Citations

Abstract Work history is associated with long term health outcomes We hypothesize that characteristics of the first work experience, such as age at first job and length of work (hereafter job) are associated with future risk of hospitalization. We further hypothesize that the length of work will be associated with hospitalization. We conducted a survey of adults >60 years using a nested case-control approach within the Mayo Clinic Biobank. We collected job related variables including age at job start, reason for ending, and length of time. To test associations between each variable and hospitalization, we used age and gender adjusted logistic regression models. Our study included 4,024 subjects: 1,801 cases and 2223 controls. The mean age at time of match was 77.3 years (SD 7.2 years) with 49.2% males. Older age at the first full-time job was associated with lower chance of hospitalization later in life (OR=0.81 [0.67, 0.97] for those who started the job over 22 compared to those started at 18 or less). Cases were more likely to have stopped working because of illness (OR=2.04 [95% CI 1.29,3.27]). Cases were less likely to have stopped working because of retirement (OR=0.82 [95% CI: 0.72, 0.93]). We found cases were employed with a slightly shorter time (20.5 yrs. (SD 16.6)) compared to controls (21.8 yrs. (SD 16.3)) (p=0.005). Cases started work earlier and stopped work more frequently because of illness/disability compared to controls. This could reflect educational attainment in controls. This study highlights work history as potential predictor of future hospitalization.

Abstract Introduction/Aims Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC‐NTF), a novel autologous cell‐therapy capable of targeting multiple pathways, could safely slow ALS disease progression. Methods This randomized, double‐blind, placebo‐controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS‐R) ≥25 (screening) and ≥3 ALSFRS‐R points decline prior to randomization. Participants received three treatments of MSC‐NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC‐NTF through a responder analysis and safety. A change in disease progression post‐treatment of ≥1.25 points/mo defines a clinical response. A pre‐specified analysis leveraged baseline ALSFRS‐R of 35 as a subgroup threshold. Results Overall, MSC‐NTF treatment was well tolerated; there were no safety concerns. Thirty‐three percent of MSC‐NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre‐specified analysis of participants with baseline ALSFRS‐R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC‐NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC‐NTF, with placebo unchanged. Discussion The study did not reach statistical significance on the primary endpoint. However, a pre‐specified subgroup suggests that MSC‐NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.

AbstractElevated blood levels of C‐reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC‐specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI‐EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC‐specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow‐up, 3547 (64.8%) were due to CRC. No variants were associated with CRC‐specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC‐specific mortality (corrected Pinteraction = .0004); women had higher CRC‐specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04‐1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82‐0.94). There was no evidence of interactions between CRP‐associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP‐associated variant in relation to CRC‐specific mortality. Future replication of this association and functional annotation of the variant are needed.

Abstract Background Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (GxE) interactions and may provide information on the underlying biological pathway. Objective We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. Methods We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based GxE approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4,839 genes with available genetically predicted expression. We meta-analyzed results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. Results We found suggestive evidence of interaction with folate intake for genes including glutathione S-Transferase Alpha 1 (GSTA1; p=4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p=4.3E-4), and Aspartylglucosaminidase (AGA: p=4.5E-4). Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein. Conclusion We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk.

BackgroundThe objective of this randomized trial was to evaluate the short‐term effect of bilingual written and interpersonal education regarding mammographic breast density (MBD).MethodsLatinas aged 40 to 74 years who were presenting for screening mammography were recruited and randomized 1:1:1 to receive a letter with their mammogram and MBD results (usual care [UC]), a letter plus a brochure (enhanced care [ENH]), or a letter plus a brochure and telephonic promotora education (interpersonal care [INT]). Surveys were administered at enrollment (T0) and 2 weeks to 6 months after intervention delivery (T1). Differences were assessed with χ2, Kruskal‐Wallis, and McNemar tests and pairwise comparisons as appropriate. INT metrics and audio recordings were analyzed with descriptive statistics and qualitative content analysis.ResultsBetween October 2016 and October 2019, 943 of 1108 Latina participants (85%) completed both surveys. At T1, INT participants were more likely (P < .001) to report seeing their MBD results in the letter (70.2%) than UC (53.1%) or ENH participants (55.1%). The percentage of INT women who reported speaking with a provider about MBD (29.0%) was significantly greater (P < .001) than the percentage of UC (14.7%) or ENH participants (15.6%). All groups saw significant (P < .001) but nondifferential improvements in their knowledge of MBD as a masking and risk factor. In the INT group, the promotora delivered education to 77.1% of the 446 participants randomized to INT and answered questions at 28.3% of the encounters for an average of $4.70 per participant.ConclusionsAmong Latinas in a low‐resource setting, MBD knowledge may increase with written or interpersonal education, but with modest investment, interpersonal education may better improve MBD awareness and prompt patient‐provider discussions.

Abstract Low-grade glioma (LGG) are generally slowly growing brain cancers, that frequently undergo malignant progression to aggressive, secondary glioblastoma with a dismal prognosis. By combining genetically engineered Idh1-mutant mice with in vivo CRISPR gene editing we generated a mouse model faithfully recapitulating the founder mutations of LGG. Clonal activation of the neomorphic Idh1 R132H mutation cooperates with Trp53 and Atrx mutations to trigger development of brain tumors but only with ~30% penetrance and very long latency. To elucidate the molecular mechanisms underlying the malignant progression of IDH1-mutant LGG, we devised and deployed a direct in vivo CRISPR screen targeting genes commonly mutated in human IDH-mutant secondary glioblastoma. Stereotaxic delivery of a lentiviral sgRNA library targeting the mouse orthologs of these genes into the brain of Idh1 R132H ;Trp53;Atrx;Cas9 and control Idh1 wt ;Trp53;Atrx;Cas9 compound mutant mice resulted in rapid formation of tumors that recapitulate human Idh1-mutant glioblastoma. Deconvoluting the screen showed that PI3K pathway members Pten and Pik3ca as well as Notch1, Smarca4 and Fat1 are preferentially enriched in Idh1 R132H-tumors, while Rb1 and NF2 were enriched in Idh1 wt tumors. Co-mutation analysis further identified additional co-occurring driver combinations such as Bcor-Met, Olig2-Met, Olig2-Med12 or Bcor-Olig2. We validated the tumor suppressive function of Notch1 and Pten using conventional floxed knock-out alleles and found that Notch1 functions in a haploinsufficient manner. Interestingly, Idh1 R132H did not alter tumor latency or pathology in a high grade p53;Pten;Rb1 mutant background, indicating that the neomorphic IDH-mutations can drive low but not high grade glioma development. Our study provides a functional landscape of gliomagenesis suppressors in vivo.

Abstract Abnormalities on brain MRI may be identified in ~15% of individuals aged 50-66. It can be difficult to discriminate glioma, CNS lymphoma, Inflammatory Demyelinating Disease (CNSIDD) and solitary metastasis, and misdiagnosis may expose patients to unnecessary anxiety, surgery, or radiotherapy. CNS lymphoma requires only biopsy, solitary metastasis may be resected and radiated or radiated empirically, and high-grade glioma requires maximal safe resection followed by chemoradiation. CNSIDD should only be biopsied when diagnostic uncertainty requires it, and resection and radiotherapy are unnecessary, introducing unwarranted morbidity. Polygenic risk models can identify patients at the highest risk of developing glioma; we hypothesized that these polygenic models could help with differential diagnosis of indeterminate brain lesions. We also hypothesized that race would be an important contributing factor in the models. In the initial discovery and validation European (EUR) cohorts the mean probability of glioma for IDHmut non-codeleted glioma was 0.55 and 0.52, respectively, and in healthy controls was 0.19 and 0.21, respectively. To further evaluate sensitivity, we analyzed additional genotype data from 867 gliomas (764 EUR, 54 AFR, 24 AMR, 15 EAS, 10 SAS) from The Cancer Genome Atlas (TCGA). Across 764 EUR IDHmut non-codeleted glioma, the mean probability 0.53, whereas across 54 AFR and 24 AMR the mean was 0.22 and 0.32, respectively. To evaluate specificity, we analyzed 3200 TCGA patients with primary tumor types that commonly metastasize to the brain (2676 EUR, 365 AFR, 46 AMR, 95 EAS, 18 SAS), and 236 AFR healthy controls. For patients with non-CNS primary tumors, the mean probability ranged from 0.09-0.18 for EUR and 0.04-0.07 for AFR. For AFR healthy controls, the mean was 0.05. Overall, race is a significant factor for polygenic risk models. Further work entails evaluating polygenic risk models in IDHwt glioma, CNS lymphoma and CNSIDD cohorts as well as in additional races.

Abstract TP53 mutations are frequent in IDH-mutant astrocytomas but unusual in oligodendroglioma and the clinical significance of TP53 mutations in oligodendroglioma are not well characterized. We reviewed genetically defined oligodendroglioma (i.e., IDH-mutant, whole-arm 1p/19q-codeleted diffuse glioma) cases that were molecularly profiled (2017-2020) at our institution and identified 7 cases with TP53 mutation (9%; n=76). Molecular testing was performed using targeted neuro-oncology NGS panel (50-gene mutation and/or 187-gene mutation/rearrangement) and OncoScan™ microarray. Four (of 7) patients were female. Median age at diagnosis was 43 years (range, 23-63). Most common presenting symptom was seizures (3 of 7). All tumors were supratentorial. Histologically, 3 tumors were WHO grade II and 4 were WHO grade III. Two (of 3) patients with a WHO grade II tumor underwent biopsy and radiotherapy at diagnosis followed by temozolomide at recurrence (progression at 67 and 157 months after diagnosis; overall survival of 124 and 201 months). Three (of 4) patients with a WHO grade III tumor were diagnosed within the last two years and are currently progression-free after standard therapy. Molecularly, in addition to TP53 mutation(s), all cases had an IDH1 and TERT promoter mutation as well as other gene mutation(s) including FUBP1 (n=5), SETD2 (n=4), PIK3R1 (n=4), PIK3CA (n=3), NF1 (n=3) and CIC (n=3). In 3 (of 7) cases, the mutational profile with high mutation count enriched for C &gt;T/G &gt;A transitions was highly suggestive of a hypermutation phenotype (2 cases were recurrent tumors treated with temozolomide; a recurrent and a treatment-naïve tumor had mismatch repair gene mutation). Five (of 7) cases, including the 3 hypermutant cases, lacked functional TP53 (1 case with 2 mutations, 2 cases with 1 mutation plus loss of other copy, 2 cases with 1 mutation plus copy neutral loss-of-heterozygosity). TP53 mutations are uncommon in oligodendroglioma and appear enriched in hypermutant tumors.

Abstract BACKGROUND Determination of the causation of germline single nucleotide polymorphisms (SNPs) located in non-coding regions of the genome is challenging. The genomic region of 8q24 has been identified as important in many kinds of cancer, linked to a topologically associated domain (TAD) encompassing MYC; this TAD contains a GWAS SNP (rs55705857) associated with IDH-mutant glioma. METHODS Germline genotyping data from 622 IDH-mutant glioma and 668 controls were used to fine map the rs55705857 locus by detailed haplotype analysis. Chromatin immunoprecipitation sequencing (ChIP-seq) of histone markers H3K4me1, H3K4me3, H3K27ac and H3K36me3 was performed on normal brain samples (n=8) and human glioma samples (n=11 IDH-wt and 52 IDH-mut). RNAseq from 9 normal and 83 brain tumors (n=26 IDH-wt and 55 IDH-mut) were used to assess differential gene expression. RESULTS Fine-mapping identified rs55705857 SNP as the most likely causative allele (OR=8.69; p&lt;0.001) within 8q24 for the development of IDH-mutant glioma. At rs55705857, both H3K27ac and H3K4me1 in IDH-mutant vs IDH-wt tumors were increased 3.05- and 1.58-fold, respectively (DiffBind; p=5.81×10-7 and p=2.31×10-3). ChromHMM analysis of the marks indicated that promoter and enhancer functions were significantly increased, and the activity broadened at rs55705857 in IDH-mut gliomas compared to IDH-wt tumors and normal brain samples. This enhancement correlated with significant increased MYC expression in IDH-mut gliomas (p=3.1×10-13), as well as alterations of Myc signaling targets. Publicly available ATACseq, ChIPseq and long-range DNA interaction data demonstrated that the rs55705857 locus is open and interacts with the MYC promoter. CONCLUSIONS Fine-mapping of the 8q24 locus provided strong evidence that rs55705857 is the causative 8q24 locus associated with IDH-mut glioma. Functional experiments suggest that IDH mutation facilitates rs55705857 interaction with MYC to alter downstream MYC targets.