Citations

Telomeres cap chromosome ends, protecting them from degradation, double‐strand breaks, and end‐to‐end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset‐based meta‐analyses of 204,993 directly‐measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene‐level p value cutoffs ≤3.08 × 10−5). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere‐related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.

If untreated, most children with severe combined immunodeficiency disorder (SCID) will die of complications of infection within the first 2 years of life. Early hematopoietic stem cell transplant (HSCT) is the current standard of care for this disease. Although potentially lifesaving, prognosis of HSCT in SCID is variable depending on a number of host and donor factors. Of the survivors, many develop secondary problems such as chronic graft-versus-host disease or even second malignancies. Posttransplant care is complex and requires great effort from parents to adhere to difficult treatment regimens. In this article, we address the difficult ethical question of what to do if parents choose not to have their child with SCID undergo HSCT but prefer palliative care.

ObjectiveInfantile spasms are seizures associated with a severe epileptic encephalopathy presenting in the first 2 years of life, and optimal treatment continues to be debated. This study evaluates early and sustained response to initial treatments and addresses both clinical remission and electrographic resolution of hypsarrhythmia. Secondarily, it assesses whether response to treatment differs by etiology or developmental status.MethodsThe National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of infantile spasms. Children were considered responders if there was clinical remission and resolution of hypsarrhythmia that was sustained at 3 months after first treatment initiation. Standard treatments of adrenocorticotropic hormone (ACTH), oral corticosteroids, and vigabatrin were considered individually, and all other nonstandard therapies were analyzed collectively. Developmental status and etiology were assessed. We compared response rates by treatment group using chi‐square tests and multivariate logistic regression models.ResultsTwo hundred thirty infants were enrolled from 22 centers. Overall, 46% of children receiving standard therapy responded, compared to only 9% who responded to nonstandard therapy (p < 0.001). Fifty‐five percent of infants receiving ACTH as initial treatment responded, compared to 39% for oral corticosteroids, 36% for vigabatrin, and 9% for other (p < 0.001). Neither etiology nor development significantly modified the response pattern by treatment group.InterpretationResponse rate varies by treatment choice. Standard therapies should be considered as initial treatment for infantile spasms, including those with impaired development or known structural or genetic/metabolic etiology. ACTH appeared to be more effective than other standard therapies. ANN NEUROL 2016;79:475–484

ObjectivesBrain‐derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early‐onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association.MethodsDNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early‐onset bipolar disorder. Bipolar cases were classified as early onset if the first manic or depressive episode occurred at age ≤19 years (versus adult‐onset cases at age >19 years). After quality control, 69 TEAM early‐onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early‐onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log‐additive allele effects.ResultsComparison of TEAM cases with controls suggested association of early‐onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early‐onset adult bipolar disorder cases from the Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early‐onset TEAM and Mayo Clinic early‐onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04).ConclusionsThese preliminary analyses of a relatively small sample with early‐onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early‐onset expression of the disorder.

Abstract PURPOSE: The purpose of this study was to determine whether a) high-grade serous ovarian cancer-associated CDK12 kinase domain mutations affect catalytic activity, b) loss of CDK12 affects BRCA1 expression levels and Homologous Recombination (HR) in ovarian cancer, c) tumor-associated CDK12 mutations cause HR defects in ovarian cancer, and d) loss of CDK12 sensitizes ovarian cancer to chemotherapy and Poly(ADP-ribose) Polymerase [PARP] inhibitors. EXPERIMENTAL PROCEDURES: We compared the kinase activities of wild-type CDK12 and tumor-associated CDK12 kinase domain mutants using in-vitro kinase assays. To determine the impact of CDK12 activity on HR, we assessed RAD51 foci formation and HR using a DR-GFP construct. To analyze the effect of tumor-associated CDK12 mutations on HR, CDK12-depleted OVCAR-8 cells were reconstituted with either wild-type CDK12 or the tumor-associated CDK12 mutant (G909R), irradiated and stained for RAD51 foci. We performed clonogenic assays using ovarian cancer cell lines (OVCAR-8, OVCAR-5 and OVCAR-3) to measure sensitivity to DNA cross-linking agents (melphalan and cisplatin) and the PARP inhibitor, veliparib, in the presence or absence of CDK12 activity. CDK12 depletion was carried out using at least two independent short-interfering RNAs (siRNAs). RESULTS: We showed that many, but not all, ovarian cancer-associated CDK12 kinase domain mutations severely disrupted kinase activity. Moreover, we found that disabling CDK12 activity in ovarian cancer cells decreased BRCA1 levels and disrupted HR. Additionally, the tumor-associated CDK12 G909R mutant did not restore impaired RAD51 foci formation in CDK12-depleted OVCAR-8 cells. Finally we show that CDK12 depletion sensitized multiple ovarian cancer cells to the DNA cross-linking agents melphalan and cisplatin and to the PARP inhibitor veliparib. CONCLUSION: Ovarian cancer-associated CDK12 mutations disrupt kinase activity and cause defects in HR, suggesting that ovarian tumors harboring deleterious CDK12 mutations may predict sensitivity to chemotherapeutic agents, including PARP inhibitors. Citation Format: Poorval M. Joshi, Shari L. Sutor, Catherine J. Huntoon, Larry M. Karnitz. Ovarian cancer-associated CDK12 mutations disable its kinase activity and cause defects in homologous recombination [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1325.

We aimed to determine variation in treatment of newly diagnosed infantile spasms, focusing on details of adrenocorticotropic hormone (ACTH) administration using a Redcap questionnaire sent to members of the Child Neurology Society. Two hundred fifty-seven members responded. Eighty-four percent prescribers used ACTH to treat infantile spasms. Seventy-six percent always admit patients. There is no difference between prescriber type (epileptologist or other) and prescriber location (state-funded or non-state-funded hospital) for decision to admit. Electroencephalographic (EEG) confirmation of spasms and education for injection were the commonest reasons to admit. Only 45% of prescribers accurately estimated the cost of ACTH. Participants in the hospital vial program were significantly more likely to always admit patients for ACTH than those who did not participate in such a program ( P = .02). Although having the hospital sample vial allows time to complete investigation of infantile spasms and eliminates delays in initiating ACTH, it adds significantly to the cost of therapy.

Summary Objective To prospectively evaluate the etiology of new‐onset infantile spasms and evaluate the yield of genetic and metabolic investigations in those without obvious cause after initial clinical evaluation and magnetic resonance imaging ( MRI ). Methods Twenty‐one U.S. pediatric epilepsy centers prospectively enrolled infants with newly diagnosed West syndrome in a central database. Etiology and investigations performed within 3 months of diagnosis were documented. Results From June 2012 to June 2014, a total of 251 infants were enrolled (53% male). A cause was identified in 161 (64.4%) of 250 cases (genetic,14.4%; genetic‐structural, 10.0%; structural‐congenital, 10.8%; structural‐acquired, 22.4%; metabolic, 4.8%; and infectious, 2.0%). An obvious cause was found after initial clinical assessment (history and physical examination) and/or MRI in 138 of 161, whereas further genetic and metabolic studies were revealing in another 23 cases. Of 112 subjects without an obvious cause after initial evaluation and MRI , 81 (72.3%) had undergone genetic testing, which showed a causal abnormality in 23.5% and a variant of unknown significance in 14.8%. Although metabolic studies were done in the majority (serum, 79.5%; urine, 69.6%; and cerebrospinal fluid [ CSF ], 38.4%), these revealed an etiology in only five cases (4.5%). No correlation was found between type of health insurance (public vs. private) and either genetic or metabolic testing. Significance Clinical evaluation and MRI provide a specific diagnosis in 55% of children presenting with West syndrome. We propose that a cost‐effective workup for those without obvious cause after initial clinical evaluation and MRI includes an array comparative genomic hybridization ( aCGH ) followed by an epilepsy gene panel if the microarray is not definitive, serum lactate, serum amino acids, and urine organic acids.

Abstract Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case–case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case–case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P &lt; 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5–2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0–5.5), and family history of CRC (ccOR = 0.6; 95% CI, 0.5–0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend &lt; 0.001) and body mass index (BMI; Ptrend = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation–based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 512–9. ©2015 AACR.