bluuebunny/crossref_metadata_2025_split huggingface dataset:
Germline Missense Variants in the BTNL2 Gene Are Associated with Prostate Cancer Susceptibility
Authors: FitzGerald Liesel M. , Kumar Akash , Boyle Evan A. , Zhang Yuzheng , McIntosh Laura M. , Kolb Suzanne , Stott-Miller Marni , Smith Tiffany , Karyadi Danielle M. , Ostrander Elaine A. , Hsu Li , Shendure Jay , Stanford Janet L. 
Published: July 2013

Abstract
Background: Rare, inherited mutations account for 5% to 10% of all prostate cancer cases. However, to date, few causative mutations have been identified.
Methods: To identify rare mutations for prostate cancer, we conducted whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early-onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 prostate cancer cases; n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case–control study (n = 1,155 incident prostate cancer cases; n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry.
Results: The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p.Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651; P = 0.0032) and 1.2% (rs28362675; P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated prostate cancer risk in the population-based study (rs41441651: OR, 2.7; 95% CI, 1.27–5.87; P = 0.010; rs28362675: OR, 2.5; 95% CI, 1.16–5.46; P = 0.019).
Conclusions: Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer.
Impact: Results implicate BTNL2 as a novel prostate cancer susceptibility gene. Cancer Epidemiol Biomarkers Prev; 22(9); 1520–8. ©2013 AACR.
Long-Term Statin Use and Risk of Ductal and Lobular Breast Cancer among Women 55 to 74 Years of Age
Authors: McDougall Jean A. , Malone Kathleen E. , Daling Janet R. , Cushing-Haugen Kara L. , Porter Peggy L. , Li Christopher I. 
Published: July 2013

Abstract
Background: Mechanistic studies largely support the chemopreventive potential of statins. However, results of epidemiologic studies investigating statin use and breast cancer risk have been inconsistent and lacked the ability to evaluate long-term statin use.
Methods: We used data from a population-based case–control study of breast cancer conducted in the Seattle–Puget Sound region to investigate the relationship between long-term statin use and breast cancer risk. Nine hundred sixteen invasive ductal carcinoma (IDC) and 1,068 invasive lobular carcinoma (ILC) cases in patients 55 to 74 years of age diagnosed between 2000 and 2008 were compared with 902 control women. All participants were interviewed in-person and data on hypercholesterolemia and all episodes of lipid-lowering medication use were collected through a structured questionnaire. We assessed the relationship between statin use and IDC and ILC risk using polytomous logistic regression.
Results: Current users of statins for 10 years or longer had a 1.83-fold increased risk of IDC [95% confidence interval (CI): 1.14–2.93] and a 1.97-fold increased risk of ILC (95% CI: 1.25–3.12) compared with never users of statins. Among women diagnosed with hypercholesterolemia, current users of statins for 10 years or longer had more than double the risk of both IDC (OR: 2.04, 95% CI: 1.17–3.57) and ILC (OR: 2.43, 95% CI: 1.40–4.21) compared with never users.
Conclusion: In this contemporary population-based case–control study, long-term use of statins was associated with increased risks of both IDC and ILC.
Impact: Additional studies with similarly high frequencies of statin use for various durations are needed to confirm this novel finding. Cancer Epidemiol Biomarkers Prev; 22(9); 1529–37. ©2013 AACR.
Cutaneous Markers of Photo-Damage and Risk of Basal Cell Carcinoma of the Skin: A Meta-Analysis
Authors: Khalesi Mohammad , Whiteman David C. , Doi Suhail A.R. , Clark Justin , Kimlin Michael G. , Neale Rachel E. 
Published: July 2013

Abstract
Epidemiologic research has shown that cutaneous markers of photo-damage are associated with risk of basal cell carcinoma (BCC). However, there has been no previous attempt to calculate pooled risk estimates. We conducted a systematic review and meta-analysis after extracting relevant studies published up to January 2013 from five electronic databases. Eligible studies were those that permitted quantitative assessment of the association between histologically confirmed BCC and actinic keratoses, solar elastosis, solar lentigines, or telangiectasia. Seven eligible studies were identified and summary odds ratios (ORs) were calculated using both random and quality effects models. Having more than ten actinic keratoses was most strongly associated with BCC, conferring up to a fivefold increase in risk (OR: 4.97; 95% CI: 3.26–7.58). Other factors, including solar elastosis, solar lentigines, and telangiectasia had weaker but positive associations with BCC with ORs around 1.5. Markers of chronic photo-damage are positively associated with BCC. The presence of actinic keratoses was the most strongly associated with BCC of the markers examined. This work highlights the relatively modest association between markers of chronic ultraviolet exposure and BCC. Cancer Epidemiol Biomarkers Prev; 22(9); 1483–9. ©2013 AACR.
Frequent Antibiotic Use and Second Breast Cancer Events
Authors: Wirtz Heidi S. , Buist Diana S.M. , Gralow Julie R. , Barlow William E. , Gray Shelly , Chubak Jessica , Yu Onchee , Bowles Erin J.A. , Fujii Monica , Boudreau Denise M. 
Published: July 2013

AbstractBackground: Antibiotic use may be associated with higher breast cancer risk and breast cancer mortality, but no study has evaluated the relation between antibiotic use and second breast cancer events (SBCE).Methods: We conducted a retrospective cohort study among women ≥18 years, diagnosed with incident stage I/II breast cancer during 1990–2008. Antibiotic use and covariates were obtained from health plan administrative databases and medical record review. Frequent antibiotic use was defined as ≥4 antibiotic dispensings in any moving 12-month period after diagnosis. Our outcome was SBCE defined as recurrence or second primary breast cancer. We used multivariable Cox proportional hazards models to estimate HR and 95% confidence intervals (CI), accounting for competing risks.Results: A total of 4,216 women were followed for a median of 6.7 years. Forty percent were frequent antibiotic users and 558 (13%) had an SBCE. Results are suggestive of a modest increased risk of SBCE (HR, 1.15; 95% CI, 0.88–1.50) among frequent antibiotic users compared with nonusers. Any potential increased risk was not supported when we evaluated recent use and past use. We observed no dose–response trends for SBCE with increasing duration of antibiotic use nor did we find evidence for altered SBCE risk in the antibiotic classes studied.Conclusions: Frequent antibiotic use may be associated with modestly elevated risk of SBCEs, but the association was not significant.Impact: Additional investigation by antibiotic class and underlying indication are important next steps given the high prevalence of frequent antibiotic use and growing number of breast cancer survivors. Cancer Epidemiol Biomarkers Prev; 22(9); 1588–99. ©2013 AACR.
Molecular Pathways: MERTK Signaling in Cancer
Authors: Cummings Christopher T. , DeRyckere Deborah , Earp H. Shelton , Graham Douglas K. 
Published: July 2013

AbstractMERTK is a receptor tyrosine kinase of the TAM (Tyro3, Axl, MERTK) family, with a defined spectrum of normal expression. However, MERTK is overexpressed or ectopically expressed in a wide variety of cancers, including leukemia, non–small cell lung cancer, glioblastoma, melanoma, prostate cancer, breast cancer, colon cancer, gastric cancer, pituitary adenomas, and rhabdomyosarcomas, potentially resulting in the activation of several canonical oncogenic signaling pathways. These include the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, as well as regulation of signal transducer and activator of transcription family members, migration-associated proteins including the focal adhesion kinase and myosin light chain 2, and prosurvival proteins such as survivin and Bcl-2. Each has been implicated in MERTK physiologic and oncogenic functions. In neoplastic cells, these signaling events result in functional phenotypes such as decreased apoptosis, increased migration, chemoresistance, increased colony formation, and increased tumor formation in murine models. Conversely, MERTK inhibition by genetic or pharmacologic means can reverse these pro-oncogenic phenotypes. Multiple therapeutic approaches to MERTK inhibition are currently in development, including ligand “traps”, a monoclonal antibody, and small-molecule tyrosine kinase inhibitors. Clin Cancer Res; 19(19); 5275–80. ©2013 AACR.
Regulation of Cell Proliferation and Migration by Keratin19-Induced Nuclear Import of Early Growth Response-1 in Breast Cancer Cells
Authors: Ju Ji-hyun , Yang Wonseok , Lee Kyung-min , Oh Sunhwa , Nam KeeSoo , Shim Sarah , Shin Soon Young , Gye Myung Chan , Chu In-Sun , Shin Incheol 
Published: July 2013

Abstract
Purpose: Keratin19 (KRT19) is the smallest known type I intermediate filament and is used as a marker for reverse transcriptase PCR–mediated detection of disseminated tumors. In this study, we investigated the functional analysis of KRT19 in human breast cancer.
Experimental Design: Using a short hairpin RNA system, we silenced KRT19 in breast cancer cells. KRT19 silencing was verified by Western blot analysis and immunocytochemistry. We further examined the effect of KRT19 silencing on breast cancer cells by cell proliferation, migration, invasion, colony formation assay, cell-cycle analysis, immunocytochemistry, immunohistochemistry, and mouse xenograft assay.
Results: Silencing of KRT19 resulted in increased cell proliferation, migration, invasion, and survival. These effects were mediated by upregulation of Akt signaling as a result of reduced PTEN mRNA expression. Silencing of KRT19 decreased the nuclear import of early growth response-1 (Egr1), a transcriptional factor for PTEN transcription, through reduced association between Egr1 and importin-7. We also confirmed that silencing of KRT19 increased tumor formation in a xenograft model.
Conclusions: KRT19 is a potential tumor suppressor that negatively regulates Akt signaling through modulation of Egr1 nuclear localization. Clin Cancer Res; 19(16); 4335–46. ©2013 AACR.
Relationships between LDH-A, Lactate, and Metastases in 4T1 Breast Tumors
Authors: Rizwan Asif , Serganova Inna , Khanin Raya , Karabeber Hazem , Ni Xiaohui , Thakur Sunitha , Zakian Kristen L. , Blasberg Ronald , Koutcher Jason A. 
Published: July 2013

Abstract
Purpose: To investigate the relationship between lactate dehydrogenase A (LDH-A) expression, lactate concentration, cell metabolism, and metastases in murine 4T1 breast tumors.
Experimental Design: Inhibition of LDH-A expression and protein levels were achieved in a metastatic breast cancer cell line (4T1) using short hairpin RNA (shRNA) technology. The relationship between tumor LDH-A protein levels and lactate concentration (measured by magnetic resonance spectroscopic imaging, MRSI) and metastases was assessed.
Results: LDH-A knockdown cells (KD9) showed a significant reduction in LDH-A protein and LDH activity, less acid production, decreased transwell migration and invasion, lower proliferation, reduced glucose consumption and glycolysis, and increase in oxygen consumption, reactive oxygen species (ROS), and cellular ATP levels, compared with control (NC) cells cultured in 25 mmol/L glucose. In vivo studies showed lower lactate levels in KD9, KD5, and KD317 tumors than in NC or 4T1 wild-type tumors (P &lt; 0.01), and a linear relationship between tumor LDH-A protein expression and lactate concentration. Metastases were delayed and primary tumor growth rate decreased.
Conclusions: We show for the first time that LDH-A knockdown inhibited the formation of metastases, and was accompanied by in vivo changes in tumor cell metabolism. Lactate MRSI can be used as a surrogate to monitor targeted inhibition of LDH-A in a preclinical setting and provides a noninvasive imaging strategy to monitor LDH-A–targeted therapy. This imaging strategy can be translated to the clinic to identify and monitor patients who are at high risk of developing metastatic disease. Clin Cancer Res; 19(18); 5158–69. ©2013 AACR.
BRAF/NRAS Wild-Type Melanomas Have a High Mutation Load Correlating with Histologic and Molecular Signatures of UV Damage
Authors: Mar Victoria J. , Wong Stephen Q. , Li Jason , Scolyer Richard A. , McLean Catriona , Papenfuss Anthony T. , Tothill Richard W. , Kakavand Hojabr , Mann Graham J. , Thompson John F. , Behren Andreas , Cebon Jonathan S. , Wolfe Rory , Kelly John W. , Dobrovic Alexander , McArthur Grant A. 
Published: July 2013

Abstract
Purpose: The mutation load in melanoma is generally high compared with other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinicopathologic features.
Experimental Design: DNA was extracted from 34 fresh-frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was reviewed by two dermatopathologists. Exome sequencing was conducted and mutation rates were correlated with age, sex, tumor site, and histopathologic variables. Differences in mutations between categories of solar elastosis, pigmentation, and BRAF/NRAS mutational status were investigated.
Results: The average mutation rate was 12 per megabase, similar to published results in metastases. The average mutation rate in severely sun damaged (SSD) skin was 21 per Mb compared with 3.8 per Mb in non-SSD skin (P = 0.001). BRAF/NRAS wild-type (WT) tumors had a higher average mutation rate compared with BRAF/NRAS–mutant tumors (27 vs. 5.6 mutations per Mb; P = 0.0001). Tandem CC&gt;TT/GG&gt;AA mutations comprised 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin (P = 0.0008) and in BRAF/NRAS WT tumors (P = 0.0007). Targetable and potentially targetable mutations in WT tumors, including NF1, KIT, and NOTCH1, were spread over various signaling pathways.
Conclusion: Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared with BRAF- and NRAS-mutant tumors indicating multigene screening approaches and combination therapies may be required for management of these patients. Clin Cancer Res; 19(17); 4589–98. ©2013 AACR.
PARP-1 Regulates Resistance of Pancreatic Cancer to TRAIL Therapy
Authors: Yuan Kaiyu , Sun Yong , Zhou Tong , McDonald Jay , Chen Yabing 
Published: July 2013

Abstract
Purpose: Activating extrinsic apoptotic pathways targeting death receptors (DR) using agonistic antibodies or TNF-related apoptosis-inducing ligand (TRAIL) is promising for cancer therapy. However, most pancreatic cancers are resistant to TRAIL therapy. The present studies aimed to identify combination therapies that enhance the efficacy of TRAIL therapy and to investigate the underlying mechanisms.
Experimental Design: A xenograft model in nude mice was used to determine pancreatic cancer tumorigenesis and therapeutic efficacy of TRA-8, a monoclonal agonistic antibody for DR5. Pancreatic cancer cells were used to characterize mechanisms underlying PARP-1 regulation of TRA-8–induced apoptosis in vitro.
Results: PARP-1 was found highly expressed in the TRA-8–resistant PANC-1 and Suit-2 cells, compared with TRA-8–sensitive BxPc-3 and MiaPaca-2. Inhibition of PARP-1 with a pharmacologic inhibitor sensitized PANC-1 and Suit2 cells to TRA-8–induced apoptosis in a dose-dependent manner. Furthermore, siRNAs specifically knocking down PARP-1 markedly enhanced TRA-8–induced apoptosis in vitro and augmented the efficacy of TRA-8 therapy on tumorigenesis in vivo. PARP-1 knockdown increased TRA-8–induced activation of caspase-8 in the death-induced signaling complex (DISC). Immunoprecipitation with DR5 antibody identified the recruitment of PARP-1 and PARP-1–mediated protein poly-ADP-ribosylation (pADPr) modification in the DR5-associated DISC. Further characterization revealed that PARP-1–mediated pADPr modification of caspase-8 inhibited caspase-8 activation, which may contribute to its function in regulating TRA-8 resistance.
Conclusions: Our studies provide molecular insights into a novel function of PARP-1 in regulating the extrinsic apoptosis machinery and also support interventions combining PARP-1 inhibitors with DR agonists for pancreatic cancer therapy. Clin Cancer Res; 19(17); 4750–9. ©2013 AACR.
Clinical, Pathologic, and Biologic Features Associated with BRAF Mutations in Non–Small Cell Lung Cancer
Authors: Cardarella Stephanie , Ogino Atsuko , Nishino Mizuki , Butaney Mohit , Shen Jeanne , Lydon Christine , Yeap Beow Y. , Sholl Lynette M. , Johnson Bruce E. , Jänne Pasi A. 
Published: July 2013

Abstract
Purpose: BRAF mutations are found in a subset of non–small cell lung cancers (NSCLC). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations.
Experimental Design: Using DNA sequencing, we successfully screened 883 patients with NSCLC for BRAF mutations between July 1, 2009 and July 16, 2012. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild-type controls consisted of patients with NSCLC without a somatic alteration in BRAF, KRAS, EGFR, and ALK. In vitro studies assessed the biologic properties of selected non-V600E BRAF mutations identified from patients with NSCLC.
Results: Of 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E, 18; non-V600E, 18) and 257 were wild-type for BRAF, EGFR, KRAS, and ALK negative. Twenty-nine of 36 patients with BRAF mutations were smokers. There were no distinguishing clinical features between BRAF-mutant and wild-type patients. Patients with advanced NSCLC with BRAF mutations and wild-type tumors showed similar response rates and progression-free survival (PFS) to platinum-based combination chemotherapy and no difference in overall survival. Within the BRAF cohort, patients with V600E-mutated tumors had a shorter PFS to platinum-based chemotherapy compared with those with non-V600E mutations, although this did not reach statistical significance (4.1 vs. 8.9 months; P = 0.297). We identified five BRAF mutations not previously reported in NSCLC; two of five were associated with increased BRAF kinase activity.
Conclusions: BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC. Clin Cancer Res; 19(16); 4532–40. ©2013 AACR.
Phase II Study of Bevacizumab in Combination with Sorafenib in Recurrent Glioblastoma (N0776): A North Central Cancer Treatment Group Trial
Authors: Galanis Evanthia , Anderson S. Keith , Lafky Jackie M. , Uhm Joon H. , Giannini Caterina , Kumar Shaji K. , Kimlinger Teresa K. , Northfelt Donald W. , Flynn Patrick J. , Jaeckle Kurt A. , Kaufmann Timothy J. , Buckner Jan C. 
Published: July 2013

AbstractPurpose: We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in patients with recurrent glioblastoma would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2 and hypoxia-inducible factor-1α single-nucleotide polymorphisms (SNP), circulating biomarkers of angiogenesis, and MRI markers such as apparent diffusion coefficient (ADC) are correlated with treatment efficacy and/or toxicity.Experimental Design: Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg twice a day, weekly, days 1–5; group A). Due to toxicity, the starting sorafenib dose was subsequently modified to 200 mg every day (group B).Results: Fifty-four patients were enrolled: 19 patients in group A and 35 in group B. Objective response rate was 18.5% with median duration of 6.7 months (range 0.5–24.1 months). Six-month progression-free survival (PFS6) was 20.4% (11/54), and median overall survival (OS) was 5.6 months [95% confidence interval (CI), 4.7–8.2]; outcome was similar between the two dose groups. We identified SNPs in the VEGF and VEGFR2 promoter regions, which were associated with PFS6 (P &lt; 0.022). Among molecular markers of angiogenesis, a higher log2 baseline level of stromal cell–derived factor-1 was associated with PFS6 success (P = 0.04). Circulating endothelial cells decreased during treatment with subsequent increase at disease progression (P = 0.022). Imaging analysis showed a trend associating ADC-L with poor outcome.Conclusions: The bevacizumab/sorafenib combination did not improve outcome of patients with recurrent glioblastoma versus historic bevacizumab-treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation. Clin Cancer Res; 19(17); 4816–23. ©2013 AACR.
Phase II Randomized Trial Comparing High-Dose IFN-α2b with Temozolomide Plus Cisplatin as Systemic Adjuvant Therapy for Resected Mucosal Melanoma
Authors: Lian Bin , Si Lu , Cui Chuanliang , Chi Zhihong , Sheng Xinan , Mao Lili , Li Siming , Kong Yan , Tang Bixia , Guo Jun 
Published: July 2013

Abstract
Purpose: Mucosal melanoma is rare and associated with extremely poor prognosis. However, standard adjuvant therapy for mucosal melanoma has not been established. We conducted a randomized phase II clinical trial in patients with resected mucosal melanoma to compare the efficacy and safety of high-dose IFN-α2b (HDI) and temozolomide-based chemotherapy as adjuvant therapy.
Experimental Design: Patients with mucosal melanoma in stage II/III after surgery were randomized into three groups: observation group (group A, surgery alone), HDI group (group B, treated with 15 × 106 U/m2/d IFN-α2b, followed by 9 × 106 U IFN-α2b), and temozolomide (200 mg/m2/d) plus cisplatin (75 mg/m2) group (group C). The endpoints were relapse-free survival (RFS), overall survival (OS), and toxicities.
Results: One hundred and eighty-nine patients were enrolled and finally analyzed. With a median follow-up of 26.8 months, the median RFS was 5.4, 9.4, and 20.8 months for group A, B, and C, respectively. Estimated median OS for group A, B, and C was 21.2, 40.4, and 48.7 months, respectively. Patients treated with temozolomide plus cisplatin showed significant improvements in RFS (P &lt; 0.001) and OS (P &lt; 0.01) than those treated with either HDI or surgery alone. Toxicities were generally mild to moderate.
Conclusion: Both temozolomide-based chemotherapy and HDI are effective and safe as adjuvant therapies for resected mucosal melanoma as compared with observation alone. However, HDI tends to be less effective than temozolomide-based chemotherapy for patients with resected mucosal melanoma in respect to RFS. The temozolomide plus cisplatin regimen might be a better choice for patients with resected mucosal melanoma. Clin Cancer Res; 19(16); 4488–98. ©2013 AACR.