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1.  Identification of a functional SNP in the 3′UTR of CXCR2 that is associated with reduced risk of lung cancer 
Cancer research  2014;75(3):566-575.
Global changes in gene expression accompany the development of cancer. Thus, inherited variants in microRNA binding sites are likely candidates for conferring inherited susceptibility. Using an in-silico approach, we compiled a comprehensive list of SNPs predicted to modulate microRNA binding in genes from several key lung cancer pathways. We then investigated whether these SNPs were associated with lung cancer risk in two independent populations. In general, SNPs in microRNA binding sites are rare. However, some allelic variation was observed. We found that rs1126579 in CXCR2 was associated with a reduced risk of lung cancer in both European American (ORTT vs. CC 0.56 [0.37 – 0.88]; P=0.008) and Japanese (ORTT vs. CC 0.62 [0.38 – 1.00]; P=0.049) populations. Further, we found that the SNP disrupted a novel binding site for miR-516a-3p, led to a moderate increase in CXCR2 mRNA and protein expression and increased MAPK signaling. Moreover, analysis of rs1126579 with serum levels of IL-8, its endogenous ligand, supported an interaction whereby rs1126579-T and high serum IL-8 conferred synergistic protection from lung cancer. Our findings demonstrate a function for a 3′UTR SNP in modulating CXCR2 expression, signaling and susceptibility to lung cancer.
PMCID: PMC4315715  PMID: 25480945
2.  The expression of four genes as a prognostic classifier for stage I lung adenocarcinoma in 12 independent cohorts 
We previously developed a prognostic classifier using the expression levels of BRCA1, HIF1A, DLC1, and XPO1 that identified stage I lung adenocarcinoma patients with a high risk of relapse. That study evaluated patients in five independent cohorts from various regions of the world. In an attempt to further validate the classifier, we have used a meta-analysis based approach to study 12 cohorts consisting of 1069 TNM stage I lung adenocarcinoma patients from every suitable, publically available dataset.
Materials and Methods
Cohorts were obtained through a systematic search of public gene expression datasets. These data were used to calculate the risk score using the previously published 4-gene risk model. A fixed effects meta-analysis model was used to generate a pooled estimate for all cohorts.
The classifier was associated with prognosis in ten of the twelve cohorts (p<0.05). This association was highly consistent regardless of the ethnic diversity or microarray platform. The pooled estimate demonstrated that patients classified as high risk had worse overall survival for all stage I (Hazard Ratio [HR], 2.66; 95% Confidence Interval [CI], 1.93-3.67; P<0.0001) patients and in stratified analyses of stage IA (HR, 2.69; 95%CI, 1.66-4.35; P<0.0001) and stage IB (HR, 2.69; 95%CI, 1.74-4.16; P<0.0001) patients.
The -4-gene classifier provides independent prognostic stratification of stage IA and stage IB patients beyond conventional clinical factors
Our results suggest that the 4-gene classifier may assist clinicians in decisions regarding postoperative management of early stage lung adenocarcinoma patients.
PMCID: PMC4257875  PMID: 25242053
3.  A combined prognostic serum IL-8 and IL-6 classifier for stage 1 lung cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 
The advent of LDCT for lung cancer screening will likely lead to an increase in the detection of stage I lung cancer. Presently, these patients are primarily treated with surgery alone and ~ 30% will develop recurrence and die. Biomarkers that can identify patients for whom adjuvant chemotherapy would be a benefit could significantly reduce both patient morbidity and mortality. Herein, we sought to build a prognostic inflammatory-based classifier for stage I lung cancer.
We performed a retrospective analysis of 548 European American lung cancer cases prospectively enrolled in the Prostate, Lung, Colorectal and Ovarian (PLCO) study. CRP, IL-6, IL-8, TNFα and IL-1β were measured using an ultrasensitive electrochemiluminescence immunoassay in serum samples collected at the time of study entry.
IL-6 and IL-8 were each associated with significantly shorter survival (HR, 1.33; 95% CI, 1.08–1.64, P=0.007) (HR, 1.3; 95% CI, 1.09–1.67, P=0.005), respectively). Moreover, a combined classifier of IL-6 and IL-8 were significantly associated with poor outcome in stage I lung cancer patients (HR, 3.39; 95% C.I. 1.54 – 7.48, P=0.002) and in stage 1 patients with ≥30 pack-years of smoking (HR, 3.15; 95% C.I. 1.54 – 6.46, P=0.002).
These results further support the association between inflammatory markers and lung cancer outcome and suggest that a combined serum IL-6/IL-8 classifier could be a useful tool for guiding therapeutic decisions in stage I lung cancer patients.
PMCID: PMC4272608  PMID: 25170636
4.  Evidence that the lung adenocarcinoma EML4-ALK fusion gene is not caused by exposure to secondhand tobacco smoke during childhood 
The EML4-ALK fusion gene is more frequently found in younger, never smoking, lung cancer patients. Meanwhile, never smokers exposed to secondhand tobacco smoke (SHS) during childhood are diagnosed at a younger age compared with never smoking lung cancer patients that are not exposed. We therefore hypothesized that SHS, which can induce DNA damage, is associated with the EML4-ALK fusion gene.
We compared the frequency of the EML4-ALK fusion gene among 197 never smoker lung cancer patients with and without a history of exposure to SHS during childhood at Mayo Clinic.
The EML4-ALK fusion gene was detected in 33% of cases from never smokers with a history of SHS exposure during childhood, while 47% of never smoking lung cancer cases without a history of childhood SHS exposure tested positive for the fusion gene.
The EML4-ALK fusion gene is not enriched in tumors from individuals exposed to SHS during childhood.
These data suggest that childhood exposure to SHS is not a significant etiologic cause of the EML4-ALK fusion gene in lung cancer.
PMCID: PMC4082445  PMID: 24755712
5.  Non-invasive urinary metabolomic profiling identifies diagnostic and prognostic markers in lung cancer 
Cancer research  2014;74(12):3259-3270.
Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1500 Da) were measured in urine collected from 469 lung cancer patients and 536 population controls using unbiased liquid chromatography-mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further validated in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared to the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA), were each significantly (P <0.00001) elevated in non–small cell lung cancer (NSCLC) and associated with worse prognosis (hazard ratio (HR) =1.81 [P =0.0002], and 1.54 [P =0.025], respectively). Creatine riboside was the strongest classifier of lung cancer status in all and stage I–II cases, important for early detection, and also associated with worse prognosis in stage I–II lung cancer (HR =1.71, P =0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 – 0.99. Both metabolites were significantly (P <0.03) enriched in tumor tissue compared to adjacent non-tumor tissue (N =48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis.
PMCID: PMC4100625  PMID: 24736543
lung cancer; metabolomics; urine; diagnosis; prognosis
6.  Prognostic Significance and Molecular Features of Signet-Ring Cell and Mucinous Components in Colorectal Carcinoma 
Annals of surgical oncology  2014;22(4):1226-1235.
Colorectal carcinoma (CRC) represents a group of histopathologically and molecularly heterogeneous diseases, which may contain signet-ring cell component and/or mucinous component to a varying extent under pathology assessment. However, little is known about the prognostic significance of those components, independent of various tumor molecular features.
Utilizing a molecular pathological epidemiology database of 1,336 rectal and colon cancers in the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined patient survival according to the proportion of signet-ring cell and mucinous components in CRCs. Cox proportional hazards models were used to compute hazard ratio (HR) for mortality, adjusting for potential confounders including stage, microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and KRAS, BRAF, and PIK3CA mutations.
Compared to CRC without signet-ring cell component, 1–50 % signet-ring cell component was associated with multivariate CRC-specific mortality HR of 1.40 [95 % confidence interval (CI) 1.02–1.93], and >50 % signet-ring cell component was associated with multivariate CRC-specific mortality HR of 4.53 (95 % CI 2.53–8.12) (Ptrend > 0.0001). Compared to CRC without mucinous component, neither 1–50 % mucinous component (multivariate HR 1.04; 95 % CI 0.81–1.33) nor >50 % mucinous component (multivariate HR 0.82; 95 % CI 0.54–1.23) was significantly associated with CRC-specific mortality (Ptrend < 0.57).
Even a minor (50 % or less) signet-ring cell component in CRC was associated with higher patient mortality, independent of various tumor molecular and other clinicopathological features. In contrast, mucinous component was not associated with mortality in CRC patients.
PMCID: PMC4346446  PMID: 25326395
7.  High miR-21 expression from FFPE tissues is associated with poor survival and response to adjuvant chemotherapy in colon cancer 
Colon cancer (CC) is a leading cause of cancer mortality. Novel biomarkers are needed to identify CC patients at high risk of recurrence and those who may benefit from therapeutic intervention. The aim of this study is to investigate if miR-21 expression from RNA isolated from formalin-fixed paraffin-embedded (FFPE) tissue sections is associated with prognosis and therapeutic outcome for patients with CC. The expression of miR-21 was measured by quantitative reverse transcriptase-polymerase chain reaction in a Japanese cohort (stage I–IV, n = 156) and a German cohort (stage II, n = 145). High miR-21 expression in tumors was associated with poor survival in both the stage II/III Japanese (P = 0.0008) and stage II German (P = 0.047) cohorts. These associations were independent of other clinical covariates in multivariable models. Receipt of adjuvant chemotherapy was not beneficial in patients with high miR-21 in either cohort. In the Japanese cohort, high miR-21 expression was significantly associated with poor therapeutic outcome (P = 0.0001) and adjuvant therapy was associated with improved survival in patients with low miR-21 (P = 0.001). These results suggest that miR-21 is a promising biomarker to identify patients with poor prognosis and can be accurately measured in FFPE tissues. The expression of miR-21 may also identify patients who will benefit from adjuvant chemotherapy.
PMCID: PMC3947446  PMID: 24122631
microRNA; prognosis; colorectal cancer
8.  Germline variation in NCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer 
Chronic inflammation has been implicated in the etiology of colorectal adenoma and cancer; however, few key inflammatory genes mediating this relationship have been identified. In this study, we investigated the association of germline variation in innate immunity genes in relation to the risk of colorectal neoplasia. Our study was based on the analysis of samples collected from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We investigated the association between 196 tag single nucleotide polymorphisms (SNPs) in 20 key innate immunity genes with risk of advanced colorectal adenoma and cancer in 719 adenoma cases, 481 cancer cases and 719 controls. Logistic regression was used to estimate odds ratios and 95% confidence intervals. After Bonferroni correction, the AG/GG genotype of rs5995355, which is upstream of NCF4, was associated with an increased risk of colorectal cancer (odds ratio [OR] 2.43, 95% confidence interval [95% CI] 1.73 – 3.39; P<0.0001). NCF4 is part of the NAPDH complex, a key factor in biochemical pathways and the innate immune response. While not definitive, our analyses suggest that the variant allele does not affect expression of NCF4, but rather modulates activity of the NADPH complex. Additional studies on the functional consequences of rs5995355 in NCF4 may help to clarify the mechanistic link between inflammation and colorectal cancer.
PMCID: PMC3947351  PMID: 23982929
colorectal cancer; single nucleotide polymorphism; innate immunity; NCF4
9.  Identification of a Metastasis-Specific MicroRNA Signature in Human Colorectal Cancer 
Distant metastasis is the major cause of mortality in colorectal cancer (CRC). We performed a systemic, comprehensive discovery for expression patterns of metastasis-specific microRNAs (miRNAs) by directly comparing primary CRCs (pCRCs) and matched liver metastases (LMs) and evaluated the feasibility of their clinical application as metastasis-specific biomarkers.
CRC metastasis–specific miRNA profiles were generated by analyzing nine pairs of pCRC and LM tissues, followed by quantitative validation in an independent cohort of 58 pairs of matched pCRC and LM tissues. We evaluated associations between miRNA expression and patient survival and ability to predict metastasis in another 84 patients with CRC. Subsequently, associations were quantitatively validated in 175 CRC tissues and 169 serum samples. Kaplan-Meier, Cox regression, and logistic regression analyses were used. All statistical tests were two-sided.
Twenty-three miRNAs were identified that were differentially expressed between pCRC and LM (P < .001; FDR < .5). Four miRNAs downregulated in LM (let-7i, miR-10b, miR-221, and miR-320a) and one upregulated miR (miR-885-5p) were quantitatively validated in pCRC (P < .0001). Low let-7i expression in pCRC tissue predicted worsened prognosis (hazard ratio [HR] = 5.0, 95% confidence interval [CI] = 1.0 to 24.4, P = .0479) as well as distant metastasis (odds ratio [OR] = 5.5, 95% CI = 1.1 to 26.8, P = .0334). High miR-10b expression in pCRC tissue independently predicted distant metastasis (OR = 4.9, 95% CI = 1.2 to 19.7, P = .0248). High serum miR-885-5p expression independently predicted prognosis (HR = 2.9, 95% CI = 1.1 to 7.5, P = .0323), LN metastasis (OR = 3.0, 95% CI = 1.3 to 7.2, P = .0116), and distant metastasis (OR = 3.1, 95% CI = 1.0 to 10.0, P = .0456), whereas tissue miR-885-5p expression did not. Expression patterns of miRNAs were confirmed by in situ hybridization.
We discovered a metastasis-specific miRNA signature in pCRCs and discovered novel tissue- and serum-based CRC metastasis–specific miRNA biomarkers through intensive validation. These unique miRNAs may be clinically applicable to predict prognosis and distant metastasis in CRC.
PMCID: PMC4334826  PMID: 25663689
10.  Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33 
Wang, Zhaoming | Zhu, Bin | Zhang, Mingfeng | Parikh, Hemang | Jia, Jinping | Chung, Charles C. | Sampson, Joshua N. | Hoskins, Jason W. | Hutchinson, Amy | Burdette, Laurie | Ibrahim, Abdisamad | Hautman, Christopher | Raj, Preethi S. | Abnet, Christian C. | Adjei, Andrew A. | Ahlbom, Anders | Albanes, Demetrius | Allen, Naomi E. | Ambrosone, Christine B. | Aldrich, Melinda | Amiano, Pilar | Amos, Christopher | Andersson, Ulrika | Andriole, Gerald | Andrulis, Irene L. | Arici, Cecilia | Arslan, Alan A. | Austin, Melissa A. | Baris, Dalsu | Barkauskas, Donald A. | Bassig, Bryan A. | Beane Freeman, Laura E. | Berg, Christine D. | Berndt, Sonja I. | Bertazzi, Pier Alberto | Biritwum, Richard B. | Black, Amanda | Blot, William | Boeing, Heiner | Boffetta, Paolo | Bolton, Kelly | Boutron-Ruault, Marie-Christine | Bracci, Paige M. | Brennan, Paul | Brinton, Louise A. | Brotzman, Michelle | Bueno-de-Mesquita, H. Bas | Buring, Julie E. | Butler, Mary Ann | Cai, Qiuyin | Cancel-Tassin, Geraldine | Canzian, Federico | Cao, Guangwen | Caporaso, Neil E. | Carrato, Alfredo | Carreon, Tania | Carta, Angela | Chang, Gee-Chen | Chang, I-Shou | Chang-Claude, Jenny | Che, Xu | Chen, Chien-Jen | Chen, Chih-Yi | Chen, Chung-Hsing | Chen, Constance | Chen, Kuan-Yu | Chen, Yuh-Min | Chokkalingam, Anand P. | Chu, Lisa W. | Clavel-Chapelon, Francoise | Colditz, Graham A. | Colt, Joanne S. | Conti, David | Cook, Michael B. | Cortessis, Victoria K. | Crawford, E. David | Cussenot, Olivier | Davis, Faith G. | De Vivo, Immaculata | Deng, Xiang | Ding, Ti | Dinney, Colin P. | Di Stefano, Anna Luisa | Diver, W. Ryan | Duell, Eric J. | Elena, Joanne W. | Fan, Jin-Hu | Feigelson, Heather Spencer | Feychting, Maria | Figueroa, Jonine D. | Flanagan, Adrienne M. | Fraumeni, Joseph F. | Freedman, Neal D. | Fridley, Brooke L. | Fuchs, Charles S. | Gago-Dominguez, Manuela | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | Garcia-Closas, Reina | Gastier-Foster, Julie M. | Gaziano, J. Michael | Gerhard, Daniela S. | Giffen, Carol A. | Giles, Graham G. | Gillanders, Elizabeth M. | Giovannucci, Edward L. | Goggins, Michael | Gokgoz, Nalan | Goldstein, Alisa M. | Gonzalez, Carlos | Gorlick, Richard | Greene, Mark H. | Gross, Myron | Grossman, H. Barton | Grubb, Robert | Gu, Jian | Guan, Peng | Haiman, Christopher A. | Hallmans, Goran | Hankinson, Susan E. | Harris, Curtis C. | Hartge, Patricia | Hattinger, Claudia | Hayes, Richard B. | He, Qincheng | Helman, Lee | Henderson, Brian E. | Henriksson, Roger | Hoffman-Bolton, Judith | Hohensee, Chancellor | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Hosgood, H. Dean | Hsiao, Chin-Fu | Hsing, Ann W. | Hsiung, Chao Agnes | Hu, Nan | Hu, Wei | Hu, Zhibin | Huang, Ming-Shyan | Hunter, David J. | Inskip, Peter D. | Ito, Hidemi | Jacobs, Eric J. | Jacobs, Kevin B. | Jenab, Mazda | Ji, Bu-Tian | Johansen, Christoffer | Johansson, Mattias | Johnson, Alison | Kaaks, Rudolf | Kamat, Ashish M. | Kamineni, Aruna | Karagas, Margaret | Khanna, Chand | Khaw, Kay-Tee | Kim, Christopher | Kim, In-Sam | Kim, Jin Hee | Kim, Yeul Hong | Kim, Young-Chul | Kim, Young Tae | Kang, Chang Hyun | Jung, Yoo Jin | Kitahara, Cari M. | Klein, Alison P. | Klein, Robert | Kogevinas, Manolis | Koh, Woon-Puay | Kohno, Takashi | Kolonel, Laurence N. | Kooperberg, Charles | Kratz, Christian P. | Krogh, Vittorio | Kunitoh, Hideo | Kurtz, Robert C. | Kurucu, Nilgun | Lan, Qing | Lathrop, Mark | Lau, Ching C. | Lecanda, Fernando | Lee, Kyoung-Mu | Lee, Maxwell P. | Le Marchand, Loic | Lerner, Seth P. | Li, Donghui | Liao, Linda M. | Lim, Wei-Yen | Lin, Dongxin | Lin, Jie | Lindstrom, Sara | Linet, Martha S. | Lissowska, Jolanta | Liu, Jianjun | Ljungberg, Börje | Lloreta, Josep | Lu, Daru | Ma, Jing | Malats, Nuria | Mannisto, Satu | Marina, Neyssa | Mastrangelo, Giuseppe | Matsuo, Keitaro | McGlynn, Katherine A. | McKean-Cowdin, Roberta | McNeill, Lorna H. | McWilliams, Robert R. | Melin, Beatrice S. | Meltzer, Paul S. | Mensah, James E. | Miao, Xiaoping | Michaud, Dominique S. | Mondul, Alison M. | Moore, Lee E. | Muir, Kenneth | Niwa, Shelley | Olson, Sara H. | Orr, Nick | Panico, Salvatore | Park, Jae Yong | Patel, Alpa V. | Patino-Garcia, Ana | Pavanello, Sofia | Peeters, Petra H. M. | Peplonska, Beata | Peters, Ulrike | Petersen, Gloria M. | Picci, Piero | Pike, Malcolm C. | Porru, Stefano | Prescott, Jennifer | Pu, Xia | Purdue, Mark P. | Qiao, You-Lin | Rajaraman, Preetha | Riboli, Elio | Risch, Harvey A. | Rodabough, Rebecca J. | Rothman, Nathaniel | Ruder, Avima M. | Ryu, Jeong-Seon | Sanson, Marc | Schned, Alan | Schumacher, Fredrick R. | Schwartz, Ann G. | Schwartz, Kendra L. | Schwenn, Molly | Scotlandi, Katia | Seow, Adeline | Serra, Consol | Serra, Massimo | Sesso, Howard D. | Severi, Gianluca | Shen, Hongbing | Shen, Min | Shete, Sanjay | Shiraishi, Kouya | Shu, Xiao-Ou | Siddiq, Afshan | Sierrasesumaga, Luis | Sierri, Sabina | Loon Sihoe, Alan Dart | Silverman, Debra T. | Simon, Matthias | Southey, Melissa C. | Spector, Logan | Spitz, Margaret | Stampfer, Meir | Stattin, Par | Stern, Mariana C. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael Z. | Stram, Daniel O. | Strom, Sara S. | Su, Wu-Chou | Sund, Malin | Sung, Sook Whan | Swerdlow, Anthony | Tan, Wen | Tanaka, Hideo | Tang, Wei | Tang, Ze-Zhang | Tardon, Adonina | Tay, Evelyn | Taylor, Philip R. | Tettey, Yao | Thomas, David M. | Tirabosco, Roberto | Tjonneland, Anne | Tobias, Geoffrey S. | Toro, Jorge R. | Travis, Ruth C. | Trichopoulos, Dimitrios | Troisi, Rebecca | Truelove, Ann | Tsai, Ying-Huang | Tucker, Margaret A. | Tumino, Rosario | Van Den Berg, David | Van Den Eeden, Stephen K. | Vermeulen, Roel | Vineis, Paolo | Visvanathan, Kala | Vogel, Ulla | Wang, Chaoyu | Wang, Chengfeng | Wang, Junwen | Wang, Sophia S. | Weiderpass, Elisabete | Weinstein, Stephanie J. | Wentzensen, Nicolas | Wheeler, William | White, Emily | Wiencke, John K. | Wolk, Alicja | Wolpin, Brian M. | Wong, Maria Pik | Wrensch, Margaret | Wu, Chen | Wu, Tangchun | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xiang, Yong-Bing | Xu, Jun | Yang, Hannah P. | Yang, Pan-Chyr | Yatabe, Yasushi | Ye, Yuanqing | Yeboah, Edward D. | Yin, Zhihua | Ying, Chen | Yu, Chong-Jen | Yu, Kai | Yuan, Jian-Min | Zanetti, Krista A. | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Zhou, Baosen | Mirabello, Lisa | Savage, Sharon A. | Kraft, Peter | Chanock, Stephen J. | Yeager, Meredith | Landi, Maria Terese | Shi, Jianxin | Chatterjee, Nilanjan | Amundadottir, Laufey T.
Human Molecular Genetics  2014;23(24):6616-6633.
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10−39; Region 3: rs2853677, P = 3.30 × 10−36 and PConditional = 2.36 × 10−8; Region 4: rs2736098, P = 3.87 × 10−12 and PConditional = 5.19 × 10−6, Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10−6; and Region 6: rs10069690, P = 7.49 × 10−15 and PConditional = 5.35 × 10−7) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10−18 and PConditional = 7.06 × 10−16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
PMCID: PMC4240198  PMID: 25027329
11.  NOS2 enhances KRAS-induced lung carcinogenesis, inflammation and microRNA-21 expression 
Mutant KRAS in lung cancers induce molecular pathways that regulate cellular proliferation, survival and inflammation, which enhance tumorigenesis. Inducible nitric oxide synthese (NOS2) up-regulation and sustained nitric oxide (NO•) generation are induced during the inflammatory response and correlate positively with lung tumorigenesis. To explore the mechanistic contribution of NOS2 to KRAS-induced lung tumorigenesis and inflammation, we used a genetic strategy of crossing NOS2 knockout (NOS2KO) C57BL6 inbred mice with a KRASG12D-driven mouse lung cancer model. KRASG12D;NOS2KO mice exhibited delayed lung tumorigenesis and a longer overall survival time compared with that of KRASG12D;NOS2WT (wild-type) controls. Correspondingly, tumors in KRASG12D;NOS2KO mice had reduced tumor cell proliferation in adenomas and carcinomas. NOS2-deficiency also led to dramatically suppressed inflammatory response by attenuation of macrophage recruitment into alveoli and within tumor foci. In contrast, FOXP3+ regulatory T cells were increased in tumors from KRASG12D;NOS2KO mice. We further analyzed the expression of microRNA-21 (miR-21), an oncogenic non-coding RNA involved in oncogenic Ras signaling, by quantitative reverse transcription PCR and in situ hybridization. Lung carcinomas dissected from KRASG12D;NOS2KO mice showed a significantly reduced miR-21 expression along with decreased tumor cell proliferation, suggesting that NOS2-deficiency could attenuate RAS signaling pathways that transactivate miR-21 expression. Therefore, deletion of NOS2 decreases lung tumor growth as well as inflammatory responses initiated by oncogenic KRAS, suggesting that both KRAS and NOS2 cooperate in driving lung tumorigenesis and inflammation. Inhibition of NOS2 may have a therapeutic value in lung cancers with oncogenic KRAS mutations.
PMCID: PMC3473150  PMID: 22618808
Lung cancer; KRAS; NOS2; miR-21; inflammation
12.  MDM2 SNP285 does not antagonize the effect of SNP309 in lung cancer 
Conflicting reports exist regarding the contribution of SNP309 in MDM2 to cancer risk. Recently, SNP285 was shown to act as an antagonist to SNP309 by over-riding the effect of SNP309 on SP1-mediated transcription. Moreover, SNP285 modified the relationship between SNP309 and risk of breast, ovarian and endometrial cancer. We assessed whether SNP285 confounded the effect of SNP309 in lung cancer in a cohort of 720 controls and 556 cases. Our cohort included both Caucasians and African Americans. Neither SNP309 nor SNP285 were associated with lung cancer risk or survival. In addition, removal of individuals who carried the variant C allele of SNP285 did not modify the association between SNP309 with either lung cancer risk or survival. While an effect of SNP285 has been demonstrated in breast, ovarian and endometrial cancer, our findings do not support a role for this SNP in lung cancer and raise the possibility that the effect of SNP285 is restricted to cancers in women.
PMCID: PMC3414691  PMID: 22487911
13.  p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes 
The Journal of Clinical Investigation  2013;123(12):5247-5257.
Cellular senescence contributes to aging and decline in tissue function. p53 isoform switching regulates replicative senescence in cultured fibroblasts and is associated with tumor progression. Here, we found that the endogenous p53 isoforms Δ133p53 and p53β are physiological regulators of proliferation and senescence in human T lymphocytes in vivo. Peripheral blood CD8+ T lymphocytes collected from healthy donors displayed an age-dependent accumulation of senescent cells (CD28–CD57+) with decreased Δ133p53 and increased p53β expression. Human lung tumor-associated CD8+ T lymphocytes also harbored senescent cells. Cultured CD8+ blood T lymphocytes underwent replicative senescence that was associated with loss of CD28 and Δ133p53 protein. In poorly proliferative, Δ133p53-low CD8+CD28– cells, reconstituted expression of either Δ133p53 or CD28 upregulated endogenous expression of each other, which restored cell proliferation, extended replicative lifespan and rescued senescence phenotypes. Conversely, Δ133p53 knockdown or p53β overexpression in CD8+CD28+ cells inhibited cell proliferation and induced senescence. This study establishes a role for Δ133p53 and p53β in regulation of cellular proliferation and senescence in vivo. Furthermore, Δ133p53-induced restoration of cellular replicative potential may lead to a new therapeutic paradigm for treating immunosenescence disorders, including those associated with aging, cancer, autoimmune diseases, and HIV infection.
PMCID: PMC3859419  PMID: 24231352
14.  Tumor LINE-1 Methylation Level and Microsatellite Instability in Relation to Colorectal Cancer Prognosis 
Hypomethylation in long interspersed nucleotide element-1 (LINE-1) and high-degree microsatellite instability (MSI-high) in colorectal cancer (CRC) have been associated with inferior and superior survival, respectively; however, it remains uncertain whether the prognostic association of LINE-1 hypomethylation differs by MSI status. We hypothesized that the adverse prognostic association of LINE-1 hypomethylation might be stronger in MSI-high CRCs than in microsatellite stable (MSS) CRCs.
Utilizing 1211 CRCs in the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined patient survival according to LINE-1 hypomethylation status in strata of MSI status. A Cox proportional hazards model was used to compute multivariable CRC-specific mortality hazard ratios (HRs) for a 10% decrease in LINE-1 methylation level (range = 23.1–93.1%), adjusting for potential confounders, including CpG island methylator phenotype, and KRAS, BRAF, and PIK3CA mutations. Statistical tests (log-rank test, chi-square test, and likelihood ratio test) were two-sided.
In MSI-high cancers, the association of LINE-1 hypomethylation with higher mortality (HR = 2.45, 95% confidence interval [CI] = 1.64 to 3.66, P < .001) was stronger than that in MSS cancers (HR = 1.10, 95% CI = 0.98 to 1.24, P = .11) (P interaction < .001, between LINE-1 and MSI statuses). In MSI-high cases with CRC family history, the association of LINE-1 hypomethylation with higher mortality (HR = 5.13, 95% CI = 1.99 to 13.2; P < .001) was stronger than that in MSI-high cases without CRC family history (HR = 1.62, 95% CI = 0.89 to 2.94, P = .11) (P interaction = .02, between LINE-1 and CRC family history statuses).
The association of LINE-1 hypomethylation with inferior survival is stronger in MSI-high CRCs than in MSS CRCs. Tumor LINE-1 methylation level may be a useful prognostic biomarker to identify aggressive carcinomas among MSI-high CRCs.
PMCID: PMC4161997  PMID: 25190725
15.  The Role of microRNAs in Colorectal Cancer 
Cancer Journal (Sudbury, Mass.)  2012;18(3):244-252.
Over the last decade, it has become clear that aberrant microRNA expression has a functional role in the initiation and progression of colorectal cancer (CRC). Specific microRNAs can act as either tumor suppressors or oncogenes depending on the cellular environment in which they are expressed. The expression of microRNAs is reproducibly altered in CRC and their expression patterns are associated with diagnosis, prognosis and therapeutic outcome in CRC. Studies have begun to examine the association of microRNA related polymorphisms and their association with CRC incidence and prognosis as well as the possibility of using circulating microRNAs or fecal microRNA expression as non-invasive early detection biomarkers. These data suggest that microRNAs may be potential molecular classifiers, early detection biomarkers and therapeutic targets for CRC. Here, we will review the evidence demonstrating a role of microRNAs in CRC.
PMCID: PMC3397427  PMID: 22647361
16.  Caught in the cross fire: p53 in inflammation 
Carcinogenesis  2014;35(8):1680-1690.
The p53 transcription factor is a major tumor suppressor, whose diverse activities serve to ensure genome stability and inhibit neoplastic processes. In recent years, it is becoming increasingly clear that p53 also plays a broader role in maintaining cellular homeostasis, as well as contributing to tissue homeostasis in a non-cell-autonomous fashion. Chronic inflammation is a potential cancer-promoting condition, and as such is also within the radar of p53, which mounts a multifaceted attempt to prevent the escalation of chronic tissue imbalance into neoplasia. Recent understanding of the p53 pathway and other family members reveals a broad interaction with inflammatory elements such as reactive oxygen and nitrogen species, cytokines, infectious agents and major immune-regulatory pathways like nuclear factor-kappaB. This complex cross talk is highly dependent on p53 status, as different p53 isoforms and p53 mutants can mediate different responses and even promote chronic inflammation and associated cancer, acting in the tumor cells as well as in the stromal and immune compartments.
PMCID: PMC4123652  PMID: 24942866
17.  3′ UTR and functional secretor haplotypes in mannose-binding lectin 2 are associated with increased colon cancer risk in African Americans 
Cancer research  2012;72(6):1467-1477.
Because chronic intestinal inflammation is a risk factor for colorectal cancer, we hypothesized that genetic variants of inflammatory mediators, such as mannose-binding lectin 2 (MBL2), are associated with colon cancer susceptibility. Here we report the association of 24 MBL2 single nucleotide polymorphisms (SNPs) and corresponding haplotypes with colon cancer risk in a case-control study. Four SNPs in the 3′-UTR region of the gene (rs10082466, rs2120132, rs2099902, and rs10450310) were associated with an increased risk of colon cancer in African Americans. Odds ratios (OR) for homozygous variants vs. wild-type ranged from 3.17 (95% CI, 1.57–6.40) to 4.51 (95% CI, 1.94–10.50), whereas the 3′-UTR region haplotype consisting of these four variants had an OR of 2.10 (95% CI, 1.42–3.12). The C allele of rs10082466 exhibited a binding affinity of miR-27a and this allele was associated with both lower MBL plasma levels and activity. We found that 5′ secretor haplotypes known to correlate with moderate and low MBL serum levels exhibited associations with increased risk of colon cancer in African Americans, specifically as driven by two haplotypes LYPA and LYQC relative to the referent HYPA haplotype (LYPA: OR 2.60; 95% CI 1.33–5.08 and LYQC: OR 2.28; 95% CI 1.20–4.30). Similar associations were not displayed in Caucasians. Together, our results support the hypothesis that genetic variations in MBL2 increase colon cancer susceptibility in African Americans.
PMCID: PMC3306468  PMID: 22282660
colon cancer; single nucleotide polymorphism; mannose-binding lectin 2; innate immunity; African American
18.  Circulating microRNA Expression Profiles in Early Stage Non-Small Cell Lung Cancer 
Circulating micro-RNA (miR) profiles have been proposed as promising diagnostic and prognostic biomarkers for cancer, including lung cancer. We have developed methods to accurately and reproducibly measure microRNA levels in serum and plasma. Here we study paired serum and plasma samples from 220 patients with early stage NSCLC and 220 matched controls. We use qRT-PCR to measure the circulating levels of 30 different miRs that have previously been reported to be differently expressed in lung cancer tissue. Duplicate RNA extractions were performed for 10% of all samples and microRNA measurements were highly correlated among those duplicates. This demonstrates high reproducibility of our assay. The expression of miR-146b, miR-221, let-7a, miR-155, miR-17-5p, miR-27a and miR-106a were significantly reduced in the serum of NSCLC cases while miR-29c was significantly increased. No significant differences were observed in plasma of patients compared to controls. Overall, expression levels in serum did not correlate well with levels in plasma. In secondary analyses, reduced plasma expression of let-7b was modestly associated with worse cancer-specific mortality in all patients and reduced serum expression of miR-223 was modestly associated with cancer-specific mortality in stage IA/B patients. MiR profiles also showed considerable differences comparing African American and European Americans. In summary, we found significant differences in miR expression when comparing cases and controls and find evidence that expression of let-7b is associated with prognosis in NSCLC.
PMCID: PMC3259258  PMID: 21544802
19.  Increased Levels of Circulating Interleukin 6, Interleukin 8, C-Reactive Protein, and Risk of Lung Cancer 
Previous studies that were based primarily on small numbers of patients suggested that certain circulating proinflammatory cytokines may be associated with lung cancer; however, large independent studies are lacking.
Associations between serum interleukin 6 (IL-6) and interleukin 8 (IL-8) levels and lung cancer were analyzed among 270 case patients and 296 control subjects participating in the National Cancer Institute-Maryland (NCI-MD) case–control study. Results were validated in 532 case patients and 595 control subjects in a nested case–control study within the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Association with C-reactive protein (CRP), a systemic inflammation biomarker, was also analyzed. Associations between biomarkers and lung cancer were estimated using logistic regression models adjusted for smoking, stage, histology, age, and sex. The 10-year standardized absolute risks of lung cancer were estimated using a weighted Cox regression model.
Serum IL-6 and IL-8 levels in the highest quartile were associated with lung cancer in the NCI-MD study (IL-6, odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.88 to 5.77; IL-8, OR = 2.06, 95% CI = 1.19 to 3.57) and with lung cancer risk in the PLCO study (IL-6, OR = 1.48, 95% CI = 1.04 to 2.10; IL-8, OR = 1.57, 95% CI = 1.10 to 2.24), compared with the lowest quartile. In the PLCO study, increased IL-6 levels were only associated with lung cancer diagnosed within 2 years of blood collection, whereas increased IL-8 levels were associated with lung cancer diagnosed more than 2 years after blood collection (OR = 1.57, 95% CI = 1.15 to 2.13). The 10-year standardized absolute risks of lung cancer in the PLCO study were highest among current smokers with high IL-8 and CRP levels (absolute risk = 8.01%, 95% CI = 5.77% to 11.05%).
Although increased levels of both serum IL-6 and IL-8 are associated with lung cancer, only IL-8 levels are associated with lung cancer risk several years before diagnosis. Combination of IL-8 and CRP are more robust biomarkers than either marker alone in predicting subsequent lung cancer.
PMCID: PMC3139587  PMID: 21685357
20.  Biomarkers of Coordinate Metabolic Reprogramming in Colorectal Tumors in Mice and Humans 
Gastroenterology  2014;146(5):1313-1324.
There are no robust noninvasive methods for colorectal cancer screening and diagnosis. Metabolomic and gene expression analyses of urine and tissue samples from mice and humans were used to identify markers of colorectal carcinogenesis.
Mass spectrometry-based metabolomic analyses of urine and tissues from wild-type C57BL/6J and ApcMin/+ mice, as well as from mice with azoxymethane-induced tumors, was employed in tandem with gene expression analysis. Metabolomics profiles were also determined on colon tumor and adjacent non-tumor tissues from 39 patients. The effects of β-catenin activity on metabolic profiles were assessed in mice with colon-specific disruption of Apc.
Thirteen markers were found in urine associated with development of colorectal tumors in ApcMin/+ mice. Metabolites related to polyamine metabolism, nucleic acid metabolism, and methylation, identified tumor-bearing mice with 100% accuracy, and also accurately identified mice with polyps. Changes in gene expression in tumor samples from mice reflected the observed changes in metabolic products detected in urine; similar changes were observed in mice with azoxymethane-induced tumors and mice with colon-specific activation of β-catenin. The metabolic alterations indicated by markers in urine therefore appear to occur during early stages of tumorigenesis, when cancer cells are proliferating. In tissues from patients, tumors had stage-dependent increases in 12 metabolites associated with the same metabolic pathways identified in mice (including amino acid metabolism and polyamine metabolism). Ten metabolites that were increased in tumor tissues, compared with non-tumor tissues (proline, threonine, glutamic acid, arginine, N1-acetylspermidine, xanthine, uracil, betaine, symmetric dimethylarginine, and asymmetric-dimethylarginine), were also increased in urine from tumor-bearing mice.
Gene expression and metabolomic profiles of urine and tissue samples from mice with colorectal tumors and of colorectal tumor samples from patients revealed metabolites associated with specific metabolic changes that are indicative of early-stage tumor development. These urine and tissue markers might be used in early detection of colorectal cancer.
PMCID: PMC3992178  PMID: 24440673
AOM; colon cancer; mouse model; mechanism
21.  Association of TP53 Mutations with Stem Cell-Like Gene Expression and Survival of Patients with Hepatocellular Carcinoma 
Gastroenterology  2010;140(3):1063-1070.e8.
Background & Aims
Mutations in TP53, a tumor suppressor gene, are associated with prognosis of many cancers. However, the prognostic values of TP53 mutation sites are not known for patients with hepatocellular carcinoma (HCC) because of heterogeneity in their geographic and etiological backgrounds.
TP53 mutations were investigated in a total of 409 HCC patients, including Chinese (n=336) and Caucasian (n=73) patients, using direct sequencing method.
A total of 125 TP53 mutations were found in Chinese patients with HCC (37.2 %). HCC patients with TP53 mutations had a shorter overall survival time compared with patients with wild-type TP53 (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.37–2.52; P<0.001). The hotspot mutations R249S and V157F were significantly associated with worse prognosis in univariate (HR, 2.11; 95% CI, 1.51–2.94; P<0.001) and multivariate analyses (HR, 1.79; 95% CI, 1.29–2.51; P<0.001). Gene expression analysis revealed the existence of stem cell-like traits in tumors with TP53 mutations. These findings were validated in breast and lung tumor samples with TP53 mutations.
TP53 mutations, particularly the hotspot mutations R249S and V157F, are associated with poor prognosis for patients with HCC. The acquisition of stem cell-like gene expression traits might contribute to the aggressive behavior of tumors with TP53 mutation.
PMCID: PMC3057345  PMID: 21094160
Liver cancer; p53; gene expression patterns; cancer stem cells
22.  Increased MicroRNA-34b and -34c Predominantly Expressed in Stromal Tissues Is Associated with Poor Prognosis in Human Colon Cancer 
PLoS ONE  2015;10(4):e0124899.
The microRNA-34 family (miR-34a, -34b and -34c) have been reported to be tumor suppressor microRNAs (miRNAs) that are regulated by the TP53 and DNA hypermethylation. However, the expression, regulation, and prognostic value of the miR-34 family have not been systematically studied in colon cancer. To elucidate the roles of miR-34 family in colon carcinogenesis, miR-34a/b/c were measured in tumors and adjacent noncancerous tissues from 159 American and 113 Chinese colon cancer patients using quantitative RT-PCR, and we examined associations between miR-34a/b/c expression with TNM staging, cancer-specific mortality, TP53 mutation status and Affymetrix microarray data. All miR-34 family members were significantly increased in colon tumors, counter to the proposed tumor suppressor role for these miRNAs. Increased miR-34b/c were observed in more advanced tumors in two independent cohorts and increased expression of miR-34b/c was associated with poor cancer-specific mortality. While the expression of miR-34 family was not associated with TP53 mutation status, TP53 transcriptional activity was associated with miR-34a/b/c expression that is consistent with the proposed regulation of miR-34a/b/c by TP53. To examine where the miR-34 family is expressed, the expression of miR-34 family was compared between epitheliums and stromal tissues using laser microdissection technique. The expression of miR-34b/c was increased significantly in stromal tissues, especially in cancer stroma, compared with epithelial tissue. In conclusion, increased miR-34b/c predominantly expressed in stromal tissues is associated with poor prognosis in colon cancer. MiR-34 may contribute to cancer-stromal interaction associated with colon cancer progression.
PMCID: PMC4404052  PMID: 25894979
23.  Inflammatory and microRNA Gene Expression as Prognostic Classifiers of Barrett's Associated Esophageal Adenocarcinoma 
Esophageal cancer is one of the most aggressive and deadly forms of cancer; highlighting the need to identify biomarkers for early detection and prognostic classification. Our recent studies have identified inflammatory gene and microRNA signatures derived from tumor and nontumor tissues as prognostic biomarkers of hepatocellular, lung, and colorectal adenocarcinoma. Here, we examine the relationship between expression of these inflammatory genes and miRNA expression in esophageal adenocarcinoma and patient survival.
Experimental Design
We measured the expression of 23 inflammation-associated genes in tumors and adjacent normal tissues from 93 patients (58 Barrett's and 35 Sporadic adenocarcinomas) by quantitative reverse transcription-polymerase chain reaction. These data were used to build an inflammatory risk model, based on multivariate Cox regression, to predict survival in a training cohort (n=47). We then determined if this model could predict survival in a cohort of 46 patients. Expression data for miRNA-375 was available for these patients and was combined with inflammatory gene expression.
IFNγ, IL-1α, IL-8, IL-21, IL-23, and PRG expression in tumor and nontumor samples were each associated with poor prognosis based on Cox regression ([Z-score]>1.5) and therefore, were used to generate an inflammatory risk score (IRS). Patients with a high IRS had poor prognosis compared to those with a low IRS in the training (P=0.002) and test (P=0.012) cohorts. This association was stronger in the group with Barrett's history. When combining with miRNA-375, the combined IRS/miR signature was an improved prognostic classifier than either one alone.
Transcriptional profiling of inflammation-associated genes and miRNA expression in resected esophageal Barrett's associated adenocarcinoma tissues may have clinical utility as predictors of prognosis.
PMCID: PMC2999658  PMID: 20947516
Inflammation; Cancer; Barrett's; Esophagus
24.  p53 governs telomere regulation feedback too, via TRF2 
Aging (Albany NY)  2011;3(1):26-32.
p53 takes critical part in a number of positive and negative feedback loops to regulate carcinogenesis, aging and other biological processes. Uncapped or dysfunctional telomeres are an endogenous DNA damage that activates ATM kinase (ataxia telangiectasia mutated) and then p53 to induce cellular senescence or apoptosis. Our recent study shows that p53, a downstream effector of the telomere damage signaling, also functions upstream of the telomere-capping protein complex by inhibiting one of its components, TRF2 (telomeric repeat binding factor 2). Since TRF2 inhibition leads to ATM activation, a novel positive feedback loop exists to amplify uncapped telomere-induced, p53-mediated cellular responses. Siah1 (seven in absentia homolog 1), a p53-inducible E3 ubiquitin ligase, plays a key role in this feedback regulation by targeting TRF2 for ubiquitination and proteasomal degradation. Biological significance and therapeutic implications of this study are discussed.
PMCID: PMC3047136  PMID: 21266744
telomere uncapping; p53; ubiquitin ligase; TRF2; feedback regulation
25.  Childhood Exposure to Secondhand Smoke and Functional Mannose Binding Lectin Polymorphisms Are Associated with Increased Lung Cancer Risk 
Exposure to secondhand smoke during adulthood has detrimental health effects, including increased lung cancer risk. Compared with adults, children may be more susceptible to secondhand smoke. This susceptibility may be exacerbated by alterations in inherited genetic variants of innate immunity genes. We hypothesized a positive association between childhood secondhand smoke exposure and lung cancer risk that would be modified by genetic polymorphisms in the mannose binding lectin-2 (MBL2) gene resulting in well-known functional changes in innate immunity.
Childhood secondhand smoke exposure and lung cancer risk was assessed among men and women in the ongoing National Cancer Institute-Maryland Lung Cancer (NCI-MD) study, which included 624 cases and 348 controls. Secondhand smoke history was collected via in-person interviews. DNA was used for genotyping the MBL2 gene. To replicate, we used an independent case-control study from Mayo Clinic consisting of 461 never smokers, made up of 172 cases and 289 controls. All statistical tests were two-sided.
In the NCI-MD study, secondhand smoke exposure during childhood was associated with increased lung cancer risk among never smokers [odds ratio (OR), 2.25; 95% confidence interval (95% CI), 1.04-4.90]. This was confirmed in the Mayo study (OR, 1.47; 95% CI, 1.00-2.15). A functional MBL2 haplotype associated with high circulating levels of MBL and increased MBL2 activity was associated with increased lung cancer risk among those exposed to childhood secondhand smoke in both the NCI-MD and Mayo studies (OR, 2.52; 95% CI, 1.13-5.60, and OR, 2.78; 95% CI, 1.18-3.85, respectively).
Secondhand smoke exposure during childhood is associated with increased lung cancer risk among never smokers, particularly among those possessing a haplotype corresponding to a known overactive complement pathway of the innate immune system.
PMCID: PMC2951599  PMID: 19959685

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