TY  - JOUR
AB  - Homologous recombination (HR) and poly ADP-ribosylation are partially redundant pathways for the repair of DNA damage in normal and cancer cells. In cell lines that are deficient in HR, inhibition of poly (ADP-ribose) polymerase (poly (ADP-ribose) polymerase [PARP]1/2) is a proven target with several PARP inhibitors (PARPis) currently in clinical use. Resistance to PARPi often develops, usually involving genetic alterations in DNA repair signaling cascades, but also metabolic rewiring particularly in HR-proficient cells. We surmised that alterations in metabolic pathways by cancer drugs such as Olaparib might be involved in the development of resistance to drug therapy. To test this hypothesis, we conducted a metabolism-focused clustered regularly interspaced short palindromic repeats knockout screen to identify genes that undergo alterations during the treatment of tumor cells with PARPis. Of about 3000 genes in the screen, our data revealed that mitochondrial pyruvate carrier 1 (MPC1) is an essential factor in desensitizing nonsmall cell lung cancer (NSCLC) lung cancer lines to PARP inhibition. In contrast to NSCLC lung cancer cells, triple-negative breast cancer cells do not exhibit such desensitization following MPC1 loss and reprogram the tricarboxylic acid cycle and oxidative phosphorylation pathways to overcome PARPi treatment. Our findings unveil a previously unknown synergistic response between MPC1 loss and PARP inhibition in lung cancer cells.
AU  - Furusawa, T.*
AU  - Cavero, R.*
AU  - Liu, Y.*
AU  - Li, H.*
AU  - Xu, X.*
AU  - Andresson, T.*
AU  - Reinhold, W.C.*
AU  - White, O.*
AU  - Boufraqech, M.*
AU  - Meyer, T.J.*
AU  - Hartmann, O.
AU  - Diefenbacher, M.
AU  - Pommier, Y.*
AU  - Weyemi, U.*
C1  - 70115
C2  - 56002
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1024-1037
TI  - Metabolism-focused CRISPR screen unveils mitochondrial pyruvate carrier 1 as a critical driver for PARP inhibitor resistance in lung cancer.
JO  - Mol. Carcinog.
VL  - 63
IS  - 6
PB  - Wiley
PY  - 2024
SN  - 0899-1987
ER  - 

TY  - JOUR
AB  - The P38MAPK pathway participates in regulating cell cycle, inflammation, development, cell death, cell differentiation, and tumorigenesis. Genetic variants of some genes in the P38MAPK pathway are reportedly associated with lung cancer risk. To substantiate this finding, we used six genome-wide association studies (GWASs) to comprehensively investigate the associations of 14,904 single nucleotide polymorphisms (SNPs) in 108 genes of this pathway with lung cancer risk. We identified six significant lung cancer risk-associated SNPs in two genes (CSNK2B and ZAK) after correction for multiple comparisons by a false discovery rate (FDR) < 0.20. After removal of three CSNK2B SNPs that are located in the same locus previously reported by GWAS, we performed the LD analysis and found that rs3769201 and rs7604288 were in high LD. We then chose two independent representative SNPs of rs3769201 and rs722864 in ZAK for further analysis. We also expanded the analysis by including these two SNPs from additional GWAS datasets of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). The overall effects of these two SNPs were assessed using all eight GWAS datasets (OR = 0.92, 95% CI = 0.89-0.95, and P = 1.03 × 10(-5) for rs3769201; OR = 0.91, 95% CI = 0.88-0.95, and P = 2.03 × 10(-6) for rs722864). Finally, we performed an expression quantitative trait loci (eQTL) analysis and found that these two SNPs were significantly associated with ZAK mRNA expression levels in lymphoblastoid cell lines. In conclusion, the ZAK rs3769201 and rs722864 may be functional susceptibility loci for lung cancer risk.
AU  - Feng, Y.*
AU  - Wang, Y.*
AU  - Liu, H.*
AU  - Liu, Z.*
AU  - Mills, C.*
AU  - Owzar, K.*
AU  - Xie, J.*
AU  - Han, Y.*
AU  - Qian, D.C.*
AU  - Rj, R.J.H.*
AU  - Brhane, Y.*
AU  - McLaughlin, J.*
AU  - Brennan, P.*
AU  - Bickeböller, H.*
AU  - Rosenberger, A.*
AU  - Houlston, R.S.*
AU  - Caporaso, N.*
AU  - Landi, M.T.*
AU  - Brüske, I.
AU  - Risch, A.*
AU  - Ye, Y.*
AU  - Wu, X.*
AU  - Christiani, D.C.*
AU  - Amos, C.I.*
AU  - Wei, Q.*
C1  - 52218
C2  - 43861
CY  - Hoboken
SP  - 216-224
TI  - Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer.
JO  - Mol. Carcinog.
VL  - 57
IS  - 2
PB  - Wiley
PY  - 2018
SN  - 0899-1987
ER  - 

TY  - JOUR
AB  - The fatty acids (FAs) metabolism is suggested to play a pivotal role in the development of lung cancer, and we explored that by conducting a pathway-based analysis. We performed a meta-analysis of published datasets of six genome wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, which included 12160 cases with lung cancer and 16838 cancer-free controls. A total of 30722 single-nucleotide polymorphisms (SNPs) from 317 genes relevant to FA metabolic pathways were identified. An additional dataset from the Harvard Lung Cancer Study with 984 cases and 970 healthy controls was also added to the final meta-analysis. In the initial meta-analysis, 26 of 28 SNPs that passed false discovery rate multiple tests were mapped to the CYP4F3 gene. Among the 26 top ranked hits was a proxy SNP, CYP4F3 rs4646904 (P=8.65×10-6, FDR=0.018), which is suggested to change splicing pattern/efficiency and to be associated with gene expression levels. However, after adding data of rs4646904 from the Harvard GWAS, the significance in the combined analysis was reduced to P=3.52×10-3 [odds ratio (OR)=1.07, 95% confidence interval (95%CI)=1.03-1.12]. Interestingly, the small Harvard dataset also pointed to the same direction of the association in subgroups of smokers (OR=1.07) and contributed to a combined OR of 1.13 (95% CI=1.06-1.20, P=6.70×10-5). The results suggest that a potentially functional SNP in CYP4F3 (rs4646904) may contribute to the etiology of lung cancer, especially in smokers. Additional mechanistic studies are warranted to unravel the potential biological significance of the finding.
AU  - Yin, J.*
AU  - Liu, H.*
AU  - Liu, Z.*
AU  - Owzar, K.*
AU  - Han, Y.*
AU  - Su, L.*
AU  - Wei, Y.*
AU  - Hung, R.J.*
AU  - Brhane, Y.*
AU  - McLaughlin, J.*
AU  - Brennan, P.*
AU  - Bickeboeller, H.*
AU  - Rosenberger, A.*
AU  - Houlston, R.S.*
AU  - Caporaso, N.*
AU  - Landi, M.T.*
AU  - Heinrich, J.
AU  - Risch, A.*
AU  - Christiani, D.C.*
AU  - Amos, C.I.*
AU  - Wei, Q.*
C1  - 50671
C2  - 42451
CY  - Hoboken
SP  - 1663-1672
TI  - Pathway-analysis of published genome-wide association studies of lung cancer: A potential role for the CYP4F3 locus.
JO  - Mol. Carcinog.
VL  - 56
IS  - 6
PB  - Wiley
PY  - 2017
SN  - 0899-1987
ER  - 

TY  - JOUR
AB  - PURPOSE: mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risk. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk. EXPERIMENTAL DESIGN: Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci. RESULTS: This pathway-based analysis included 6,816 single nucleotide polymorphisms (SNP) in 68 genes in 14,463 lung cancer cases and 44,188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score "1f" was chosen as the tagSNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04-1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association. CONCLUSION: The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk.
AU  - Zhou, F.S.*
AU  - Wang, Y.*
AU  - Liu, H.*
AU  - Ready, N.*
AU  - Han, Y.*
AU  - Hung, R.J.*
AU  - Brhane, Y.*
AU  - McLaughlin, J.*
AU  - Brennan, P.*
AU  - Bickeböller, H.*
AU  - Rosenberger, A.*
AU  - Houlston, R.S.*
AU  - Caporaso, N.*
AU  - Landi, M.T.*
AU  - Brüske, I.
AU  - Risch, A.*
AU  - Ye, Y.*
AU  - Wu, X.*
AU  - Christiani, D.C.*
AU  - Goodman, G.*
AU  - Chen, C.*
AU  - Amos, C.I.*
AU  - Qingyi, W.*
C1  - 49868
C2  - 41828
CY  - Hoboken
SP  - 1227-1238
TI  - Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk - a re-analysis of eight GWASs.
JO  - Mol. Carcinog.
VL  - 56
IS  - 4
PB  - Wiley
PY  - 2017
SN  - 0899-1987
ER  - 

TY  - JOUR
AU  - Ahlemann, M.*
AU  - Zeidler, R.*
AU  - Lang, S.*
AU  - Mack, B.*
AU  - Münz, M.
AU  - Gires, O.
C1  - 5329
C2  - 23941
SP  - 957-967
TI  - Carcinoma-associated elF3i overexpression facilitates mTOR-dependent growth transformation.
JO  - Mol. Carcinog.
VL  - 45
IS  - 12
PY  - 2006
SN  - 0899-1987
ER  - 

TY  - JOUR
AU  - Hergenhahn, M.*
AU  - Soto, U.*
AU  - Weninger, A.*
AU  - Polack, A.
AU  - Hsu, C.-H.*
AU  - Cheng, A.-L.*
AU  - Rösl, F.*
C1  - 21967
C2  - 20491
SP  - 137-145
TI  - The Chemopreventive Compound Curcumin is an Efficient Inhibitor of Epstein-Barr Virus BZLF1  Transcription in Raji DR-LUC Cells.
JO  - Mol. Carcinog.
VL  - 33
PY  - 2002
SN  - 0899-1987
ER  -