Christopher Mason
· Ph.D.Cornell University · Physiology and Biophysics
Active 2005–2022
About
Christopher Mason, Ph.D., is a Professor of Physiology and Biophysics at Weill Cornell Medicine, where he also serves as the Director of the WorldQuant Initiative for Quantitative Prediction and the WorldQuant Foundation Research Scholar. He holds a secondary appointment as a Professor of Computational Genomics in Computational Biomedicine at the Institute for Computational Biomedicine and is involved with the Brain and Mind Institute. His research utilizes computational and experimental methodologies to identify and characterize essential genetic elements that guide the function of the human genome, with a particular emphasis on those that orchestrate the development of the human brain. Mason's lab creates detailed cell-specific molecular maps of genetic, epigenetic, transcriptional, and translational activity, aiming to develop a comprehensive molecular recipe for brain creation. The research also focuses on developing methods to detect, catalog, and functionally annotate variants in genetic pathways that control developmental processes and their perturbations in disease. His work aspires to understand the functional elements of the human genome sufficiently to enable repair, re-engineering, or fortification of these genetic networks within human cells.
Research topics
- Biology
- Medicine
- Internal medicine
- Cell biology
- Cancer research
Selected publications
Research Square · 2022-07-21
preprintOpen accessAbstract Background: The microbial community composition of urban environments is primarily determined by human activity. The use of metagenomics to explore how microbial communities are shaped in a city provides a novel input that can improve decisions on public health measures, architectural design, and urban resilience. Of note, the sewage system in a city acts as a complex reservoir of bacteria, pharmaceuticals, and antimicrobial resistant (AMR) genes that can be an important source of epidemiological information. Hospital effluents are rich in patient-derived bacteria, and can thus readily become a birthplace and hotspot reservoir for antibiotic resistant pathogens which are eventually incorporated into the environment. Yet, the scope to which nosocomial outbreaks impact the urban environment is still poorly understood. Results: In this work, we extensively show that different urban waters from creeks, beaches, sewage spillways and collector pipes enclose discrete microbial communities that are characterized by a differential degree of contamination and admixture with human-derived bacteria. The abundance of human bacteria correlates with the abundance of AMR genes in the environment, with beta-lactamases being the top-contributing class to distinguish low vs. highly-impacted urban environments. Indeed, the abundance of beta-lactamase resistance and carbapenem resistance determinants in the urban environment significantly increased in a one-year period. This was in line with a pronounced increase of nosocomial carbapenem-resistant infections reported during the same period, that was mainly driven by an outbreak-causing, carbapenemase-producing Klebsiella pneumoniae (KPC) ST-11 strain. Genome-resolved metagenomics of urban waters before and after this outbreak, coupled with high-resolution whole-genome sequencing, confirmed the dissemination of the ST-11 strain and a novel KPC megaplasmid from the hospital to the urban environment. City-wide analysis showed that geospatial dissemination of the KPC megaplasmid in the urban environment inversely depended on the sewage system infrastructure. Conclusions: We show how urban metagenomics and outbreak genomic surveillance can be coupled to generate relevant information for infection control, antibiotic stewardship, and pathogen epidemiology. Our results highlight the need to better characterize and understand how human-derived bacteria and antimicrobial resistance disseminate in the urban environment to incorporate this information in the development of effluent treatment infrastructure and public health policies.
Cureus · 2021-07-02 · 11 citations
articleOpen accessBackground The presenting symptoms and co-morbidities contributing to mortality in young patients (age < 50 years old) with colorectal cancer (CRC) are poorly understood. We reviewed these features in our patient population with non-hereditary early-onset CRC (EO-CRC). Study aim This study aimed to assess characteristics of patients with a diagnosis of non-hereditary EO-CRC, including presenting symptoms and metabolic disorders contributing to mortality in underserved areas of southwest Virginia. Methods In this retrospective observational study, we selected patients aged 18-50 years with a diagnosis of non-hereditary EO-CRC from 2008 to 2016 at Carilion Roanoke Memorial Hospital. The electronic medical record was queried to identify demographic data, medical history, histopathology results, lab values, and mortality. The cumulative risks of symptoms and co-morbid metabolic disorders was estimated using Kaplan-Meier curves. Results We identified 139 patients with non-hereditary EO-CRC (mean age 41.6 ± 6.9 years). Almost half of these patients were obese (BMI > 30), 30.9% had a diagnosis of hypertension, 29% had hyperlipidemia (HLD), and 17.35% had diabetes mellitus type 2 (DM2). Diagnosis was delayed by 4.5 months from initial presentation, and 17% had advanced disease (stage III/IV). Also, 68.5% of patients were symptomatic with one to three symptoms, most commonly with rectal bleeding (45.3%). The chronicity of HLD (≥5 years) was associated with reduced survival in our patients with EO-CRC. The survival of females with multiple metabolic disorders was reduced compared to females with a single metabolic disorder. Conclusions Multiple symptoms, chronic HLD, and female gender with multiple metabolic disorders were factors associated with poor outcomes in non-hereditary EO-CRC patients.
Blood · 2021-11-05 · 2 citations
articleAbstract Introduction: Ibrutinib is widely used for relapsed/refractory mantle cell lymphoma (MCL), however nearly 1/3 of patients have primary resistance and the remaining patients will inevitably acquire resistance with poor overall survival. There is an urgent need for novel therapies targeting pro-survival signaling pathways triggered by ibrutinib resistance. Pharmacologic inhibition of Protein Arginine Methyltransferase 5 (PRMT5) represents a novel therapeutic approach to overcome ibrutinib resistant MCL (IR-MCL). PRMT5 has many essential functions in normal and malignant B cells, however in the context of IR-MCL the mechanisms of PRMT5 inhibitor mediated cell death have not been described. Genomic co-deletions of MTAP/CDKN2A are commonly detected in IR-MCL cells. MTAP deletion and subsequent accumulation of the metabolite MTA, sensitizes cells to further inhibition of PRMT5. Although the published literature defines this therapeutic rationale for targeting PRMT5 in cancers with co-deletion of MTAP/CDKN2A, the literature lacks studies specifically targeting PRMT5 in IR-MCL. Methods: Here we report the primary mechanism of PRMT5 inhibitor mediated cell death in the context of IR-MCL, utilizing a combination of Whole Exome Sequencing (WES), RNA-seq, protein expression, and cell cycle analysis (PI-DNA staining with flow cytometry) in 8 MCL cell lines and 3 patient derived xenografts (PDXs) of IR-MCL. Pharmacologic inhibition of PRMT5 was performed with two selective compounds: PRT-382 and C220 (Prelude Therapeutics). Inducible CRISPR/CAS9-gRNA was used to selectively knock out MTAP and CDKN2A. Results: Comparing MCL cell lines with primary ibrutinib resistance, we found an inverse correlation between PRT-382 ic50 and ibrutinib ic50 (Spearman: r = -0.94, p = 0.017). In MCL cell lines, low expression of MTAP also correlated with lower global Symmetric Di-Methyl Arginine (SDMA) and enhanced sensitivity to C220 respectively (Pearson: r = 0.84, p = 0.01; r = 0.87, p = 0.01). Genomic deletion of MTAP in a cell line with primary ibrutinib resistance (Jeko MTAP-WT) enhanced sensitivity to PRMT5i, whereas MTAP knock-in (KI) in CCMCL, an MTAP-null cell line, decreased sensitivity to PRMT5i. The treatment of Jeko-MTAP-KI and CCMCL-MTAP-KO with MTA, further confirmed that genomic deletion of MTAP confers enhanced vulnerability to PRMT5i in MCL cell lines. In a PDX generated in our lab from an MCL patient with acquired IR, treatment with PRT-382 decreased tumor infiltration of multiple organs and ki-67 compared to ibrutinib or control (H&E and IHC staining). To mechanistically address the nature of the anti-tumor activity of PRMT5i in IR-MCL, we treated PDX mice with PRT-382 or vehicle control for 2 weeks to obtain ex-vivo samples for NGS methods. Splenic MCL tumor cells (Hu-CD19+) where subjected to transcriptomic profiling by RNA-seq (n=3 per Tx group). RNA-seq revealed 1014 down and 1124 up differentially expressed genes (DEGs) (q &lt; 0.01, |log2FC| &gt; 0.05). Gene Set Enrichment Analysis (GSEA) identified activation of the p53 pathway (NES = 1.73), with repression of E2F targets, G2M checkpoints, Epithelial to Mesenchymal Transition (EMT), and PRMT5 targets among the top gene sets modulated with PRMT5i (NES = -2.51, -2.26, -2.06, -1.79). Comparing genomic alterations across MCL cell lines and 3 PDXs of IR-MCL, co-deletion of MTAP/CDKN2A and/or a functional/WT copy of TP53 defines a therapeutic vulnerability to PRMT5i in 9 out of 11 cases (82%). In MCL, PRMT5i resulted in p53-dependent G1/S cell cycle arrest and p53-dependent DNA damage induced apoptosis by transcriptional activation of the p53 target genes (CDKN1A, BBC3, BAX, PHLDA3, andSESN1). Western blot analysis confirmed E2F target gene repression (TK1, CCNA2, CHK1, CDK1) and accumulation of DNA damage response proteins (cleaved PARP, cleaved CASP3, p-H2AX) that are further enhanced with combination of doxorubicin. Conclusion: Pharmacologic inhibition of PRMT5 with the clinical-grade, novel small molecule inhibitor (PRT543, Prelude Therapeutics) merits further investigation in ongoing clinical trials (NCT03886831, clinicaltrials.gov), specifically for the treatment of IR-MCL with deletion of MTAP and prior to the genomic mutation of TP53. We are currently exploring novel combinations to maximize the therapeutic potential of PRMT5 inhibition in this disease. Disclosures Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Vaddi: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Scherle: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy.
The American Journal of Gastroenterology · 2020-10-01
articleINTRODUCTION: Young patients with non-hereditary colorectal cancer (CRC) have unfavorable pathologic characteristics. The features and survival outcomes in different colonic segments are to be determined. METHODS: In this retrospective observational study we randomly selected patients (aged 18–50) with a histopathologic diagnosis of CRC at Carilion Clinic, Roanoke, from 2002 to 2017. Patients with inflammatory bowel disease and predisposing genetic syndromes were excluded. Demographics, polyp and tumor features, and mortality were obtained from the electronic medical record. Two pathologists reviewed histopathology to minimize diagnostic variability. The cumulative risk of mortality among patients with different pathologic features was estimated using Kaplan Meier curves. RESULTS: We identified 139 patients (Mean age, 41.6 ± 6.9 years; 53.2% males) with non-hereditary CRC. Thirty percent of tumors were located in the right colon (RC), 35.4% in the left colon (LC), and 34.5% in the rectum (Rec). In patients with resected tumors, a cancer-adjacent polyp was identified in 78.8% (RC), 73.7% (LC), and 47.4% (Rec). Lymphovascular invasion (LVI) was present in 59.0% compared to 38% (LC) and 25% (Rec). Perineural invasion (PNI) was present in 25.0% compared to 10.8% (LC) and 14.35% (Rec). RC tumor budding was (14%) compared to 13.1% (LC) and 2.9% (Rec), and tumor deposits in 30% compared 18.9% (LC) and 17.7% (Rec). Intratumoral lymphocytes were present in 32.1% (RC) compared to 15.8% (LC) and 3.03% (Rec). Intratumoral neutrophils were present in 3.6% in the RC compared to 10.5% (LC) and 3.03% (Rec). Thirty-two percent (RC) had Crohn’s like response compared to 26.3% (LC) and 3.0% (Rec). Microsatellite instability (MSI) accounted for 9.4% of (RC) tumors and 8.1% of (LC) tumors but was not present in rectal tumors. Among patients who had repeat colonoscopy for surveillance, about 90.0% of patients with RC cancer did not receive surveillance colonoscopy within 1 year of cancer diagnosis compared to 42% (LC) and 55.6% (Rec). Patients with Rec cancer had decreased survival compared to patients diagnosed with RC and LC cancers (P = 0.04) (Figure 1). CONCLUSION: Right colon tumors accounted for higher rates of unfavorable pathologic features compared to left colon and rectal tumors. Adherence to USMSTF surveillance recommendations is poor, especially in RC tumors. Patients with rectal cancer had the poorest survival outcomes compared to right and left colon tumors.Figure 1.: Interval time of diagnosis until last visit based on segment.
The American Journal of Gastroenterology · 2020-10-01
articleINTRODUCTION: It was reported that young patients diagnosed with non-hereditary colorectal cancer have unfavorable pathologic characteristics. we aimed to assess pathologic features of non-hereditary young onset colorectal tumors and its impact on survival and to assess risk factors associated with poor outcomes. METHODS: we randomly selected young patients (18–50 years old) with histopathologic diagnosis of non-hereditary colorectal adenocarcinoma at Carilion Clinic, Roanoke, from 2002 to 2017 and followed through 11-2019. The cumulative risk of mortality among patients with different pathologic features were estimated using Kaplan Meier curves. Multivariable Cox regression models were built for the analysis of risk factors. RESULTS: One hundred thirty-nine patients (Mean age, 41.6 ± 6.9 years; 53.2% males) with non-hereditary colorectal cancer were identified. Pathology revealed tumors arising in adenoma in 61.5% of the cases (88.8% tubulovillous, 11.2% tubular adenomas). The rectum was the most common location (32.2%). The most common histologic type was invasive adenocarcinoma (86.0%). About seventy percent of the tumors were low-intermediate grade. Among patients with resected tumors, lymphovascular invasion (LVI) was present in 40.4%, perineural invasion (PNI) was present in 15.4%, intratumoral lymphocytes were present in 16.3%, and intratumoral neutrophils were present in 5.8%. About half of the resected tumors had low score tumor budding, 21.1% had Crohn’s like response, and 19.0% had tumor deposits. Microsatellite instability (MSI) accounted for 9.0% of the tumors tested for it. Twenty four percent had stage 1(T1), 11.5% (T2), 40.7% (T3), 15.9% (T4), and 8.0% (Tx). Only 29.0% received colonoscopy within 1 year after the clearing first full colonoscopy. On last follow up, 30% of the patients died. The survival of patients with tumor deposits were decreased compared to patients without tumor deposits (P = 0.02) (Figure 1). With multivariate analysis, increased N stage (Hazard ratio [HR], 6.23; 95% CI, 1.45–26.77. P = 0.01) and not undergoing surveillance colonoscopy (Hazard ratio [HR], 6.0; 95% CI, 2.50–14.4. P < 0.01) were associated with decreased survival.Figure 1CONCLUSION: Tumor-adjacent polyps were identified in about 60% of the cases; none of them was a sessile serrated lesion. Tumor deposits was associated with decreased survival. About 1/3 of the patients died on last follow up. Increased N stage and missing surveillance colonoscopy were associated with poor outcomes.
Gastroenterology · 2020-05-01
articleGastroenterology · 2020-05-01
articleTelomeres and genomic instability during long-duration spaceflight
Physiology News · 2020-01-01
articleSenior authorThe American Journal of Gastroenterology · 2020-10-01
articleINTRODUCTION: Tumor budding is an adverse prognostic factor in colorectal cancer, has been studied extensively in patients with somatic, microsatellite stable variants, and is found in 20–40% of such cases. However, the presence and significance of this histopathologic phenomenon in young patients diagnosed with non-hereditary colon cancer is to be determined. In this study, our aim was to ascertain presence of tumor budding in young patients diagnosed with non-hereditary cancer and investigate correlations of this prognostic feature with other prognostic factors such as staging, invasion, and immune response trends. METHODS: In this retrospective observational study, we selected young patients (18–50 years old) with histopathologic diagnosis of non-hereditary colorectal adenocarcinoma at Carilion Clinic, Roanoke, from 2002 to 2017 and followed through 2011–2019. Patients with inflammatory bowel disease and those with predisposing genetic syndromes were excluded. Patient demographics, polyps’ features, cancer features, colonoscopy reports, and mortality were obtained from electronic medical record. Two pathologists reviewed pathology slides to minimize inter-pathologist variability in histologic diagnosis. The cumulative risk of mortality among patients with different pathologic features were estimated using Kaplan Meier curves. RESULTS: One hundred and thirty nine patients (mean age, 41.6 ± 6.9 years) with non-hereditary colorectal cancer were identified. One hundred and four of these cases displayed tumor budding on histology (74.8%). Tumor budding was significantly correlated with lymphovascular and perineural invasion (P < 0.01 for both). Tumor budding grade was also significantly correlated with high cancer stage (P < 0.01), with intratumoral lymphocyte and neutrophil presence (P < 0.01) and the presence of tumor deposits (P < 0.01). Lastly, the occurrence of a Crohn-like response, a histologic indicator for an immune reaction to the colon cancer, was noted to be significantly higher in neoplasms affected by higher grade tumor budding (P < 0.01). CONCLUSION: Tumor budding was found in the majority (74.8%) of young non-hereditary colorectal cancer patients, suggesting that this phenomenon is much more prevalent in this subpopulation than in the somatic, microsatellite stable colorectal cancer group. Tumor budding was also significantly correlated with low and high tumor stages as well as lymphovascular and perineural invasion in young patients with non-hereditary colon cancer.Table 1.: Table summarizing tumor budding correlations with staging, invasion, and immune response trends
Blood · 2019-11-13 · 1 citations
articleDeregulation of long non-coding RNAs (lncRNAs) is emerging as a common feature of different human tumors and their investigation may uncover novel biomarkers and oncogenic mechanisms. Previous studies have suggested that the alteration of some lncRNAs may play an important role in the pathogenesis of multiple myeloma (MM); however, the complete expression landscape of lncRNAs has not been elucidated. In the present work we characterized the lncRNAs transcriptome of MM and determined the potential involvement of lncRNAs in the pathogenesis and clinical behavior of MM. To characterize the MM transcriptome, we performed paired-end strand-specific RNA sequencing (ssRNA-seq) in 38 purified plasma cell (PC) samples from MM patients and in 3 bone marrow PCs (BMPCs) of healthy donors, as well as in distinct normal B-cell populations (Naïve, Centroblasts, Centrocytes, Memory and Tonsilar PCs). We identified 40,511 novel lncRNAs that were expressed, accounting for more than half of MM transcriptome (56%). This group of novel lncRNAs together with previously annotated lncRNAs comprised most (82%) of the MM transcriptome. We studied the transcriptional heterogeneity in MM samples and observed that lncRNAs showed a much more heterogeneous expression than coding genes, suggesting that these elements could contribute to the biological heterogeneity of the disease. Moreover, to determine differentially expressed genes, each MM patient was compared to normal BMPCs, detecting 19,886 lncRNAs deregulated (10,351 overexpressed and 9,535 downregulated) in more than 50% of patients. We then analyzed the transcriptional dynamics of MM considering the different stages of B-cell differentiation and focused on a group of 989 lncRNAs that were upregulated specifically in plasma cells from MM in comparison with the rest of B-cell stages (MM-specific lncRNAs). Next, we aimed to determine whether upregulation of MM-specific lncRNAs in MM was under epigenetic control so we analyzed the distribution of six histone modifications with non-overlapping functions (H3K4me3, H3K4me1, H3K27ac, H3K36me3, H3K27me3, and H3K9me3) of within the lncRNAs of interest by ChIP-seq in MM cases as compared to normal B cell subtypes. We detected 89 lncRNAs with de novo epigenomic activation. These data suggest an epigenetic rewiring in MM where the loci of most MM-specific lncRNAs are in an inactive state in normal cells and become active in MM. We focused on a specific lncRNA, LINC-SMILO, de novo epigenetically active and expressed in MM cells to determine whether upregulation of this lncRNA could play a role in the pathogenesis of the disease. Knockdown of LINC-SMILO in 3 different MM cell lines (MM.1S, MM.1R and KMS-11) using two different shRNAs, resulted in reduced proliferation and induction of apoptosis of myeloma cells. Using low input RNA-seq (MARS-seq), we found that inhibition of LINC-SMILO was associated with activation of ERVs (Endogenous retroviruses) and increase in interferon (IFN) induced genes and activation of IFN pathways, essential for MM cells survival. Finally, we aimed to determine whether the use of specific lncRNAs could improve the current prognostic stratification of MM patients using the IA11 release of CoMMpass data. We analyzed the prognostic value of lncRNAs using COX regression analysis and Backward elimination of Stepwise regression analysis, obtaining that the overexpression of the lncRNA PDLIM1P4 together with 1q amplification and 17p deletion stratified MM patients in three different risk groups (Figure 1). In summary, our study shows that the lncRNA transcriptome is widely altered in MM and suggests that some of the identified lncRNAs have marked prognostic influence and can be used as potential therapeutic targets for MM. Disclosures Paiva: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Melnick:KDAc Therapeutics: Membership on an entity's Board of Directors or advisory committees; Constellation Pharmaceuticals: Consultancy; Epizyme: Consultancy; Janssenn: Research Funding.
Frequent coauthors
- 30 shared
Douglas J. Grider
Carilion Clinic
- 28 shared
David P. LeBel
Carilion Clinic
- 26 shared
Shravani Reddy
- 24 shared
Lindsey A. Bierle
- 24 shared
Marrieth Rubio
Pontificia Universidad Católica de Valparaíso
- 22 shared
Adil S. Mir
- 22 shared
Miranda R. Gerrard
Carilion Clinic
- 16 shared
Chirstopher Walsh
Virginia Tech
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