Citations

Abstract Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy is standard of care for patients with newly diagnosed DLBCL. A majority of patients respond to R-CHOP, however ∼9% will have primary refractory disease and outcomes in these patients are extremely poor. While there is some knowledge of the pharmacogenomic (PGx) determinants of individual agents within R-CHOP, little is known about the PGx determinants of combination therapy. Our study aims to elucidate germline PGx determinants of drug bioavailability and undesirable side chain reactions in DLBCL patients treated with R-CHOP having potential to influence refractory disease. Methods: Newly diagnosed, DLBCL patients treated with R-CHOP between 2002 and 2012 with germline DNA and genotyping data were selected from the Molecular Epidemiology Resource within the Iowa/Mayo Lymphoma SPORE. Refractory disease was defined as either i) a best response of stable or progressive disease or ii) progressive disease by the end of the planned number of cycles of R-CHOP. PGx candidates within known pharmacokinetics and pharmacodynamics (PD) pathways for 11 genes (1,040 single nucleotide polymorphisms (SNPs)) were selected for study (CPT 2012;92(4):414-7). Odds ratios (ORs) and 95% confidence intervals (CI) were used to estimate the association of SNPs with refractory disease, controlling for age, gender, and age-adjusted International Prognostic Index. Results: The median age at diagnosis of 424 of DLBCL patients treated with R-CHOP was 62 years (range 18-92); 45.7% were female; and 58.4% had Ann Arbor Stage III-IV. By the end of initial therapy 40 patients had primary refractory disease. Of the 1,040 SNPs evaluated, 120 (12%) were significantly associated with refractory disease at the 5% significance threshold suggesting novel associations with drug metabolism. The top SNP from each PGx candidate gene are shown in Table, with ALDH5A1 and CYP2B6 showing the most significant associations. Conclusions: While needing replication, we identified associations within two PGx candidate genes that are potentially functionally related to cyclophosphamide PD: alleles within CYP2B6 may have relevance in R-CHOP outcomes due to potential competition with other drug metabolizing enzymes shared with prednisone and vincristine biotransformation in the liver, and alleles withinALDH5A1 may impact a deactivating side chain reaction in B lymphocytes. Table: R-CHOP PGx candidates with known side chain reactionsPGx candidaten SNPsTop SNPChrOR* (95% CI)P-valueMAFABCB1365rs3480093571.86 (1.14 – 3.04)1.32E-020.29ADH1A32rs122996841.66 (0.60 - 4.53)3.27E-010.038ALDH3A116rs2228100171.26 (0.71 - 2.22)4.28E-010.24ALDH5A1192rs946103466.30 (2.43 - 16.4)1.55E-040.030CBR110rs2835266212.10 (0.90 - 4.89)8.76E-020.052CBR356rs45527331212.12 (0.91 - 4.98)8.29E-020.050CYP2B6107rs1038376192.38 (1.44 - 3.94)7.74E-040.27CYP3A421rs2898858372.32 (0.80 - 6.78)1.23E-010.028CYP3A531rs778032871.69 (0.68 - 4.16)2.57E-010.054SLC22A16193rs11217403561.80 (1.06 - 3.03)2.78E-020.21SOD116rs1041740211.35 (0.83 - 2.19)2.26E-010.32Chr=chromosome, MAF=minor allele frequency, *Adjusted for age, sex, and age-adjusted International Prognostic Index Citation Format: Matthew K. Breitenstein, Susan L. Slager, Anne J. Novak, Matthew J. Maurer, Carrie A. Thompson, Umar Farooq, Brian K. Link, Thomas M. Habermann, Curtis L. Olswold, Andrew L. Feldman, Grzegorz S. Nowakowski, Stephen M. Ansell, Thomas E. Witzig, Richard M. Weinshilboum, Liewei Wang, James R. Cerhan. Pharmacogenomic of refractory response to R-CHOP therapy in diffuse large B-cell lymphoma (DLBCL) patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B143.

AbstractBackgroundOutcomes of neonates with congenital diaphragmatic hernia (CDH) are variable; reports are frequently limited to the experience of single tertiary care centres—a possible source of bias. Population‐based studies decrease survivor bias and provide additional insight into this high‐mortality condition. The objective of this study was to examine the incidence and outcomes of CDH in Croatia.MethodsAll cases of CDH in Croatia from 2001 through 2013 were ascertained from public health records. Overall and sex‐ and region‐specific incidence rates were calculated, and characteristics associated with 1‐year survival were assessed.ResultsWe identified 145 cases of CDH during the study period, for an incidence of 2.67 per 10 000 total births. The incidence did not differ by calendar year (P = 0.38) or geographic region (P = 0.67). There was a slightly higher incidence among males (rate ratio, 1.37, 95% CI 0.99, 1.91). The 1‐year survival rate was 33.1% for the entire cohort and 47.9% for liveborns who received any treatment at an intensive care unit. From multivariable analysis, survival was decreased in neonates with left CDH, liver up (odds ratio 0.1, 95% CI, 0.03, 0.4) and increased when treated in a centre with higher case volume (odds ratio 12.8, 95% CI, 2.2, 72.1).ConclusionsThe incidence of CDH in Croatia is within the range of previous reports. Survival was substantially higher in neonates treated in a centre with higher case volume, which suggests that centralisation of medical care for CDH may be warranted in Croatia.

Abstract Background: Excess adiposity has been associated with lymphomagenesis, possibly mediated by increased cytokine production causing a chronic inflammatory state. The relationship between obesity, cytokine polymorphisms, and selected mature B-cell neoplasms is reported. Method: Data on 4,979 cases and 4,752 controls from nine American/European studies from the InterLymph consortium (1988–2008) were pooled. For diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), joint associations of body mass index (from self-reported height and weight) and 12 polymorphisms in cytokines IL1A (rs1800587), IL1B (rs16944, rs1143627), IL1RN (rs454078), IL2 (rs2069762), IL6 (rs1800795, rs1800797), IL10 (rs1800890, rs1800896), TNF (rs1800629), LTA (rs909253), and CARD15 (rs2066847) were investigated using unconditional logistic regression. BMI-polymorphism interaction effects were estimated using the relative excess risk due to interaction (RERI). Results: Obesity (BMI ≥ 30 kg/m2) was associated with DLBCL risk [OR = 1.33; 95% confidence interval (CI), 1.02–1.73], as was TNF-308GA+AA (OR = 1.24; 95% CI, 1.07–1.44). Together, being obese and TNF-308GA+AA increased DLBCL risk almost 2-fold relative to those of normal weight and TNF-308GG (OR = 1.93; 95% CI, 1.27–2.94), with a RERI of 0.41 (95% CI, −0.05–0.84; Pinteraction = 0.13). For FL and CLL/SLL, no associations with obesity or TNF-308GA+AA, either singly or jointly, were observed. No evidence of interactions between obesity and the other polymorphisms were detected. Conclusions: Our results suggest that cytokine polymorphisms do not generally interact with BMI to increase lymphoma risk but obesity and TNF-308GA+AA may interact to increase DLBCL risk. Impact: Studies using better measures of adiposity are needed to further investigate the interactions between obesity and TNF-308G>A in the pathogenesis of lymphoma. Cancer Epidemiol Biomarkers Prev; 24(7); 1061–70. ©2015 AACR.

Abstract Objectives and Rationale: Structural variants (SV) including large copy number aberrations (CNV), translocations, inversions, and large insertions and deletions (INDEL) play a critical role in tumorigenesis and progression. In fact, we now know that tumors can be categorized according to the size of mutations harbored. In several cancers, including ovarian and breast cancer, the large structural mutations, rather than single site mutations, play a dominate role in tumor etiology. Therefore, it's critical to implement reliable algorithm for the detection of structural variants in DNA sequencing data. Mate-pair sequencing is a protocol specifically implemented for detection of the whole-genome level structural variants. It requires less sequencing depth therefor is cost effective, and enables the detection of CNVs, translocations, and inversions simultaneously. However, so far there has been no reliable bioinformatics pipeline for the analyses of the mate-pair sequencing data. Methods: Our novel algorithm, the SnowShoes-SV, is an exhaustive search algorithm designed specifically for mate-pair DNA sequencing data analyses. It calls the SVs based on disconcordant read pairs. The false SVs are filtered according to the following criteria: (i) the number of the supporting read pairs; (ii) the lack of reads from control data that implicate SV at the same region; (iii) the mappability and uniqueness of the region based on data from the ENCODE project; (iv) consistencies of the mapping orientations of the supporting read pairs; (v) the similar sizes between sequencing library and the two end read clusters. Results: Using a set of samples previously genotyped by aCGH, the SnowShoes-SV successfully detected all known CNVs and other SVs. It also identified copy number neutral translocations and inversions previously not identified by aCGH. In addition, the algorithm nominated novel SVs which are to be validated by PCR. Conclusions: SnowShoes-SV is a highly sensitive and specific algorithm for SV detection from the mate-pair DNA sequencing data. Citation Format: Yan W Asmann, Chen Wang, Brian M Necela, Xianfeng Chen, Jean-Pierre A Kocher, Matthew J Maurer, Thomas M Habermann, Susan L Slager, Andrew L Feldman, Anne J Novak, James R Cerhan, Edith A Perez, E Aubrey Thompson. An exhaustive algorithm for detecting copy number aberrations and large structural variants in whole-genome mate-pair sequencing data [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-07-03.

SummaryDeubiquitinase enzymes (DUBs) of the proteasomal 19S regulatory particle are emerging as important therapeutic targets in several malignancies. Here we demonstrate that inhibition of two proteasome‐associated DUBs (USP14 and UCHL5) with the small molecule DUB inhibitor b‐AP15, results in apoptosis of human Waldenström macroglobulinaemia (WM) cell lines and primary patient‐derived WM tumour cells. Importantly, b‐AP15 produced proteotoxic stress and apoptosis in WM cells that have acquired resistance to the proteasome inhibitor bortezomib. In silico modelling identified protein residues that were critical for the binding of b‐AP15 with USP14 or UCHL5 and proteasome enzyme activity assays confirmed that b‐AP15 does not affect the proteolytic capabilities of the 20S proteasome β‐subunits. In vitro toxicity from b‐AP15 appeared to result from a build‐up of ubiquitinated proteins and activation of the endoplasmic reticulum stress response in WM cells, an effect that also disrupted the mitochondria. Focused transcriptome profiling of b‐AP15‐treated WM cells revealed modulation of several genes regulating cell stress and NF‐κB signalling, the latter whose protein translocation and downstream target activation was reduced by b‐AP15 in vitro. This is the first report to define the effects and underlying mechanisms associated with inhibition of USP14 and UCHL5 DUB activity in WM tumour cells.

Key Points BCL2 mutations in FL correlate with activation-induced cytidine deaminase expression and frequently alter the amino acid sequence of the protein. Mutations in the BCL2 coding sequence at diagnosis are associated with shortened time to transformation and earlier death due to lymphoma.

Key Points Elevated IL-2R, IL-1RA, and CXCL9 are associated with shorter event-free survival in newly diagnosed FL, treated with chemoimmunotherapy. Increased serum IL-12 and IL-1RA is associated with shorter event-free survival in patients who were observed or treated with rituximab alone.