Citations

Abstract Purpose: Glioblastoma is a devastating, incurable disease with few known prognostic factors. Here, we present the first genome-wide survival and validation study for glioblastoma. Experimental Design: Cox regressions for survival with 314,635 inherited autosomal single-nucleotide polymorphisms (SNP) among 315 San Francisco Adult Glioma Study patients for discovery and three independent validation data sets [87 Mayo Clinic, 232 glioma patients recruited from several medical centers in Southeastern United States (GliomaSE), and 115 The Cancer Genome Atlas patients] were used to identify SNPs associated with overall survival for Caucasian glioblastoma patients treated with the current standard of care, resection, radiation, and temozolomide (total n = 749). Tumor expression of the gene that contained the identified prognostic SNP was examined in three separate data sets (total n = 619). Genotype imputation was used to estimate hazard ratios (HR) for SNPs that had not been directly genotyped. Results: From the discovery and validation analyses, we identified a variant in single-stranded DNA-binding protein 2 (SSBP2) on 5q14.1 associated with overall survival in combined analyses (HR, 1.64; P = 1.3 × 10−6). Expression of SSBP2 in tumors from three independent data sets also was significantly related to patient survival (P = 5.3 × 10−4). Using genotype imputation, the SSBP2 SNP rs17296479 had the strongest statistically significant genome-wide association with poorer overall patient survival (HR, 1.79; 95% CI, 1.45-2.22; P = 1.0 × 10−7). Conclusion: The minor allele of SSBP2 SNP rs17296479 and the increased tumor expression of SSBP2 were statistically significantly associated with poorer overall survival among glioblastoma patients. With further confirmation, previously unrecognized inherited variations influencing survival may warrant inclusion in clinical trials to improve randomization. Unaccounted for genetic influence on survival could produce unwanted bias in such studies. Clin Cancer Res; 18(11); 3154–62. ©2012 AACR.

Abstract Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.

SummaryBackgroundIt remains unclear whether a long‐acting preparation of octreotide (Sandostatin LAR) can be safely used for portal hypertension in patients with compensated cirrhosis.AimTo determine the safety and efficacy of LAR among patients with Child Pugh Class A or B cirrhosis and small oesophageal varices.MethodsA randomised, double‐blind, placebo‐controlled study was conducted in 39 patients with cirrhosis and small oesophageal varices. Safety was based on frequency and severity of adverse events. Efficacy was determined by hepatic vein pressure gradient (HVPG) measured at baseline and day 84 following administration of LAR 10 mg (n = 15), 30 mg (n = 10) or saline (n = 14). Fasting and postprandial portal blood flow (PBF), superior mesenteric artery pulsatility index (SMA‐PI), glucagon and octreotide levels were measured. An intention‐to‐treat analysis was performed.ResultsFour patients in the LAR 30 group (40%) withdrew from the study due to serious adverse events. No patient in the LAR 10 or control group had serious adverse events. There was no statistically significant decrease between HVPG at day 84 and baseline with LAR 30 mg (11.8 ± 2.3 mmHg vs. 14.1 ± 3.2), LAR 10 mg (15.3 ± 4.8 mmHg vs. 15.1 ± 3.8), or saline (13.3 ± 3.8 mmHg vs. 15.1 ± 4.3) (P = 0.26). Neither PBF, SMA‐PI nor plasma glucagon levels were significantly decreased from baseline (P = 0.56).ConclusionsThe absence of significant haemodynamic benefit, as well as the high frequency of severe adverse events associated with use of LAR, do not support the use of this agent in the treatment of portal hypertension.

SummaryThe pathological background in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) consists of lymphocytes and histocytes. This study analysed the peripheral blood absolute lymphocyte count/absolute monocyte count ratio at diagnosis (ALC/AMC‐DX) on the impact of survival inNLPHL. One hundred and three consecutiveNLPHLpatients that were followed atMayoClinic from 1974 to 2010 were included in the study. Receiver operating characteristic and area under the curve were used forALC/AMC‐DXcut‐off value analysis and proportional‐hazards models were used to compare survival based on theALC/AMC‐DXratio. With a median follow‐up of 8·9 years (range: 0·3–31 years), anALC/AMC‐DX≥2·1 was the best cut‐off value for survival with an area under the curve of 0·82, a sensitivity of 70% and specificity of 84%. After adjusting for theInternationalPrognosticScore (IPS),ALC/AMC‐DXremained an independent prognostic factor for overall survival [HazardRatio (HR), 0·33, 95% confidence interval (CI), 0·15–0·71%,P < 0·004]; lymphoma‐specific survival (HR, 0·05; 95%CI, 0·01–0·68%,P < 0·002); progression‐free survival (HR, 0·30; 95%CI, 0·14–0·60%,P < 0·006), and time to progression (HR, 0·06, 95%CI, 0·04–0·30%,P < 0·004).ALC/AMC‐DXis a low cost, already standarized, biomarker to predict clinical outcomes inNLPHL.