan I.B. Robson P. Prabhakar S. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors.Nat Genet. 2017; 49: 708-718Crossref PubMed Scopus (549) Google Scholar, 20Ogino S. Jhun I. Mata D.A. Soong T.R. Hamada T. Liu L. Nishihara R. Giannakis M. Cao Y. Manson J.E. Nowak J.A. Chan A.T. Integration of pharmacology, molecular pathology, and population data science to support precision gastrointestinal oncology.NPJ Precis Oncol. 2017; 1: 40Crossref PubMed Google Scholar, 21Gagliani N. Hu B. Huber S. Elinav E. Flavell R.A. The fire within: microbes inflame tumors.Cell. 2014; 157: 776-783Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Accumulating evidence suggests that the presence of members of Bifidobacterium genus in the gut lumen may suppress colorectal carcinogenesis through prevention of enteropathogenic infection and inhibition of secondary bile acid production.22Fukuda S. Toh H. Hase K. Oshima K. Nakanishi Y. Yoshimura K. Tobe T. Clarke J.M. Topping D.L. Suzuki T. Taylor T.D. Itoh K. Kikuchi J. Morita H. Hattori M. Ohno H. Bifidobacteria can protect from enteropathogenic infection through production of acetate.Nature. 2011; 469: 543-547Crossref PubMed Scopus (1510) Google Scholar, 23Laforest-Lapointe I. Arrieta M.C. Patterns of early-life gut microbial colonization during human immune development: an ecological perspective.Front Immunol. 2017; 8: 788Crossref PubMed Scopus (91) Google Scholar, 24Ubeda C. Djukovic A. Isaac S. Roles of the intestinal microbiota in pathogen protection.Clin Transl Immunology. 2017; 6: e128Crossref PubMed Scopus (17) Google Scholar In in vitro and in vivo experiments, bacteria, including bifidobacteria, appear to modulate intestinal epithelial cell differentiation factors.25Becker S. Oelschlaeger T.A. Wullaert A. Vlantis K. Pasparakis M. Wehkamp J. Stange E.F. Gersemann M. Bacteria regulate intestinal epithelial cell differentiation factors both in vitro and in vivo.PLoS One. 2013; 8: e55620Crossref PubMed Scopus (46) Google Scholar, 26Wolnerhanssen B.K. Moran A.W. Burdyga G. Meyer-Gerspach A.C. Peterli R. Manz M. Thumshirn M. Daly K. Beglinger C. Shirazi-Beechey S.P. Deregulation of transcription factors controlling intestinal epithelial cell differentiation: a predisposing factor for reduced enteroendocrine cell number in morbidly obese individuals.Sci Rep. 2017; 7: 8174Crossref PubMed Scopus (32) Google Scholar Experimental studies have shown that bifidobacteria activate antitumor immunity and boost the efficacy of immunotherapy blocking CD274 (PDCD1 ligand 1).3Snyder A. Pamer E. Wolchok J. IMMUNOTHERAPY: could microbial therapy boost cancer immunotherapy?.Science. 2015; 350: 1031-1032Crossref PubMed Scopus (31) Google Scholar, 27Sivan A. Corrales L. Hubert N. Williams J.B. Aquino-Michaels K. Earley Z.M. Benyamin F.W. Lei Y.M. Jabri B. Alegre M.L. Chang E.B. Gajewski T.F. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.Science. 2015; 350: 1084-1089Crossref PubMed Scopus (2113) Google Scholar Immune cells in the tumor microenvironment may be the key players in regulating tumor progression,13Ogino S. Galon J. Fuchs C.S. Dranoff G. Cancer immunology: analysis of host and tumor factors for personalized medicine.Nat Rev Clin Oncol. 2011; 8: 711-719Crossref PubMed Scopus (230) Google Scholar, 14Ogino S. Nowak J.A. Hamada T. Phipps A.I. Peters U. Milner Jr., D.A. Giovannucci E.L. Nishihara R. Giannakis M. Garrett W.S. Song M. Integrative analysis of exogenous, endogenous, tumour and immune factors for precision medicine.Gut. 2018; 67: 1168-1180Crossref PubMed Scopus (126) Google Scholar, 28Mlecnik B. Bindea G. Angell H.K. Maby P. Angelova M. Tougeron D. Church S.E. Lafontaine L. Fischer M. Fredriksen T. Sasso M. Bilocq A.M. Kirilovsky A. Obenauf A.C. Hamieh M. Berger A. Bruneval P. Tuech J.J. Sabourin J.C. Le Pessot F. Mauillon J. Rafii A. Laurent-Puig P. Speicher M.R. Trajanoski Z. Michel P. Sesboue R. Frebourg T. Pages F. Valge-Archer V. Latouche J.B. Galon J. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability.Immunity. 2016; 44: 698-711Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar, 29Giannakis M. Mu X.J. Shukla S.A. Qian Z.R. Cohen O. Nishihara R. Bahl S. Cao Y. Amin-Mansour A. Yamauchi M. Sukawa Y. Stewart C. Rosenberg M. Mima K. Inamura K. Nosho K. Nowak J.A. Lawrence M.S. Giovannucci E.L. Chan A.T. Ng K. Meyerhardt J.A. Van Allen E.M. Getz G. Gabriel S.B. Lander E.S. Wu C.J. Fuchs C.S. Ogino S. Garraway L.A. Genomic correlates of immune-cell infiltrates in colorectal carcinoma.Cell Rep. 2016; 15: 857-865Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar, 30Nosho K. Baba Y. Tanaka N. Shima K. Hayashi M. Meyerhardt J.A. Giovannucci E. Dranoff G. Fuchs C.S. Ogino S. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review.J Pathol. 2010; 222: 350-366Crossref PubMed Scopus (395) Google Scholar, 31Ogino S. Nosho K. Irahara N. Meyerhardt J.A. Baba Y. Shima K. Glickman J.N. Ferrone C.R. Mino-Kenudson M. Tanaka N. Dranoff G. Giovannucci E.L. Fuchs C.S. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype.Clin Cancer Res. 2009; 15: 6412-6420Crossref PubMed Scopus (309) Google Scholar, 32Ogino S. Giannakis M. Immunoscore for (colorectal) cancer precision medicine.Lancet. 2018; 391: 2084-2086Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 33Pages F. Mlecnik B. Marliot F. Bindea G. Ou F.S. Bifulco C. et al.International validation of the consensus immunoscore for the classification of colon cancer: a prognostic and accuracy study.Lancet. 2018; 391: 2128-2139Abstract Full Text Full Text PDF PubMed Scopus (1083) Google Scholar indicating that the assessment of microorganisms, host immunity, and cancer cells in the tumor microenvironment is increasingly significant in translational research and clinical practice for tumor classification. Therefore, we hypothesized that the amount of bifidobacteria in colorectal carcinoma tissue might be associated with tumor differentiation and higher immune response to colorectal cancer. To test this hypothesis, a molecular pathologic epidemiology database of colorectal cancer cases within two large US prospective cohort studies was used, and the amount of Bifidobacterium DNA in relation to tumor differentiation and immune response in the tumor microenvironment were examined. In addition, as a secondary exploratory analysis, the prognostic association of the amount of bifidobacteria in colorectal carcinoma was assessed. Data from two prospective cohort studies in the United States, the Nurses' Health Study (121,701 women aged 30 to 55 years, followed up since 1976) and the Health Professionals Follow-Up Study (51,529 men aged 40 to 75 years, followed up since 1986), were collected.34Nishihara R. Wu K. Lochhead P. Morikawa T. Liao X. Qian Z.R. Inamura K. Kim S.A. Kuchiba A. Yamauchi M. Imamura Y. Willett W.C. Rosner B.A. Fuchs C.S. Giovannucci E. Ogino S. Chan A.T. Long-term colorectal-cancer incidence and mortality after lower endoscopy.N Engl J Med. 2013; 369: 1095-1105Crossref PubMed Scopus (982) Google Scholar Study participants have completed follow-up questionnaires to submit information on lifestyle factors and medical history, including colorectal cancer, every 2 years. The National Death Index was used to ascertain deaths of study participants and identify unreported lethal colorectal cancer cases. Participating physicians reviewed medical records to confirm diagnosis of colorectal cancer and to record tumor characteristics (eg, size, location, and the American Joint Committee on Cancer TNM classification) and causes of death for deceased participants. Formalin-fixed, paraffin-embedded tissue blocks were gathered from hospitals in which participants diagnosed with colorectal cancer had undergone tumor resection. A total of 1313 colorectal carcinoma patients with available tissue materials were included for measurement of the amount of intratumor Bifidobacterium DNA (Figure 1). Both colon and rectal carcinomas were included on the basis of the colorectal continuum model.35Yamauchi M. Morikawa T. Kuchiba A. Imamura Y. Qian Z.R. Nishihara R. Liao X. Waldron L. Hoshida Y. Huttenhower C. Chan A.T. Giovannucci E. Fuchs C. Ogino S. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum.Gut. 2012; 61: 847-854Crossref PubMed Scopus (463) Google Scholar, 36Mima K. Cao Y. Chan A.T. Qian Z.R. Nowak J.A. Masugi Y. Shi Y. Song M. da Silva A. Gu M. Li W. Hamada T. Kosumi K. Hanyuda A. Liu L. Kostic A.D. Giannakis M. Bullman S. Brennan C.A. Milner D.A. Baba H. Garraway L.A. Meyerhardt J.A. Garrett W.S. Huttenhower C. Meyerson M. Giovannucci E.L. Fuchs C.S. Nishihara R. Ogino S. Fusobacterium nucleatum in colorectal carcinoma tissue according to tumor location.Clin Transl Gastroenterol. 2016; 7: e200Crossref PubMed Scopus (176) Google Scholar Patients were followed up until death or the end of follow-up (January 1, 2014, for the Health Professionals Follow-Up Study; May 31, 2014, for the Nurses' Health Study), whichever came first. Informed consent was obtained from every study participant. This study was approved by the institutional review boards at Harvard T.H. Chan School of Public Health and Brigham and Women's Hospital (Boston, MA). A single pathologist (S.O.), blinded to other data, reviewed hematoxylin and eosin–stained tissue sections of all colorectal carcinoma cases and recorded pathologic features, including tumor differentiation, patterns and degrees of lymphocytic reactions, tumor growth pattern, and the extent of signet ring cells and extracellular mucin.37Inamura K. Yamauchi M. Nishihara R. Kim S.A. Mima K. Sukawa Y. Li T. Yasunari M. Zhang X. Wu K. Meyerhardt J.A. Fuchs C.S. Harris C.C. Qian Z.R. Ogino S. Prognostic significance and molecular features of signet-ring cell and mucinous components in colorectal carcinoma.Ann Surg Oncol. 2015; 22: 1226-1235Crossref PubMed Scopus (75) Google Scholar Tumor differentiation was categorized as well to moderate or poor (>50% versus ≤50% glandular area, respectively). The proportions of signet ring cell component and extracellular mucinous component were recorded as percentage and categorized as 0%, 1% to 50%, or ≥51% of the tumor volume, as previously described.37Inamura K. Yamauchi M. Nishihara R. Kim S.A. Mima K. Sukawa Y. Li T. Yasunari M. Zhang X. Wu K. Meyerhardt J.A. Fuchs C.S. Harris C.C. Qian Z.R. Ogino S. Prognostic significance and molecular features of signet-ring cell and mucinous components in colorectal carcinoma.Ann Surg Oncol. 2015; 22: 1226-1235Crossref PubMed Scopus (75) Google Scholar The cutoff value of 50% of signet ring cell or extracellular mucinous component was used, on the basis of the World Health Organization Classification of Tumors of the Digestive System, which defines signet ring cell carcinoma or mucinous carcinoma as carcinoma with >50% of signet ring cell or extracellular mucinous component, respectively.38Bosman F.T. World Health OrganizationInternational Agency for Research on CancerWHO Classification of Tumours of the Digestive System.ed 4. International Agency for Research on Cancer, Lyon2010Google Scholar Any colorectal cancer can have signet ring cell or extracellular mucinous component to any extent (from 0% to 100%). Any colorectal cancer can have both signet ring cell component and mucinous component, either one of them, or neither of them. Histopathologic lymphocytic reaction to tumor was evaluated, as previously described.31Ogino S. Nosho K. Irahara N. Meyerhardt J.A. Baba Y. Shima K. Glickman J.N. Ferrone C.R. Mino-Kenudson M. Tanaka N. Dranoff G. Giovannucci E.L. Fuchs C.S. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype.Clin Cancer Res. 2009; 15: 6412-6420Crossref PubMed Scopus (309) Google Scholar Four components of lymphocytic reaction were examined, including tumor-infiltrating lymphocytes, intratumoral periglandular reaction, peritumoral lymphocytic reaction, and Crohn-like lymphoid reaction. Tumor-infiltrating lymphocytes were defined as lymphocytes on top of cancer cells. Intratumoral periglandular reaction was defined as lymphocytic reaction in tumor stroma within a tumor mass. Peritumoral lymphocytic reaction was defined as discrete lymphoid reaction surrounding a tumor mass. Crohn-like lymphoid reaction was defined as transmural lymphoid reaction. Each of the four components was graded as negative/low, intermediate, or high. Genomic DNA was extracted from colorectal carcinoma tissue in whole-tissue sections of archival formalin-fixed, paraffin-embedded tissue blocks using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany). Custom TaqMan primer-probe sets (Applied Biosystems, Foster City, CA) were used for the 16S ribosomal RNA gene DNA sequence of Bifidobacterium at the genus level and for the reference gene, 16S, as described elsewhere.27Sivan A. Corrales L. Hubert N. Williams J.B. Aquino-Michaels K. Earley Z.M. Benyamin F.W. Lei Y.M. Jabri B. Alegre M.L. Chang E.B. Gajewski T.F. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.Science. 2015; 350: 1084-1089Crossref PubMed Scopus (2113) Google Scholar, 39Furet J.P. Firmesse O. Gourmelon M. Bridonneau C. Tap J. Mondot S. Dore J. Corthier G. Comparative assessment of human and farm animal faecal microbiota using real-time quantitative PCR.FEMS Microbiol Ecol. 2009; 68: 351-362Crossref PubMed Scopus (279) Google Scholar, 40Sobhani I. Tap J. Roudot-Thoraval F. Roperch J.P. Letulle S. Langella P. Corthier G. Tran Van Nhieu J. Furet J.P. Microbial dysbiosis in colorectal cancer (CRC) patients.PLoS One. 2011; 6: e16393Crossref PubMed Scopus (593) Google Scholar Each reaction contained 80 ng of genomic DNA and was assayed in 20-μL reactions containing 1× final concentration TaqMan Environmental Master Mix 2.0 (Applied Biosystems) and each TaqMan Gene Expression Assay (Applied Biosystems), in a 96-well optical PCR plate. The StepOnePlus Real-Time PCR System (Applied Biosystems) was used for amplification and detection of DNA using the following reaction conditions: 10 minutes at 95°C and 45 cycles of 15 seconds at 95°C and 1 minute at 60°C. The primer and probe sequences for each TaqMan Gene Expression Assay were as follows: Bifidobacterium forward primer, 5′-CGGGTGAGTAATGCGTGACC-3′; Bifidobacterium reverse primer, 5′-TGATAGGACGCGACCCCA-3′; Bifidobacterium FAM probe, 5′-CTCCTGGAAACGGGTG-3′; universal 16S forward primer, 5′-CGGTGAATACGTTCCCGG-3′; universal 16S reverse primer, 5′-TACGGCTACCTTGTTACGACTT-3′; and universal 16S FAM probe, 5′-CTTGTACACACCGCCCGTC-3′. In colorectal carcinoma cases with detectable bifidobacteria, the cycle threshold (CT) values in the quantitative PCR for Bifidobacterium DNA and 16S decreased linearly with the amount of input DNA (in a log scale) from the same specimen (r2 > 0.97) (Supplemental Figure S1). The interassay CV of CT values from the same specimen in five different batches was 1% or less for all targets in this validation study using six colorectal carcinomas (Supplemental Table S1). Each specimen was analyzed in duplicate for each target in a single batch, and the mean of the two CT values for each target was used. The amount of bifidobacteria in each specimen was calculated as a relative unitless value normalized with 16S using the 2−ΔCt method (where ΔCT = the average CT value of Bifidobacterium DNA − the average CT value of 16S), as previously described.41Schmittgen T.D. Livak K.J. Analyzing real-time PCR data by the comparative C(T) method.Nat Protoc. 2008; 3: 1101-1108Crossref PubMed Scopus (17280) Google Scholar Cases with detectable bifidobacteria were categorized as low versus high based on the median cut point amount of bifidobacteria, whereas cases without detectable bifidobacteria were categorized as negative. Quantitative PCR was used for F. nucleatum to measure the amount of tissue F. nucleatum DNA, as previously described.10Mima K. Nishihara R. Qian Z.R. Cao Y. Sukawa Y. Nowak J.A. Yang J. Dou R. Masugi Y. Song M. Kostic A.D. Giannakis M. Bullman S. Milner D.A. Baba H. Giovannucci E.L. Garraway L.A. Freeman G.J. Dranoff G. Garrett W.S. Huttenhower C. Meyerson M. Meyerhardt J.A. Chan A.T. Fuchs C.S. Ogino S. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.Gut. 2016; 65: 1973-1980Crossref PubMed Scopus (494) Google Scholar, 11Mima K. Sukawa Y. Nishihara R. Qian Z.R. Yamauchi M. Inamura K. Kim S.A. Masuda A. Nowak J.A. Nosho K. Kostic A.D. Giannakis M. Watanabe H. Bullman S. Milner D.A. Harris C.C. Giovannucci E. Garraway L.A. Freeman G.J. Dranoff G. Chan A.T. Garrett W.S. Huttenhower C. Fuchs C.S. Ogino S. Fusobacterium nucleatum and T cells in colorectal carcinoma.JAMA Oncol. 2015; 1: 653-661Crossref PubMed Scopus (367) Google Scholar We categorized colorectal carcinoma cases with detectable F. nucleatum DNA as low or high in relation to the median cut point amount of F. nucleatum DNA.10Mima K. Nishihara R. Qian Z.R. Cao Y. Sukawa Y. Nowak J.A. Yang J. Dou R. Masugi Y. Song M. Kostic A.D. Giannakis M. Bullman S. Milner D.A. Baba H. Giovannucci E.L. Garraway L.A. Freeman G.J. Dranoff G. Garrett W.S. Huttenhower C. Meyerson M. Meyerhardt J.A. Chan A.T. Fuchs C.S. Ogino S. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.Gut. 2016; 65: 1973-1980Crossref PubMed Scopus (494) Google Scholar, 11Mima K. Sukawa Y. Nishihara R. Qian Z.R. Yamauchi M. Inamura K. Kim S.A. Masuda A. Nowak J.A. Nosho K. Kostic A.D. Giannakis M. Watanabe H. Bullman S. Milner D.A. Harris C.C. Giovannucci E. Garraway L.A. Freeman G.J. Dranoff G. Chan A.T. Garrett W.S. Huttenhower C. Fuchs C.S. Ogino S. Fusobacterium nucleatum and T cells in colorectal carcinoma.JAMA Oncol. 2015; 1: 653-661Crossref PubMed Scopus (367) Google Scholar Genomic DNA was extracted from colorectal carcinoma tissue in whole-tissue sections of archival formalin-fixed, paraffin-embedded tissue blocks. MSI status was determined using PCR of 10 microsatellite markers (D2S123, D5S346, D17S250, BAT25, BAT26, BAT40, D18S55, D18S56, D18S67, and D18S487), and MSI-high was defined as presence of instability in ≥30% of the markers, as previously described.35Yamauchi M. Morikawa T. Kuchiba A. Imamura Y. Qian Z.R. Nishihara R. Liao X. Waldron L. Hoshida Y. Huttenhower C. Chan A.T. Giovannucci E. Fuchs C. Ogino S. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum.Gut. 2012; 61: 847-854Crossref PubMed Scopus (463) Google Scholar, 42Ogino S. Nosho K. Kirkner G.J. Kawasaki T. Meyerhardt J.A. Loda M. Giovannucci E.L. Fuchs C.S. 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• W2892008658 title "The Amount of Bifidobacterium Genus in Colorectal Carcinoma Tissue in Relation to Tumor Characteristics and Clinical Outcome" @default.
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