Citations

INTRODUCTION: Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management. METHODS: Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases. RESULTS: The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all P trend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; P trend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend. DISCUSSION: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.

AbstractBackgroundMeningiomas are the most common primary central nervous system (CNS) tumor in adults and CNS World Health Organization grade 2 (atypical) meningiomas show an intermediate risk of recurrence/progression. Molecular parameters are needed to better inform management following gross total resection (GTR).MethodsWe performed comprehensive genomic analysis of tumor tissue from 63 patients who underwent radiologically confirmed GTR of a primary grade 2 meningioma, including a CLIA-certified target next-generation sequencing panel (n = 61), chromosomal microarray (n = 63), genome-wide methylation profiling (n = 62), H3K27me3 immunohistochemistry (n = 62), and RNA-sequencing (n = 19). Genomic features were correlated with long-term clinical outcomes (median follow-up: 10 years) using Cox proportional hazards regression modeling and published molecular prognostic signatures were evaluated.ResultsThe presence of specific copy number variants (CNVs), including -1p, -10q, -7p, and -4p, was the strongest predictor of decreased recurrence-free survival (RFS) within our cohort (P &lt; .05). NF2 mutations were frequent (51%) but did not show a significant association with RFS. DNA methylation-based classification assigned tumors to DKFZ Heidelberg benign (52%) or intermediate (47%) meningioma subclasses and was not associated with RFS. H3K27 trimethylation (H3K27me3) was unequivocally lost in 4 tumors, insufficient for RFS analysis. Application of published integrated histologic/molecular grading systems did not improve prediction of recurrence risk over the presence of -1p or -10q alone.ConclusionsCNVs are strong predictors of RFS in grade 2 meningiomas following GTR. Our study supports incorporation of CNV profiling into clinical evaluation to better guide postoperative patient management, which can be readily implemented using existing, clinically validated technologies.

Abstract Background: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10−8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20–1.30] compared with the other genotypes (OR &lt;1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10−8) and 8q24.23 (rs7005722, P = 2.88 × 10−8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09–1.16) compared with the other genotypes (OR &lt;1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07–1.28) compared with the other genotypes (OR &lt;1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. Impact: These findings can guide potential prevention treatments.

Background: Bibliometric citation analyses have been widely used in medicine to help researchers gain foundational knowledge about a topic and identify subtopics of popular interest for further investigations. Purpose: To identify the 50 most cited research publications related to American football. Study Design: Cross-sectional study. Methods: The Clarivate Analytics Web of Science database was used to generate a list of publications relating to football. Articles were filtered by the total number of citations, and the top 50 most cited articles studying the sport of football were selected for this analysis. Articles were analyzed by author, publication year, country of origin, institution affiliation, journal, article type, main research topic area, competitive level, and the level of evidence. A total of 247 articles were reviewed to reach the top 50 articles. Results: The most studied topic within the top 50 articles was concussion/chronic traumatic encephalopathy (n = 40). Collegiate football was the most studied level of competition (n = 25). The journal publishing the greatest number of top articles was Neurosurgery. Two institutions, the University of North Carolina at Chapel Hill and Boston University School of Medicine, produced over one-third of top 50 articles (n = 18). Conclusion: Our analysis indicated that most of the top 50 publications related to the sport of football focused on concussion and CTE, were observational, and were published during or after 2000. The most studied level of competition was collegiate football.

AbstractBackgroundIn the Alzheimer’s disease sequencing project (ADSP) whole exome dataset, only the well‐known TREM2.pR47H variant shows genome‐wide significance by conventional single variant analysis. To identify novel AD genes related to TREM2, we used gene‐based polygenic score analysis (PGSA) to evaluate an immune, temporal cortical co‐expression network with 229 genes including TREM2.MethodThe most recent whole exome variant call files from the ADSP (NG00067.v7) were subjected to stringent quality control. Post‐QC samples were divided into discovery (4174 samples sequenced at Broad), test (3299 samples sequenced at WashU), and follow‐up (2273 samples sequenced at Baylor) sets. The pruned variants (r2 < 0.2) with a minor allele count over 20 in each gene were analyzed by Broad/WashU PGSA thereby obtaining P‐values (gPbr.wa) for each gene in WashU samples. To assess significance in independent Baylor samples, cumulative Broad/Baylor PGSA was performed using a novel approach in which variants were stratified by both gene (gPbr.wa) and variant (Broad.P).ResultAfter excluding TREM2, the five variants with gPbr.wa ≤ 0.08 and Broad.P ≤ 0.03 showed significant association in Broad/Baylor PGSA. One of these variants showed no evidence of association with AD in the combined dataset. Polygenic scores for the other four variants, which were in three genes, showed significant association in Baylor samples, and significant, essentially identical association in WashU samples. Polygenic scores for nine additional variants in these genes (0.03> Broad.P ≤ 0.13) also showed significant, essentially identical association in Baylor and WashU samples. The association of these 13 variants with AD was driven primarily by six deleterious, protein‐altering variants with minor allele frequencies less than 1%, but the other 7 variants also contributed.ConclusionUsing gene‐based polygenic score analysis to analyze an immune co‐expression network, we identify three novel immune genes with actionable nonsynonymous and stopgain variants that show significant, replicable association with AD in the most recent release of the ADSP whole exome dataset.

Respiratory tract resident memory T cells (T RM ), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory T RM . We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron–based nanoparticles. Here, we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influenced influenza-specific cell–mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 T RM in the lung and draining lymph nodes. Contralateral, compared with ipsilateral, intramuscular boosting broadened the distribution of lymph node T RM and T follicular helper cells but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory but augmented distribution to the respiratory mucosa. Combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung T RM . Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung T RM that can be further expanded by an additional intranasal immunization.

Abstract Background: The microbiome in colorectal cancer (CRC) tumors is now recognized as a potent facilitator of tumorigenesis. Identification of the intra-tumoral microbiome may provide an avenue to enhance prediction of adverse outcomes and ultimately lead to improved survival of CRC, the second leading cause of cancer death. Methods: We performed targeted sequencing of tumor and matched normal DNA samples for 3695 colorectal cancer cases within the Genetics and Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR). Tumor DNA was extracted primarily from formalin fixed paraffin embedded (FFPE) or from fresh frozen tissue. FFPE slides were dissected to ensure &gt;70% tumor content. Normal DNA was primarily extracted from blood and otherwise normal surrounding colorectal tissue. We designed probes for bacterial pathogens including Bacteroides fragilis (ETBF), polyketide synthase positive E. coli (pks+ EC), enterotoxigenic and Fusobacterium nucleatum (Fn). Logistic regression was used to assess tumor-associated bacteria and various clinical parameters, tumor molecular characteristics, and tumor stage adjusted for age, sex, and study and a Cox promotional hazard to assess association with CRC-specific survival adjusted for age at diagnosis, sex, mutational burden and microsatellite instability (MSI) and stratified baseline hazards by study. Survival data were available for 2357 patients. Results: The prevalence of patients with bacteria in tumors varied for ETBF (5.2%), pks+ EC (12.9%), and Fn (10.4%). Men had a lower probability of tumors with Fn (odds ratio (OR)=0.8, 95% confidence interval (CI)=0.64-0.99,p=0.04) but higher odds of tumors with pks+ EC (OR=1.38, CI=1.14-1.68,p=0.001). Patients with proximal tumors had higher odds of carrying Fn (OR=1.76, CI=1.38-2.26, p&lt;0.001) as did patients with MSI high tumors (OR 2.79, CI=2.08-3.74) p&lt;0.001). Patients with MSI-high tumors had lower odds of carrying pks+ EC (OR=0.63, CI=0.44-0.88, p=0.008) when compared to patients with microsatellite stable tumors. Among non-hypermutated tumors, we observed that tumors positive for pks+ EC were associated with better CRC-specific survival (OR=0.73, CI=0.57-0.93,p=0.01 whereas in patients with ETBF positive tumors had shorter survival (OR=1.99,CI=1,18-3.36,p=0.009) as did patients with tumors positive for Fn (OR=1.33, CI=1.04-1.72, p=0.03). Conclusions: In this largest investigation of intra-tumoral bacteria in CRC, we demonstrate that inclusion of pathogenic intra-tumoral microbiome may enhance prediction of survival and can identify a subset of patients with CRC that may benefit from targeted therapies that modulate the tumor microbiome. Citation Format: Meredith A. J. Hullar, Keith R. Curtis, Tabitha A. Harrison, Yi Lin, Robert S. Steinfelder, Sonja I. Berndt, Daniel D. Buchanan, Andrew T. Chan, David Drew, Jane C. Figueiredo, Amy J. French, Ellen L. Goode, Mark A. Jenkins, Yohannes A. Melaku, Victor Moreno, Shuji Ogino, Stephen N. Thibideau, Amanda I. Phipps, Ulrike Peters. Evaluation of intra-tumoral pathogenic bacteria pks+ E. coli, enterotoxigenic B. fragilis and fusobacterium nucleatum in 3695 colorectal cancer cases [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr PR008.

Abstract Background: Evidence suggests that, compared to later-onset colorectal cancer (CRC), early-onset CRC (diagnosed before 50 years of age) occur more frequently in rectal location and less frequently in proximal colon location. Studies also indicate heterogeneity of molecular characteristics within early-onset CRCs and between early-onset and later-onset CRCs. Understanding how tumor molecular features and biological aggressiveness of early-onset CRC differ by detailed tumor location is important in personalized patient management. Methods: Using 14,004 CRC cases including 3,089 early-onset cases from The Cancer Genome Atlas and the Genetics and Epidemiology of CRC Consortium (GECCO), we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in cancers of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum. We further conducted CRC-specific survival analyses of detailed tumor location stratified by molecular characteristics using multivariable Cox proportional hazards models. Results: The proportions of MSI-high, CIMP-high, and BRAF-mutated early-onset tumors gradually increased from the rectum (8.8%, 3.4%, and 3.5%, respectively) to the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF-mutated), followed by declines in the cecum for MSI-high (36%) and BRAF-mutated (4.6%) tumors. Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend &lt;0.001) followed by an increase in the cecum (14%), while early-onset MSI-high cancer showed no such trend. In survival analyses, there was a trend for better CRC-specific survival from the cecum to sigmoid colon (Ptrend&lt;0.001) (but not to rectum), which did not significantly differ by age of diagnosis (Pinteraction=0.61). Multivariable-adjusted hazard ratios (HRs) for sigmoid vs. cecum were 0.86 (95% CI, 0.64-1.14) for early-onset cases and 0.81 (95% CI, 0.70-0.93) for later-onset cases. Notably, the prognostic association of tumor location differed by MSI status (Pinteraction=0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better CRC-specific survival [Ptrend &lt;0.001; multivariable-adjusted HR for the sigmoid colon (vs. cecum), 0.80; 95% CI, 0.70-0.92], whereas MSI-high tumors demonstrated an opposite cecum-to-sigmoid trend for worse survival (Ptrend = 0.020; the corresponding HR, 2.13; 95% CI, 1.15-3.92). Conclusions: Our findings support biogeographical and pathogenic heterogeneity of CRC in different age groups and colorectal subsites. Both detailed colorectal location and tumor molecular features need to be accounted for prognostication of early-onset and later-onset CRCs to advance precision medicine. Citation Format: Tomotaka Ugai, Yin Cao, Koichiro Haruki, Tabitha A. Harrison, Daniel D. Buchanan, Peter T. Campbell, Andrew T. Chan, Steven Gallinger, Marc J. Gunter, Michael Hoffmeister, Mark A. Jenkins, Roger L. Milne, Polly A. Newcomb, Rish K. Pai, Andrew J. Pellatt, Robert E. Schoen, Bethany Van Guelpen, Michael O. Woods, Amanda I. Phipps, Ulrike Peters, Shuji Ogino. Molecular characteristics and prognosis of early-onset colorectal cancer according to detailed anatomical locations: Comparison to later-onset cases [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A010.