Publications by authors named "Stephen Gruber"

Background: Whether blood lipids are causally associated with colorectal cancer (CRC) risk remains unclear.

Methods: Using two-sample Mendelian randomisation (MR), our study examined the associations of genetically-predicted blood concentrations of lipids and lipoproteins (primary: LDL-C, HDL-C, triglycerides, and total cholesterol), and genetically-proxied inhibition of HMGCR, NPC1L1, and PCSK9 (which mimic therapeutic effects of LDL-lowering drugs), with risks of CRC and its subsites. Genetic associations with lipids were obtained from the Global Lipids Genetics Consortium (n = 1,320,016), while genetic associations with CRC were obtained from the largest existing CRC consortium (n = 58,221 cases and 67,694 controls).

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  • * A study identified a specific genetic variation at Chr6:31373718C>G that is associated with increased CRC risk, particularly in the younger population, with stronger odds for EOCRC compared to older adults.
  • * Analysis showed that individuals carrying the minor G allele have reduced expression of the immune-related MICA gene and lower levels of Natural Killer (NK) cell infiltration in tumors, suggesting a link between this genetic variation and tumor immune response.
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  • Colorectal cancer (CRC) is a major health concern, and understanding how genetic and environmental factors interact can help identify at-risk groups.
  • This study analyzed data from over 45,000 CRC cases to assess both multiplicative and additive interactions between genetic risk scores and various environmental factors, finding no multiplicative interactions but significant additive ones for high genetic susceptibility individuals.
  • Results suggest that individuals with high genetic risk could benefit more from lifestyle interventions like reducing alcohol intake or increasing fruit and fiber consumption, emphasizing the need for targeted prevention strategies in CRC care.
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A polymorphic variant in the ataxia telangiectasia-mutated (ATM) gene, rs56009889, was recently associated with an increased risk of lung cancer. We studied the role of this variant in the etiology of other cancers. Data from three population-based case-control studies of colon, breast, and lung cancer were used.

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  • Folate intake plays a crucial role in genetic and metabolic processes, and low levels are linked to higher cancer risk, specifically colorectal cancer (CRC).
  • The study analyzed dietary and supplemental folate intake among participants with CRC, investigating how this intake relates to specific genetic mutations using advanced sequencing techniques.
  • Results indicated that higher total folate intake generally reduced CRC risk, but the impact varied when considering mutation status in tumors, with a few specific gene mutations showing different associations with folate intake.
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The incidence of colorectal cancer (CRC) among individuals younger than age 50 (early-onset CRC [EOCRC]) has substantially increased, and yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. We compared tumor-associated T-cell repertoires between EOCRC and average-onset CRC (AOCRC) to uncover potentially unique immune microenvironment-related features by age of onset. Our discovery cohort included 242 patients who underwent surgical resection at Cleveland Clinic from 2000 to 2020.

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Identifying risk protein targets and their therapeutic drugs is crucial for effective cancer prevention. Here, we conduct integrative and fine-mapping analyses of large genome-wide association studies data for breast, colorectal, lung, ovarian, pancreatic, and prostate cancers, and characterize 710 lead variants independently associated with cancer risk. Through mapping protein quantitative trait loci (pQTL) for these variants using plasma proteomics data from over 75,000 participants, we identify 365 proteins associated with cancer risk.

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  • * Researchers analyzed data from 52 studies, including nearly 31,000 CRC cases and over 41,000 controls, to explore the genetic interactions with regular aspirin/NSAID use.
  • * They found significant interactions with genetic variants in two specific regions (6q24.1 and 5p13.1), which could help uncover new targets for understanding how aspirin provides its protective effects against colorectal cancer.
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Alternative polyadenylation (APA) modulates mRNA processing in the 3'-untranslated regions (3' UTR), affecting mRNA stability and translation efficiency. Research into genetically regulated APA has the potential to provide insights into cancer risk. In this study, we conducted large APA-wide association studies to investigate associations between APA levels and cancer risk.

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  • Consumption of fiber, fruits, and vegetables may lower the risk of colorectal cancer (CRC), but genetic factors might influence this connection.
  • A large study involving nearly 70,000 participants identified two significant genetic variants linked to dietary intake and CRC risk using advanced statistical methods.
  • The findings suggest specific genetic loci (SLC26A3 and NEGR1) may affect how fiber and fruit consumption interacts with CRC risk, highlighting the need for more research on the underlying mechanisms.
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  • Colorectal cancer (CRC) is a widely increasing disease linked to high body mass index (BMI), but the exact biological processes connecting these two factors are not well understood.
  • The study employed Mendelian randomization to explore various biomarkers and lifestyle factors potentially mediating the impact of BMI on CRC risk, focusing on elements like inflammation, insulin levels, and physical activity.
  • The findings indicated that higher genetically predicted BMI correlates with increased CRC risk, with evidence suggesting that the relationship might be partly mediated by plasma IGF1, while smoking and physical activity appear to complicate the association rather than mediate it.
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Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV.

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Objective: To evaluate the contribution of germline genetics to regulating the briskness and diversity of T cell responses in CRC, we conducted a genome-wide association study to examine the associations between germline genetic variation and quantitative measures of T cell landscapes in 2,876 colorectal tumors from participants in the Molecular Epidemiology of Colorectal Cancer Study (MECC).

Methods: Germline DNA samples were genotyped and imputed using genome-wide arrays. Tumor DNA samples were extracted from paraffin blocks, and T cell receptor clonality and abundance were quantified by immunoSEQ (Adaptive Biotechnologies, Seattle, WA).

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  • Menopausal hormone therapy (MHT) may lower the risk of colorectal cancer (CRC), especially in women with a higher genetic predisposition to the disease.
  • In a study of nearly 30,000 postmenopausal women, those in the highest genetic risk quartile saw a significantly greater reduction in CRC risk when using MHT compared to those in the lowest quartile.
  • The findings suggest that integrating genetic risk information could improve CRC risk predictions and inform the assessment of MHT benefits in postmenopausal women.
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  • Obesity is linked to various types of colorectal cancer (CRC), but the strength and cause of these links are not fully understood.
  • By using Mendelian randomization, researchers studied how body size traits like BMI, waist circumference, and body fat percentage affect risks for different CRC subtypes.
  • Results showed that higher BMI and body fat significantly increased the risks for serrated and alternate CRC pathways (Jass types 1, 2, and 3), while associations with the traditional pathway (Jass type 4) were weaker.
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  • The genotoxin colibactin is linked to a specific mutation signature in colorectal cancer (SBS88), affecting tumor characteristics and possibly influencing risk and survival outcomes.
  • A study involving over 4,300 tumors found that higher fruit intake lowers the risk of SBS88-positive colorectal cancer, and some epidemiological factors like BMI and alcohol consumption show different associations based on the presence of SBS88.
  • While most risk and survival factors were similar regardless of SBS88 status, higher BMI might lead to worse survival outcomes for those with SBS88, suggesting a need for further research with more comprehensive genetic data.
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  • High consumption of red and processed meats is linked to an increased risk of colorectal cancer, with a study analyzing data from over 29,000 cancer cases and 39,000 control subjects confirming this association.
  • The research identified two significant genetic markers (SNPs) that interact with meat consumption levels, suggesting that certain genetic variants can influence individual cancer risk based on dietary habits.
  • These findings highlight the potential for using genetic information to better understand colorectal cancer risks related to diet, which may lead to personalized dietary recommendations for specific population subgroups.
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Alternative polyadenylation (APA) modulates mRNA processing in the 3' untranslated regions (3'UTR), which affect mRNA stability and translation efficiency. Here, we build genetic models to predict APA levels in multiple tissues using sequencing data of 1,337 samples from the Genotype-Tissue Expression, and apply these models to assess associations between genetically predicted APA levels and cancer risk with data from large genome-wide association studies of six common cancers, including breast, ovary, prostate, colorectum, lung, and pancreas among European-ancestry populations. At a Bonferroni-corrected □<□0.

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Background: In the United States, sorafenib monotherapy was approved in 2007 for first-line (1L) treatment of patients with unresectable hepatocellular carcinoma (uHCC). As other therapies have been approved in recent years for hepatocellular carcinoma treatment in later lines, it is essential to assess clinical effectiveness of older therapies in actual clinical practice to inform healthcare practitioners' decisions for better patient care.

Aim: To assess patient characteristics/clinical effectiveness of 1L sorafenib in uHCC patients treated in United States academic and community practice settings.

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Objective: Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC).

Methods: We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC).

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  • Polygenic risk scores (PRS) can help identify individuals at higher risk for colorectal cancer (CRC), but current models based on European ancestry data don't perform well for non-European populations.
  • A study expands PRS development by adding Asian ancestry data alongside European data, resulting in improved predictive accuracy across diverse racial and ethnic groups in the US.
  • The findings emphasize the need for including more non-European ancestry populations to enhance risk prediction and ensure equitable clinical application of PRS in CRC prevention.
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Deep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on convolutional neural networks (CNNs) and have mostly been validated on small patient cohorts. Here, we develop a new transformer-based pipeline for end-to-end biomarker prediction from pathology slides by combining a pre-trained transformer encoder with a transformer network for patch aggregation.

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  • A study is exploring how genetic variations might influence the relationship between folate intake and colorectal cancer risk, focusing on specific genetic interactions.
  • The research analyzed data from over 30,000 colorectal cancer cases and 42,000 controls, examining the effects of dietary folate and folic acid supplements.
  • Results indicated that while higher folate intake is generally linked to lower CRC risk, certain genetic variants (like rs150924902) can modify this effect, with some genotypes showing increased risk with folate supplementation.
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In recent decades, cancer biology and medicine have ushered in a new age of precision medicine through high-throughput approaches that led to the development of novel targeted therapies and immunotherapies for different cancers. The availability of multifaceted high-throughput omics data has revealed that cancer, beyond its genomic heterogeneity, is a complex system of microenvironments, sub-clonal tumor populations, and a variety of other cell types that impinge on the genetic and non-genetic mechanisms underlying the disease. Thus, a systems approach to cancer biology has become instrumental in identifying the key components of tumor initiation, progression, and the eventual emergence of drug resistance.

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