TY  - JOUR
AB  - BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC = 0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI : 0.629,0.653) and odds ratio of 1.71 (95% CI : 1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.
AU  - Blechter, B.*
AU  - Wang, X.*
AU  - Dai, J.*
AU  - Karsonaki, C.*
AU  - Shi, J.*
AU  - Shiraishi, K.*
AU  - Choi, J.*
AU  - Matsuo, K.*
AU  - Chen, T.Y.*
AU  - Hung, R.J.*
AU  - Chen, K.*
AU  - Shu, X.O.*
AU  - Kim, Y.T.*
AU  - Choudhury, P.P.*
AU  - Williams, J.*
AU  - Landi, M.T.*
AU  - Lin, D.*
AU  - Zheng, W.*
AU  - Yin, Z.*
AU  - Zhou, B.*
AU  - Wang, J.*
AU  - Seow, W.J.*
AU  - Song, L.*
AU  - Chang, I.S.*
AU  - Hu, W.*
AU  - Chien, L.H.*
AU  - Cai, Q.*
AU  - Hong, Y.C.*
AU  - Kim, H.N.*
AU  - Wu, Y.L.*
AU  - Wong, M.P.*
AU  - Richardson, B.D.*
AU  - Li, S.*
AU  - Zhang, T.*
AU  - Breeze, C.*
AU  - Wang, Z.*
AU  - Bassig, B.A.*
AU  - Kim, J.H.*
AU  - Albanes, D.*
AU  - Wong Sm, J.Y.*
AU  - Shin, M.H.*
AU  - Chung, L.P.*
AU  - Yang, Y.*
AU  - Zheng, H.*
AU  - Dai, H.*
AU  - Yatabe, Y.*
AU  - Zhang, X.C.*
AU  - Kim, Y.C.*
AU  - Caporaso, N.E.*
AU  - Chang, J.*
AU  - Ho, J.C.M.*
AU  - Daigo, Y.*
AU  - Momozawa, Y.*
AU  - Kamatani, Y.*
AU  - Kobayashi, M.*
AU  - Okubo, K.*
AU  - Honda, T.*
AU  - Hosgood, H.D.*
AU  - Kunitoh, H.*
AU  - Watanabe, S.i.*
AU  - Miyagi, Y.*
AU  - Matsumoto, S.*
AU  - Horinouchi, H.*
AU  - Tsuboi, M.*
AU  - Hamamoto, R.*
AU  - Goto, K.*
AU  - Takahashi, A.*
AU  - Goto, A.*
AU  - Minamiya, Y.*
AU  - Hara, M.*
AU  - Nishida, Y.*
AU  - Takeuchi, K.*
AU  - Wakai, K.*
AU  - Matsuda, K.*
AU  - Murakami, Y.*
AU  - Shimizu, K.*
AU  - Suzuki, H.*
AU  - Saito, M.*
AU  - Ohtaki, Y.*
AU  - Tanaka, K.*
AU  - Wu, T.*
AU  - Wei, F.*
AU  - Machiela, M.J.*
AU  - Kim, Y.H.*
AU  - Oh, I.J.*
AU  - Lee, V.H.F.*
AU  - Chang, G.C.*
AU  - Chen, K.Y.*
AU  - Su, W.C.*
AU  - Chen, Y.M.*
AU  - Seow, A.*
AU  - Park, J.Y.*
AU  - Kweon, S.S.*
AU  - Gao, Y.T.*
AU  - Liu, J.*
AU  - Schwartz, A.G.*
AU  - Houlston, R.*
AU  - Gorlov, I.P.*
AU  - Wu, X.*
AU  - Yang, P.*
AU  - Lam, S.*
AU  - Tardón, A.*
AU  - Chen, C.*
AU  - Bojesen, S.E.*
AU  - Johansson, M.*
AU  - Risch, A.*
AU  - Bickeböller, H.*
AU  - Ji, B.T.*
AU  - Wichmann, H.-E.
AU  - Christiani, D.C.*
AU  - Rennert, G.*
AU  - Arnold, S.M.*
AU  - Brennan, P.*
AU  - McKay, J.*
AU  - Field, J.K.*
AU  - Davies, M.P.A.*
AU  - Shete, S.S.*
AU  - Le Marchand, L.*
AU  - Liu, G.*
AU  - Andrew, A.S.*
AU  - Kiemeney, L.A.*
AU  - Zienolddiny-Narui, S.*
AU  - Grankvist, K.*
AU  - Cox, A.*
AU  - Taylor, F.*
AU  - Yuan, J.M.*
AU  - Lazarus, P.*
AU  - Schabath, M.B.*
AU  - Aldrich, M.C.*
AU  - Jeon, H.S.*
AU  - Jiang, S.S.*
AU  - Chen, C.H.*
AU  - Hsiao, C.F.*
AU  - Hu, Z.*
AU  - Burdett, L.*
AU  - Yeager, M.*
AU  - Hutchinson, A.*
AU  - Hicks, B.*
AU  - Berndt, S.I.*
AU  - Wu, W.*
AU  - Li, Y.*
AU  - Choi, J.E.*
AU  - Park, K.H.*
AU  - Sung, S.W.*
AU  - Kang, C.H.*
AU  - Wang, W.C.*
AU  - Xu, J.*
AU  - Guan, P.*
AU  - Tan, W.*
AU  - Yu, C.J.*
AU  - Yang, G.*
AU  - Sihoe, A.D.L.*
AU  - Choi, Y.Y.*
AU  - Park, I.K.*
AU  - Hung, H.H.*
AU  - Vermeulen, R.C.H.*
AU  - Cheng, I.*
AU  - Wu, J.*
AU  - Tsai, F.Y.*
AU  - Chan, J.K.C.*
AU  - Li, J.*
AU  - Lin, H.C.*
AU  - Song, B.*
AU  - Sawada, N.*
AU  - Yamaji, T.*
AU  - Wyatt, K.*
AU  - Ma, H.*
AU  - Zhu, M.*
AU  - Wang, Y.*
AU  - Qi, T.*
AU  - Li, X.*
AU  - Ren, Y.*
AU  - Chao, A.*
AU  - Iwasaki, M.*
AU  - Zhu, J.*
AU  - Wu, G.*
AU  - Chen, C.Y.*
AU  - ScD, C.C.*
AU  - Yang, P.C.*
AU  - Stevens, V.L.*
AU  - Fraumeni, J.F.*
AU  - Lin, K.*
AU  - Walters, R.G.*
AU  - Chen, Z.*
AU  - Chatterjee, N.*
AU  - Gorlova, O.Y.*
AU  - Amos, C.I.*
AU  - Shen, H.*
AU  - Hsiung, C.A.*
AU  - Chanock, S.J.*
AU  - Rothman, N.*
AU  - Kohno, T.*
AU  - Lan, Q.*
AU  - Zhang, H.*
C1  - 75679
C2  - 58274
TI  - Stratifying lung adenocarcinoma risk with multi-ancestry polygenic risk scores in East Asian never-smokers.
JO  - J. Natl. Cancer Inst.
PY  - 2025
SN  - 0027-8874
ER  - 

TY  - JOUR
AU  - Kratz, C.P.*
AU  - Smirnov, D.
AU  - Autry, R.*
AU  - Jäger, N.*
AU  - Waszak, S.M.*
AU  - Großhennig, A.*
AU  - Berutti, R.
AU  - Wendorff, M.*
AU  - Hainaut, P.*
AU  - Pfister, S.M.*
AU  - Prokisch, H.
AU  - Ripperger, T.*
AU  - Malkin, D.*
C1  - 67637
C2  - 53944
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 760-761
TI  - Reply to Li and colleagues.
JO  - J. Natl. Cancer Inst.
VL  - 115
IS  - 6
PB  - Oxford Univ Press Inc
PY  - 2023
SN  - 0027-8874
ER  - 

TY  - JOUR
AB  - BACKGROUND: Genetic predisposition is a significant cause of cancer, yet little is known about the role of "adult cancer predisposition syndromes" in childhood cancer. We examined the extent to which heterozygous pathogenic germline variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, MSH2, MSH6, MLH1, and PMS2 contribute to cancer risk in children and adolescents. METHODS: We conducted a meta-analysis of 11 studies that incorporated comprehensive germline testing for children and adolescents with cancer. ClinVar pathogenic/likely pathogenic variants (PVs) in genes of interest were compared to two control groups. Results were validated in a cohort of mainly European cases and controls. We employed the Proxy External Controls Association Test to account for different pipelines. RESULTS: Among 3,975 children/adolescents with cancer, significant associations with cancer risk were observed for PVs in BRCA1/2 (26 PVs vs 63 PVs among 27,501 controls, OR 2.78, 95%-CI 1.69-4.45, p<.001) and mismatch repair (MMR) genes (19 PVs vs 14 PVs among 27,501 controls, OR 7.33, 95%-CI 3.64-14.82, p<.001). Associations were seen in brain and other solid tumors, yet not in hematologic neoplasms. We confirmed similar findings in 1,664 pediatric cancer patients primarily of European descent. CONCLUSION: These data suggest that heterozygous PVs in BRCA1/2 and MMR genes contribute with reduced penetrance to cancer risk in children/adolescents. No changes to predictive genetic testing and surveillance recommendations are required.
AU  - Kratz, C.P.*
AU  - Smirnov, D.
AU  - Autry, R.*
AU  - Jäger, N.*
AU  - Waszak, S.M.*
AU  - Großhennig, A.*
AU  - Berutti, R.
AU  - Wendorff, M.*
AU  - Hainaut, P.*
AU  - Pfister, S.M.*
AU  - Prokisch, H.
AU  - Ripperger, T.*
AU  - Malkin, D.*
C1  - 66009
C2  - 53037
SP  - 1523-1532
TI  - Heterozygous BRCA1 and BRCA2 and mismatch repair gene pathogenic variants in children and adolescents with cancer.
JO  - J. Natl. Cancer Inst.
VL  - 114
IS  - 11
PY  - 2022
SN  - 0027-8874
ER  - 

TY  - JOUR
AU  - Kratz, C.P.*
AU  - Smirnov, D.
AU  - Autry, R.*
AU  - Jäger, N.*
AU  - Waszak, S.M.*
AU  - Großhennig, A.*
AU  - Berutti, R.
AU  - Wendorff, M.*
AU  - Hainaut, P.*
AU  - Pfister, S.M.*
AU  - Prokisch, H.
AU  - Ripperger, T.*
AU  - Malkin, D.*
C1  - 66999
C2  - 53365
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 231-232
TI  - Reply to Evans and Woodward.
JO  - J. Natl. Cancer Inst.
VL  - 115
IS  - 2
PB  - Oxford Univ Press Inc
PY  - 2022
SN  - 0027-8874
ER  - 

TY  - JOUR
AU  - Baumeister, S.
AU  - Leitzmann, M.F.*
AU  - Linseisen, J.
AU  - Schlesinger, S.*
C1  - 56898
C2  - 47357
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 653
TI  - RE: Physical activity and the risk of liver cancer: A systematic review and meta-analysis of prospective studies and a bias analysis.
JO  - J. Natl. Cancer Inst.
VL  - 112
IS  - 6
PB  - Oxford Univ Press Inc
PY  - 2020
SN  - 0027-8874
ER  - 

TY  - JOUR
AB  - Background Physical inactivity is an established risk factor for several cancers of the digestive system and female reproductive organs, but the evidence for liver cancers is less conclusive.Methods The aim of this study was to synthesize prospective observational studies on the association of physical activity and liver cancer risk by means of a systematic review and meta-analysis. We searched Medline, Embase, and Scopus from inception to January 2019 for prospective studies investigating the association of physical activity and liver cancer risk. We calculated mean hazard ratios (HRs) and 95% confidence intervals (CIs) using a random-effects model. We quantified the extent to which an unmeasured confounder or an unaccounted selection variable could shift the mean hazard ratio to the null.Results Fourteen prospective studies, including 6,440 liver cancers, were included in the systematic review and meta-analysis. The mean hazard ratio for high compared with low physical activity was 0.75 (95% CI=0.63 to 0.89; 95% prediction interval=0.52 to 1.07; I-2=64.2%). We estimated that 67.6% (95% CI=56.6% to 78.5%) of all true effect estimates would have a hazard ratio less than 0.8. Bias analysis suggested than an unobserved confounder would have to be associated with a 1.99-fold increase in the risk of physical activity or liver cancer to explain away the observed mean hazard ratio. An unaccounted for selection variable would have to be related to exposure and endpoint with a relative risk of 1.58 to explain away the mean hazard ratio.Conclusions Physical activity is inversely related to the risk of liver cancer. Further studies with objectively measured physical activity and quasi-experimental designs addressing confounding are needed.
AU  - Baumeister, S.
AU  - Leitzmann, M.F.*
AU  - Linseisen, J.
AU  - Schlesinger, S.*
C1  - 56272
C2  - 46948
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 1142-1151
TI  - Physical activity and the risk of liver cancer: A systematic review and meta-analysis of prospective studies and a bias analysis.
JO  - J. Natl. Cancer Inst.
VL  - 111
IS  - 11
PB  - Oxford Univ Press Inc
PY  - 2019
SN  - 0027-8874
ER  - 

TY  - JOUR
AB  - BACKGROUND: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade. METHODS: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided. RESULTS: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, Pheterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (OR = 0.43, 95% CI = 0.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (OR = 0.29, 95% CI = 0.22 to 0.40, Ptrend < .001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (OR = 0.33, 95% CI = 0.22 to 0.50) and aggressive disease (OR = 0.18, 95% CI = 0.11 to 0.31, Pheterogeneity = .08). CONCLUSIONS: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-term selenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation.
AU  - Allen, N.E.*
AU  - Travis, R.C.*
AU  - Appleby, P.N.*
AU  - Albanes, D.*
AU  - Barnett, M.J.*
AU  - Black, A.*
AU  - Bueno-de-Mesquita, H.B.*
AU  - Deschasaux, M.*
AU  - Galan, P.*
AU  - Goodman, G.E.*
AU  - Goodman, P.J.*
AU  - Gunter, M.J.*
AU  - Heliövaara, M.*
AU  - Helzlsouer, K.J.*
AU  - Henderson, B.E.*
AU  - Hercberg, S.*
AU  - Knekt, P.*
AU  - Kolonel, L.N.*
AU  - Lasheras, C.*
AU  - Linseisen, J.
AU  - Metter, E.J.*
AU  - Neuhouser, M.L.*
AU  - Olsen, A.*
AU  - Pala, V.*
AU  - Platz, E.A.*
AU  - Rissanen, H.*
AU  - Reid, M.E.*
AU  - Schenk, J.M.*
AU  - Stampfer, M.J.*
AU  - Stattin, P.*
AU  - Tangen, C.M.*
AU  - Touvier, M.*
AU  - Trichopoulou, A.*
AU  - van den Brandt, P.A.*
AU  - Key, T.J.*
C1  - 49031
C2  - 41552
CY  - Cary
TI  - Selenium and prostate cancer: Analysis of individual participant data from fifteen prospective studies.
JO  - J. Natl. Cancer Inst.
VL  - 108
IS  - 11
PB  - Oxford Univ Press Inc
PY  - 2016
SN  - 0027-8874
ER  - 

TY  - JOUR
AB  - BACKGROUND: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. METHODS: Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided. RESULTS: The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)). CONCLUSION: These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.
AU  - Chen, L.S.*
AU  - Hung, R.J.*
AU  - Baker, T.*
AU  - Horton, A.*
AU  - Culverhouse, R.*
AU  - Saccone, N.L.*
AU  - Cheng, I.*
AU  - Deng, B.*
AU  - Han, Y.*
AU  - Hansen, H.M.*
AU  - Horsman, J.*
AU  - Kim, C.*
AU  - Lutz, S.*
AU  - Rosenberger, A.*
AU  - Aben, K.K.*
AU  - Andrew, A.S.*
AU  - Breslau, N.*
AU  - Chang, S.C.*
AU  - Dieffenbach, A.K.*
AU  - Dienemann, H.*
AU  - Frederiksen, B.*
AU  - Han, J.*
AU  - Hatsukami, D.K.*
AU  - Johnson, E.O.*
AU  - Pande, M.*
AU  - Wrensch, M.R.*
AU  - McLaughlin, J.*
AU  - Skaug, V.*
AU  - van der Heijden, H.F.M.*
AU  - Wampfler, J.*
AU  - Wenzlaff, A.*
AU  - Woll, P.J.*
AU  - Zienolddiny, S.*
AU  - Bickeböller, H.*
AU  - Brenner, H.*
AU  - Duell, E.J.*
AU  - Haugen, A.*
AU  - Heinrich, J.
AU  - Hokanson, J.E.*
AU  - Hunter, D.J.*
AU  - Kiemeney, L.A.*
AU  - Lazarus, P.*
AU  - Le Marchand, L.*
AU  - Liu, G.*
AU  - Mayordomo, J.I.*
AU  - Risch, A.*
AU  - Schwartz, A.G.*
AU  - Teare, D.*
AU  - Wu, X.*
AU  - Wiencke, J.K.*
AU  - Yang, P.*
AU  - Zhang, Z.F.*
AU  - Spitz, M.R.*
AU  - Kraft, P.*
AU  - Amos, C.I.*
AU  - Bierut, L.J.*
C1  - 44737
C2  - 36983
CY  - Cary
TI  - CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis - a meta-analysis.
JO  - J. Natl. Cancer Inst.
VL  - 107
IS  - 5
PB  - Oxford Univ Press Inc
PY  - 2015
SN  - 0027-8874
ER  - 

TY  - JOUR
AB  - BACKGROUND: Signaling from integrins and receptor tyrosine kinases (RTKs) contributes substantially to therapy resistance of malignant tumors. We investigated simultaneous β1 integrin-epidermal growth factor receptor (EGFR) targeting plus radiotherapy in human head and neck squamous cell carcinomas (HNSCCs). METHODS: Ten HNSCC cell lines were grown in three-dimensional laminin-rich extracellular matrix cell cultures and two of them as tumor xenografts in nude mice (n = 12-16 per group). Targeting of β1 integrin and EGFR with monoclonal inhibitory antibodies (AIIB2 and cetuximab, respectively) was combined with x-ray irradiation. Clonogenic survival, tumor growth, and tumor control (evaluated by Kaplan-Meier analysis), apoptosis, phosphoproteome (interactome, network betweeness centrality analysis), receptor expression (immunohistochemistry), and downstream signaling (western blotting) were assessed. Various mutants of the integrin signaling mediator focal adhesion kinase (FAK) were employed for mechanistic studies. All statistical tests were two-sided. RESULTS: Compared with β1 integrin or EGFR single inhibition, combined β1 integrin-EGFR targeting resulted in enhanced cytotoxicity and radiosensitization in eight out of 10 tested HNSCC cell lines, which responded with an FAK dephosphorylation after β1 integrin inhibition. In vivo, simultaneous anti-β1 integrin/anti-EGFR treatment and radiotherapy of UTSCC15 responder xenografts enabled better tumor control compared with anti-EGFR monotherapy and irradiation (hazard ratio [HR] = 6.9, 95% confidence interval [CI] = 1.6 to 30.9, P = .01), in contrast to the SAS nonresponder tumor model (HR = 0.9, 95% CI = 0.4 to 2.3, P = .83). Mechanistically, a protein complex consisting of FAK- and Erk1-mediated prosurvival signals for radiation resistance, which was effectively compromised by β1 integrin and EGFR blocking. CONCLUSIONS: Concomitant targeting of β1 integrin and EGFR seems a powerful and promising approach to overcome radioresistance of HNSCCs.
AU  - Eke, I.*
AU  - Zscheppang, K.*
AU  - Dickreuter, E.*
AU  - Hickmann, L.*
AU  - Mazzeo, E.*
AU  - Unger, K.
AU  - Krause, M.*
AU  - Cordes, N.*
C1  - 43266
C2  - 36374
CY  - Cary
TI  - Simultaneous β1 integrin-EGFR targeting and radiosensitization of human head and neck cancer.
JO  - J. Natl. Cancer Inst.
VL  - 107
IS  - 2
PB  - Oxford Univ Press Inc
PY  - 2015
SN  - 0027-8874
ER  - 

TY  - JOUR
AB  - BACKGROUND: One bottleneck for adoptive T cell therapy (ACT) is recruitment of T cells into tumors. We hypothesized that combining tumor-specific T cells, modified with a marker antigen and a bispecific antibody (BiAb) that selectively recognizes transduced T cells and tumor cells would improve T cell recruitment to tumors and enhance therapeutic efficacy. METHODS: SV40 T antigen-specific T cells from T cell receptor (TCR)-I-transgenic mice were transduced with a truncated human epidermal growth factor receptor (EGFR) as a marker protein. Targeting and killing by combined ACT and anti-EGFR-anti-EpCAM BiAb therapy was analyzed in C57Bl/6 mice (n = six to 12 per group) carrying subcutaneous tumors of the murine gastric cancer cell line GC8 (SV40(+) and EpCAM(+)). Anti-EGFR x anti-c-Met BiAb was used for targeting of human tumor-specific T cells to c-Met(+) human tumor cell lines. Differences between experimental conditions were analyzed using the Student's t test, and differences in tumor growth with two-way analysis of variance. Overall survival was analyzed by log-rank test. All statistical tests were two-sided. RESULTS: The BiAb linked EGFR-transduced T cells to tumor cells and enhanced tumor cell lysis. In vivo, the combination of ACT and Biab produced increased T cell infiltration of tumors, retarded tumor growth, and prolonged survival compared with ACT with a control antibody (median survival 95 vs 75 days, P < .001). In human cells, this strategy enhanced recruitment of human EGFR-transduced T cells to immobilized c-Met and recognition of tyrosinase(+) melanoma cells by TCR-, as well as of CEA(+) colon cancer cells by chimeric antigen receptor (CAR)-modified T cells. CONCLUSIONS: BiAb recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of ACT.
AU  - Kobold, S.*
AU  - Steffen, J.*
AU  - Chaloupka, M.*
AU  - Grassmann, S.*
AU  - Henkel, J.*
AU  - Castoldi, R.*
AU  - Zeng, Y.*
AU  - Chmielewski, M.*
AU  - Schmollinger, J.C.*
AU  - Schnurr, M.*
AU  - Rothenfußer, S.*
AU  - Schendel, D.J.
AU  - Abken, H.*
AU  - Sustmann, C.*
AU  - Niederfellner, G.*
AU  - Klein, C.*
AU  - Bourquin, C.*
AU  - Endres, S.*
C1  - 42848
C2  - 35535
CY  - Cary
TI  - Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer.
JO  - J. Natl. Cancer Inst.
VL  - 107
IS  - 1
PB  - Oxford Univ Press Inc
PY  - 2015
SN  - 0027-8874
ER  - 

TY  - JOUR
AB  - BACKGROUND: Clinical guidelines for breast cancer chemoprevention and MRI screening involve estimates of remaining lifetime risk (RLR); in the United States, women with an RLR of 20% or higher meet "high-risk" criteria for MRI screening. METHODS: We prospectively followed 1764 women without breast cancer to compare the RLRs and 10-year risks assigned by the risk models International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and to compare both sets of model-assigned 10-year risks to subsequent incidence of breast cancer in the cohort. We used chi-square statistics to assess calibration and the area under the receiver operating characteristic curve (AUC) to assess discrimination. All statistical tests are two-sided. RESULTS: The models classified different proportions of women as high-risk (IBIS = 59.3% vs BOADICEA = 20.1%) using the RLR threshold of 20%. The difference was smaller (IBIS = 52.9% vs BOADICEA = 43.2%) using a 10-year risk threshold of 3.34%. IBIS risks (mean = 4.9%) were better calibrated to observed breast cancer incidence (5.2%, 95% confidence interval (CI) = 4.2% to 6.4%) than were those of BOADICEA (mean = 3.7%) overall and within quartiles of model risk (P = .20 by IBIS and P = .07 by BOADICEA). Both models gave similar discrimination, with AUCs of 0.67 (95% CI = 0.61 to 0.73) using IBIS and 0.68 (95% CI = 0.62 to 0.74) using BOADICEA. Model sensitivities at thresholds for a 20% false-positive rate were also similar, with 41.8% using IBIS and 38.0% using BOADICEA. CONCLUSION: RLR-based guidelines for high-risk women are limited by discordance between commonly used risk models. Guidelines based on short-term risks would be more useful, as models are generally developed and validated under a short fixed time horizon (≤10 years).
AU  - Quante, A.S.
AU  - Whittemore, A.S.*
AU  - Shriver, T.*
AU  - Hopper, J.L.*
AU  - Strauch, K.
AU  - Terry, M.B.*
C1  - 44815
C2  - 37028
CY  - Cary
TI  - Practical problems with clinical guidelines for breast cancer prevention based on remaining lifetime risk.
JO  - J. Natl. Cancer Inst.
VL  - 107
IS  - 7
PB  - Oxford Univ Press Inc
PY  - 2015
SN  - 0027-8874
ER  - 

TY  - JOUR
AB  - BACKGROUND: Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed. METHODS: We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non-lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10(-5) was used to assign statistical significance. RESULTS: The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10(-6)). This association was strongest for women with adenocarcinoma (P = 1.2×10(-4)) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10(-8)) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10(-5)), respectively. CONCLUSIONS: Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.
AU  - Park, S.L.*
AU  - Fesinmeyer, M.D.*
AU  - Timofeeva, M.*
AU  - Caberto, C.P.*
AU  - Kocarnik, J.M.*
AU  - Han, Y.*
AU  - Love, S.A.*
AU  - Young, A.*
AU  - Dumitrescu, L.*
AU  - Lin, Y.*
AU  - Goodloe, R.*
AU  - Wilkens, L.R.*
AU  - Hindorff, L.*
AU  - Fowke, J.H.*
AU  - Carty, C.*
AU  - Buyske, S.*
AU  - Schumacher, F.R.*
AU  - Butler, A.*
AU  - Dilks, H.*
AU  - Deelman, E.*
AU  - Cote, M.L.*
AU  - Chen, W.*
AU  - Pande, M.*
AU  - Christiani, D.C.*
AU  - Field, J.K.*
AU  - Bickebller, H.*
AU  - Risch, A.*
AU  - Heinrich, J.
AU  - Brennan, P.*
AU  - Wang, Y.*
AU  - Eisen, T.*
AU  - Houlston, R.S.*
AU  - Thun, M.*
AU  - Albanes, D.*
AU  - Caporaso, N.*
AU  - Peters, U.*
AU  - North, K.E.*
AU  - Heiss, G.*
AU  - Crawford, D.C.*
AU  - Bush, W.S.*
AU  - Haiman, C.A.*
AU  - Landi, M.T.*
AU  - Hung, R.J.
AU  - Kooperberg, C.*
AU  - Amos, C.I.*
AU  - Le Marchand, L.*
AU  - Cheng, I.*
C1  - 30943
C2  - 34039
CY  - Cary
TI  - Pleiotropic associations of risk variants identified for other cancers with lung cancer risk: The PAGE and TRICL consortia.
JO  - J. Natl. Cancer Inst.
VL  - 106
IS  - 4
PB  - Oxford Univ Press Inc
PY  - 2014
SN  - 0027-8874
ER  - 

TY  - JOUR
AB  - BackgroundHepatocellular carcinoma (HCC) is a highly aggressive cancer that is linked to chronically dysregulated liver inflammation. However, appropriate immune responses can control HCC progression. Here we investigated the role and underlying mechanism of toll-like receptor 3 (TLR3) in HCC.MethodsHCC cell death, and natural killer (NK) cell activation and cytotoxicity were assessed in vitro after treatment with the TLR3 ligand poly(I:C). The effect of TLR3 on the tumor parenchyma and infiltrating immune cells was investigated in a spontaneous liver tumor mouse model and a transplanted tumor mouse model (n = 3-9 mice per group). Immunohistochemistry and quantitative polymerase chain reaction were used to analyze tumor samples from 172 HCC patients. Paired t-tests and analysis of variance tests were used to calculate P-values. The relationship between TLR3 expression and survival was determined by the Kaplan-Meier univariate survival analysis and a log-rank test. All statistical tests were two-sided.ResultsTLR3 activation increased cell death in the TLR3(+) SNU182 HCC cell line (30.5% vs 8.5%, P = .03) and promoted NK-cell activation (32.6% vs 19.4%, P < .001) and cytotoxicity (relative fourfold increase, P = .03) in vitro. In vivo, poly(I:C) treatment increased intratumoral chemokine expression, NK-cell activation and tumor infiltration, and proliferation of tumor-infiltrating T and NK cells. Proliferation of tumor parenchyma cells was decreased. Also, expression of chemokines or treatment with poly(I:C) decreased tumor growth. TLR3 expression in patient samples correlated with NK-cell activation, NK- and T-cell tumor infiltration, and inversely correlated with tumor parenchyma cell viability. TLR3 expression was also associated with longer survival in HCC patients (hazard ratio of survival = 2.1, 95% confidence interval = 1.3 to 3.4, P = .002).ConclusionsTLR3 is an important modulator of HCC progression and is a potential target for novel immunotherapy.
AU  - Chew, V.*
AU  - Tow, C.*
AU  - Huang, C.*
AU  - Bard-Chapeau, E.*
AU  - Copeland, N.G.*
AU  - Jenkins, N.A.*
AU  - Weber, A.*
AU  - Lim, K.H.*
AU  - Toh, H.C.*
AU  - Heikenwälder, M.
AU  - Ng, I.O.*
AU  - Nardin, A.*
AU  - Abastado, J.-P.*
C1  - 11199
C2  - 30965
SP  - 1796-1807
TI  - Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients.
JO  - J. Natl. Cancer Inst.
VL  - 104
IS  - 23
PB  - Oxford Univ. Press
PY  - 2012
SN  - 0027-8874
ER  - 

TY  - JOUR
AB  - BACKGROUND: Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies. METHODS: Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided. RESULTS: Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, P(trend) = 2 x 10(-26)), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, P(trend) = 1 x 10(-10)) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, P(trend) = 5 x 10(-8)) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, P(trend) = 2 x 10(-5); rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, P(trend) = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer. CONCLUSIONS: In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.
AU  - Truong, T.*
AU  - Hung, R.J.*
AU  - Amos, C.I.*
AU  - Wu, X.F.*
AU  - Bickeböller, H.*
AU  - Rosenberger, A.*
AU  - Sauter, W.
AU  - Illig, T.
AU  - Wichmann, H.-E.
AU  - Risch, A.*
AU  - Dienemann, H.*
AU  - Kaaks, R.*
AU  - Yang, P.*
AU  - Jiang, R.X.*
AU  - Wiencke, J.K.*
AU  - Wrensch, M.*
AU  - Hansen, H.*
AU  - Kelsey, K.T.*
AU  - Matsuo, K.*
AU  - Tajima, K.*
AU  - Schwartz, A.G.*
AU  - Wenzlaff, A.*
AU  - Seow, A.*
AU  - Ying, C.*
AU  - Staratschek-Jox, A.*
AU  - Nürnberg, P.*
AU  - Stoelben, E.*
AU  - Wolf, J.*
AU  - Lazarus, P.*
AU  - Muscat, J.E.*
AU  - Gallagher, C.J.*
AU  - Zienolddiny, S.*
AU  - Haugen, A.*
AU  - van der Heijden, H.F.M.*
AU  - Kiemeney, L.A.*
AU  - Isla, D.*
AU  - Mayordomo, J.I.*
AU  - Rafnar, T.*
AU  - Stefansson, K.*
AU  - Zhang, Z.F.*
AU  - Chang, S.C.*
AU  - Kim, J.H.*
AU  - Hong, Y.C.*
AU  - Duell, E.J.*
AU  - Andrew, A.S.*
AU  - Lejbkowicz, F.*
AU  - Rennert, G.*
AU  - Müller, H.*
AU  - Brenner, H.*
AU  - Le Marchand, L.*
AU  - Benhamou, S.*
AU  - Bouchardy, C.*
AU  - Teare, M.D.*
AU  - Xue, X.Y.*
AU  - McLaughlin, J.*
AU  - Liu, G.*
AU  - McKay, J.D.*
AU  - Brennan, P.*
AU  - Spitz, M.R.*
C1  - 2019
C2  - 27388
SP  - 959-971
TI  - Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: A pooled analysis from the International Lung Cancer Consortium.
JO  - J. Natl. Cancer Inst.
VL  - 102
IS  - 13
PB  - Oxford Univ. Press
PY  - 2010
SN  - 0027-8874
ER  - 

TY  - JOUR
AU  - Vineis, P.*
AU  - Alavanja, M.*
AU  - Buffler, P.*
AU  - Fontham, E.*
AU  - Franceschi, S.*
AU  - Gao, Y.T.*
AU  - Gupta, P.C.*
AU  - Hackshaw, A.*
AU  - Matos, E.*
AU  - Samet,J.*
AU  - Sitas, F.*
C1  - 205
C2  - 22054
SP  - 99-106
TI  - Tobacco and Cancer: Recent epidemiological evidence.
JO  - J. Natl. Cancer Inst.
VL  - 96
PY  - 2004
SN  - 0027-8874
ER  - 

TY  - JOUR
AU  - Brennan, P.*
AU  - Butler, J.*
AU  - Agudo, A.*
AU  - Benhamou, S.*
AU  - Darby, S.*
AU  - Fortes, C.*
AU  - Jöckel, K.-H.*
AU  - Kreuzer, M.
AU  - Nyberg, F.*
AU  - Pohlabeln, H.*
AU  - Saracci, R.*
AU  - Wichmann, H.-E.
C1  - 21366
C2  - 19482
SP  - 426-427
TI  - Joint Effect of Diet and Environmental Tobacco Smoke on Risk of Lung Cancer Among Nonsmokers.
JO  - J. Natl. Cancer Inst.
VL  - 92
PY  - 2000
SN  - 0027-8874
ER  - 

TY  - JOUR
AU  - Boffetta, P.*
AU  - Pershagen, G.*
AU  - Jöckel, K.-H.*
AU  - Forastiere, F.*
AU  - Gabrorieau, V.*
AU  - Heinrich, J.
AU  - Kreuzer, M.
AU  - Jahn, I.*
AU  - Nyberg, F.*
AU  - Simonato, L.*
C1  - 21090
C2  - 19123
SP  - 697-701
TI  - Cigar and pipe smoking and lung cancer risk: a multicenter study from Europe.
JO  - J. Natl. Cancer Inst.
VL  - 91
PY  - 1999
SN  - 0027-8874
ER  - 

TY  - JOUR
AU  - Bonnet, M.*
AU  - Guinebretiere, J.-M.*
AU  - Kremmer, E.
AU  - Grunewald, V.*
AU  - Benhamou, E.*
AU  - Contesso, G.*
AU  - Joab, I.*
C1  - 21064
C2  - 19094
SP  - 1376-1381
TI  - Detection of Epstein-Barr Virus in Invasive Breast Cancers.
JO  - J. Natl. Cancer Inst.
VL  - 91
PY  - 1999
SN  - 0027-8874
ER  - 

TY  - JOUR
AU  - Stürzl, M.
AU  - Hohenadl, C.
AU  - Zietz, C.*
AU  - Castanos-Velez, E.*
AU  - Wunderlich, A.*
AU  - Ascherl, G.*
AU  - Biberfeld, P.*
AU  - Monini, P.*
AU  - Browning, P.J.*
AU  - Ensoli, B.*
C1  - 21380
C2  - 19496
SP  - 1725-1733
TI  - Expression of K13/v-FLIP Gene of Human Herpesvirus 8 and Apoptosis in Kaposi's Sarcoma Spindle Cells.
JO  - J. Natl. Cancer Inst.
VL  - 91
PY  - 1999
SN  - 0027-8874
ER  -