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Yin J.,Duke University | Liu H.,Duke University | Liu Z.,Duke University | Owzar K.,Duke University | And 12 more authors.
Molecular Carcinogenesis | Year: 2017

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. © 2017 Wiley Periodicals, Inc.

Berman T.A.,National Cancer InstituteNational Institutes of HealthBethesda | Schiller J.T.,National Cancer InstituteNational Institutes of HealthBethesda
Cancer | Year: 2017

Human papillomavirus (HPV) causes greater than 5% of cancers worldwide, including all cervical cancers and an alarmingly increasing proportion of oropharyngeal cancers (OPCs). Despite markedly reduced cervical cancer incidence in industrialized nations with organized screening programs, cervical cancer remains the second most common cause of death from cancer in women worldwide, as developing countries lack resources for universal, high-quality screening. In the United States, HPV-related OPC is only 1 of 5 cancers with a rising incidence since 1975 and now has taken over the cervix as the most common site of HPV-related cancer. Similar trends follow throughout North America and Europe. The need for early detection and prevention is paramount. Despite the common etiologic role of HPV in the development of cervical cancer and HPV-associated OPC, great disparity exists between incidence, screening modalities (or lack thereof), treatment, and prevention in these 2 very distinct cohorts. These differences in cervical cancer and HPV-associated OPC and their impact are discussed here. Cancer 2017. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. © 2017 American Cancer Society.

Kil W.J.,Radiology ServiceCleveland Veterans Affairs Medical CenterCleveland | Camphausen K.,National Cancer InstituteNational Institutes of HealthBethesda
Head and Neck | Year: 2017

Background: Palliative radiotherapy (RT) is not commonly offered to patients with head and neck cancer because of the belief that toxicity from the RT would not provide great palliative benefits. The purpose of this study was for us to report the advantages of cyclical hypofractionated RT (QUAD Shot) using intensity-modulated RT (IMRT) for an elderly comorbid patient with head and neck cancer. Methods: An 85-year-old multiple comorbid man with squamous cell carcinoma in the left parotid gland with left facial pain received the IMRT-QUAD Shot (14 Gy/4 fractions, twice-daily treatment with 6 hours interval, on 2 consecutive days) to lesions, which were repeated every 4 weeks 3 times. Results: With the IMRT-QUAD Shot, he achieved complete left facial pain relief without acute toxicity. At 12 months after the first IMRT-QUAD Shot, he remained without left facial pain, late toxicity, or disease recurrence impacting positively on his quality of life. Conclusion: The IMRT-QUAD shot is reasonable and safe to apply for symptom palliation in elderly multiple comorbid patients with head and neck cancer. © 2017 Wiley Periodicals, Inc.

Agarwal H.K.,Philips | Peeters J.M.,Philips | Choyke P.L.,National Cancer InstituteNational Institutes of HealthBethesda
Magnetic Resonance in Medicine | Year: 2017

Purpose: To evaluate the performance of a multi-echo spin-echo sequence with k-t undersampling scheme (k-t T2) in prostate cancer. Methods: Phantom experiments were performed at five systems to estimate the bias, short-term repeatability, and reproducibility across all systems expressed with the within-subject coefficient of variation (wCV). Monthly measurements were performed on two systems for long-term repeatability estimation. To evaluate clinical repeatability, two T2 maps (voxel size 0.8×0.8×3mm3; 5min) were acquired at separate visits on one system for 13 prostate cancer patients. Repeatability was assessed per patient in relation to spatial resolution. T2 values were compared for tumor, peripheral zone, and transition zone. Results: Phantom measurements showed a small bias (median= -0.9 ms) and good short-term repeatability (median wCV= 0.5%). Long-term repeatability was 0.9 and 1.1% and reproducibility between systems was 1.7%. The median bias observed in patients was -1.1 ms. At voxel level, the median wCV was 15%, dropping to 4% for structures of 0.5cm3. The median tumor T2 values (79 ms) were significantly lower (P<0.001) than in the peripheral zone (149 ms), but overlapped with the transition zone (91 ms). Conclusions: Reproducible T2 mapping of the prostate is feasible with good spatial resolution in a clinically reasonable scan time, allowing reliable measurement of T2 in structures as small as 0.5cm3. © 2017 International Society for Magnetic Resonance in Medicine.

Pusch S.,Institute of PathologyUniversity Hospital HeidelbergHeidelberg Germany | Wang X.W.,National Cancer InstituteNational Institutes of HealthBethesda
Hepatology | Year: 2016

Several chronic inflammatory liver diseases, e.g., chronic hepatitis B or C viral infection and steatohepatitis, have been shown to predispose to the development of hepatocellular carcinoma (HCC). In patients with chronic liver disease, interleukin-6 (IL-6) serum levels are elevated and increase even more when HCC develops. However, the impact and regulatory mechanisms of IL-6 signaling during hepatocarcinogenesis are still poorly defined. Here, we show that gene expression profiles of patients with chromosome 8p loss correlate with increased IL-6 signaling. In addition, the chromosome 8p tumor suppressor genes Src homology 2 domain containing 4A (SH2D4A) and Sorbin and Src homology 3 domain containing 3 (SORBS3) together exerted greater inhibition of cell growth and clonogenicity compared to a single gene. Overexpression of SH2D4A and SORBS3 in HCC cells led to decreased IL-6 target gene expression and reduced signal transducer and activator of transcription 3 (STAT3) signaling. In situ and in vitro coimmunoprecipitation assays revealed that SH2D4A directly interacts with STAT3, thereby retaining STAT3 in the cytoplasm and inhibiting STAT3 transcriptional activity. On the other hand, SORBS3 coactivated estrogen receptor α signaling, leading indirectly to repression of STAT3 signaling. In human HCC tissues, SH2D4A was positively associated with infiltrating regulatory and cytotoxic T-cell populations, suggesting distinct immunophenotypes in HCC subgroups with chromosome 8p loss. Thus, the genetically linked tumor suppressors SH2D4A and SORBS3 functionally cooperate to inhibit STAT3 signaling in HCC. Conclusion: The chromosome 8p tumor suppressor genes SORBS3 and SH2D4A are physically and functionally linked and provide a molecular mechanism of inhibiting STAT3-mediated IL-6 signaling in HCC cells. © 2016 by the American Association for the Study of Liver Diseases.

Jansen L.A.,Center for Ethics in Health CareOregon Health and Science UniversityPortland | Mahadevan D.,Arizona Cancer Center | Appelbaum P.S.,New York University | Klein W.M.,National Cancer InstituteNational Institutes of HealthBethesda | And 2 more authors.
Cancer | Year: 2016

BACKGROUND: Prior research has identified unrealistic optimism as a bias that might impair informed consent among patient-subjects in early-phase oncology trials. However, optimism is not a unitary construct; it also can be defined as a general disposition, or what is called dispositional optimism. The authors assessed whether dispositional optimism would be related to high expectations for personal therapeutic benefit reported by patient-subjects in these trials but not to the therapeutic misconception. The authors also assessed how dispositional optimism related to unrealistic optimism. METHODS: Patient-subjects completed questionnaires designed to measure expectations for therapeutic benefit, dispositional optimism, unrealistic optimism, and the therapeutic misconception. RESULTS: Dispositional optimism was found to be significantly associated with higher expectations for personal therapeutic benefit (Spearman rank correlation coefficient [r], 0.333; P<.0001), but was not associated with the therapeutic misconception (Spearman r, -0.075; P = .329). Dispositional optimism was found to be weakly associated with unrealistic optimism (Spearman r, 0.215; P = .005). On multivariate analysis, both dispositional optimism (P = .02) and unrealistic optimism (P<.0001) were found to be independently associated with high expectations for personal therapeutic benefit. Unrealistic optimism (P = .0001), but not dispositional optimism, was found to be independently associated with the therapeutic misconception. CONCLUSIONS: High expectations for therapeutic benefit among patient-subjects in early-phase oncology trials should not be assumed to result from misunderstanding of specific information regarding the trials. The data from the current study indicate that these expectations are associated with either a dispositionally positive outlook on life or biased expectations concerning specific aspects of trial participation. Not all manifestations of optimism are the same, and different types of optimism likely have different consequences for informed consent in early-phase oncology research. © 2016 American Cancer Society.

Goey A.K.L.,National Cancer InstituteNational Institutes of HealthBethesda | Sissung T.M.,National Cancer InstituteNational Institutes of HealthBethesda | Peer C.J.,National Cancer InstituteNational Institutes of HealthBethesda | Trepel J.B.,National Cancer InstituteNational Institutes of HealthBethesda | And 9 more authors.
Journal of Clinical Pharmacology | Year: 2015

The histone deacetylase inhibitor belinostat is eliminated through glucuronidation by UGT1A1. Polymorphisms that reduce UGT1A1 function could result in increased belinostat exposure and toxicities. We wanted to determine which single-nucleotide polymorphisms alter belinostat exposure and toxicity. In a phase 1 trial (belinostat over 48 hours in combination with cisplatin and etoposide), belinostat (400, 500, 600, or 800mg/m2/24h, 48-hour continuous infusion) was administered to patients with cancer in combination with cisplatin and etoposide (n=25). Patients were genotyped for UGT1A1 variants associated with reduced function: UGT1A1*6, UGT1A1*28, and UGT1A1*60. End points were associations between UGT1A1 genotype and belinostat pharmacokinetics (PK), toxicities, and global protein lysine acetylation (AcK). Belinostat AUC was increased (P=.003), and t1/2 increased (P=.0009) in UGT1A1*28 and UGT1A1*60 carriers who received more than 400mg/m2/24h. The incidence of grades 3-4 thrombocytopenia (P=.0081) was associated with UGT1A1 polymorphisms. The US Food and Drug Administration-approved package insert recommends dose adjustment of belinostat for UGT1A1*28. However, our data suggest dose adjustment is also necessary for UGT1A1*60. UGT1A1 polymorphisms were associated with increased systemic belinostat exposure, increased AcK, and increased incidence of toxicities, particularly at doses > 400mg/m2/24h. Published 2015.

Sawyer I.A.,Franklin University | Sturgill D.,National Cancer InstituteNational Institutes of HealthBethesda | Sung M.-H.,National Institute on AgingNational Institutes of HealthBaltimore | Hager G.L.,National Cancer InstituteNational Institutes of HealthBethesda | Dundr M.,Franklin University
BioEssays | Year: 2016

Nuclear bodies contribute to non-random organization of the human genome and nuclear function. Using a major prototypical nuclear body, the Cajal body, as an example, we suggest that these structures assemble at specific gene loci located across the genome as a result of high transcriptional activity. Subsequently, target genes are physically clustered in close proximity in Cajal body-containing cells. However, Cajal bodies are observed in only a limited number of human cell types, including neuronal and cancer cells. Ultimately, Cajal body depletion perturbs splicing kinetics by reducing target small nuclear RNA (snRNA) transcription and limiting the levels of spliceosomal snRNPs, including their modification and turnover following each round of RNA splicing. As such, Cajal bodies are capable of shaping the chromatin interaction landscape and the transcriptome by influencing spliceosome kinetics. Future studies should concentrate on characterizing the direct influence of Cajal bodies upon snRNA gene transcriptional dynamics. Also see the video abstract here. © 2016 WILEY Periodicals, Inc.

Makarova-Rusher O.V.,National Cancer InstituteNational Institutes of HealthBethesda | Altekruse S.F.,National Cancer InstituteNational Institutes of HealthBethesda | Mcneel T.S.,Information Management Services IncCalverton | Ulahannan S.,National Cancer InstituteNational Institutes of HealthBethesda | And 4 more authors.
Cancer | Year: 2016

BACKGROUND: Hepatocellular carcinoma (HCC) incidence has been increasing in the United States for several decades; and, as the incidence of hepatitis C virus (HCV) infection declines and the prevalence of metabolic disorders rises, the proportion of HCC attributable to various risk factors may be changing. METHODS: Data from the Surveillance, Epidemiology, and End Results-Medicare linkage were used to calculate population attributable fractions (PAFs) for each risk factor over time. Patients with HCC (n = 10,708) who were diagnosed during the years 2000 through 2011 were compared with a 5% random sample of cancer-free controls (n = 332,107) residing in the Surveillance, Epidemiology, and End Results areas. Adjusted odds ratios (ORs) and PAFs were calculated for HCV, hepatitis B virus (HBV), metabolic disorders, alcohol-related disorders, smoking, and genetic disorders. RESULTS: Overall, the PAF was greatest for metabolic disorders (32%), followed by HCV (20.5%), alcohol (13.4%), smoking (9%), HBV (4.3%), and genetic disorders (1.5%). The PAF for all factors combined was 59.5%. PAFs differed by race/ethnicity and sex. Metabolic disorders had the largest PAF among Hispanics (PAF, 39.3%; 95% confidence interval [CI], 31.9%-46.7%) and whites (PAF, 34.8%; 95% CI, 33.1%-36.5%), whereas HCV had the largest PAF among blacks (PAF, 36.1%; 95% CI, 31.8%-40.4%) and Asians (PAF, 29.7%; 95% CI, 25.9%-33.4%). Between 2000 and 2011, the PAF of metabolic disorders increased from 25.8% (95% CI, 22.8%-28.9%) to 36% (95% CI, 33.6%-38.5%). In contrast, the PAFs of alcohol-related disorders and HCV remained stable. CONCLUSIONS: Among US Medicare recipients, metabolic disorders contribute more to the burden of HCC than any other risk factor, and the fraction of HCC caused by metabolic disorders has increased in the last decade. © 2016 American Cancer Society.

Park J.W.,National Cancer InstituteNational Institutes of HealthBethesda | Zhao L.,National Cancer InstituteNational Institutes of HealthBethesda | Willingham M.C.,National Cancer InstituteNational Institutes of HealthBethesda | Cheng S.-y.,National Cancer InstituteNational Institutes of HealthBethesda
Molecular Carcinogenesis | Year: 2016

We have recently identified that phosphorylation at tyrosine (Y)406 is critical for the tumor suppressor functions of the thyroid hormone receptor β1 (TRβ) in a breast cancer line. However, still unclear is whether the critical tumor suppressor role of phosphorylated Y406 of TRβ is limited to only breast cancer cells or could be extended to other cell types. In the present studies, we addressed this question by stably expressing TRβ, a mutated TRβ oncogene (PV), or a TRβ mutated at Y406 (TRβY406F) in rat PCCL3 thyroid follicular cells and evaluated their tumor characteristics in athymic mice with elevated thyroid stimulating hormone. PCCL3 cells stably expressing PV (PCCL3-PV), TRβY406F (PCCL3-TRβY406F), or vector only (PCCL3-Neo) developed tumors with sizes in the rank order of TRβY406F>PV=Neo, whereas PCCL3 cells expressing TRβ (PCCL3-TRβ) barely developed tumors. As evidenced by markedly elevated Ki67, cyclin D1, and p-Rb protein abundance, proliferative activity was high in PV and TRβY406F tumors, but low in TRβ tumors. These results indicate that TRβ acted as a tumor suppressor in PCCL3 cells, whereas TRβY406F and PV had lost tumor suppressor activity. Interestingly, TRβY406F tumors had very low necrotic areas with decreased TNFα-NFκB signaling to lower apoptotic activity. In contrast, PV tumors had prominent large necrotic areas, with no apparent changes in TNFα-NFκB signaling, indicating distinct oncogenic activities of mutant PV and TRβY406F. Thus, the present studies uncovered a novel mechanism by which TRβ could function as a tumor suppressor through modulation of the TNFα-NFκB signaling. © 2016 Wiley Periodicals, Inc.

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