bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for diet-gene interaction in early-onset colorectal cancer.
Authors: Merchant Juanita L. , Song Heyu L , Stoffel Elena Martinez 
Published: January 2023

182 Background: About 10 percent of all colorectal cancers are in subjects who are not yet 50 (EO-CRC) and the occurrence of early onset colorectal cancer (EO-CRC) is rising in the US. Patients with CRC are twice as likely to have diabetes or be overweight. Using targeted exome sequencing of germline DNA from EO-CRC subjects, we identified a missense mutation at Ala98Val within the DNA binding domain of Hepatic Nuclear Factor 1 alpha (HNF1A, 12q24.31, Rs1800574). HNF1A is the most frequently mutated gene in diabetic individuals whose onset of diabetes occurs typically before age 25 (MODY3 locus). Our aim was to demonstrate that the HNF1A variant provides a genomic landscape for EO-CRC to develop in the setting of a specific diet type. Methods: HNF1A was identified using targeted exon sequencing of archived leukocyte DNA from subjects with EO-CRC. Flag-tagged WT and HNF1AA98V expressing plasmids were transfected into HCT116 colon cancer cells and nuclear extracts were prepared for Electrophoretic Mobility Shift Assays (EMSAs) to test binding differences. An Hnf1aA98V mutant mouse model was generated using CRISPR/Cas9. WT, Hnf1a A98V/+ and Hnf1a A98V/A98V mice were placed on 3 diets--normal chow, a high fat (~34%) diet (HFD) or a high sugar (~62% fructose) diet (HSD) after weaning at 3 weeks. The mice were followed for 12 months, weighed monthly, and observed for clinical signs of morbidity. After euthanizing, blood, colon and liver were collected for histology and qPCR. Results: HNF1AA98V was identified in 13/145 subjects with EO-CRC. An additional 3 subjects exhibited mutations elsewhere in HNF1A. Flag-tagged WT and mutant HNF1A-expressing plasmids were transfected into HCT116 colon cancer cells and nuclear extracts showed reduced HNF1AA98V binding to its consensus DNA element by EMSA. Only heterozygous or homozygous Hnf1aA98V mice on the HFD showed a significant number of colon polyps (~19%). Only 1/22 heterozygous mice developed a polyp on the HSD. RNA-Seq analysis of colonic mucosa from the homozygous mutant compared to WT mice revealed an increase lipid and b-catenin regulated genes. Specifically, there was an increase in β-catenin, LEF 1 and MYC by immunohistochemistry in the polyp of HNF1AA98V, but not in the adjacent normal tissue. Liver steatosis in the Hnf1aA98V versus WT mice on the HFD was observed. Conclusions: Occurrence of the HNF1AA98V variant is increased among a cohort of EO-CRC patients and is a loss of function mutation that creates a genetic landscape for colon polyps on a HFD.
Racial/ethnic differences of germline pathogenic variants in cancer susceptibility genes among patients with early-onset colorectal cancer.
Authors: Holowatyj Andreana N , Seagle Hannah M , Keller Samantha , Tavtigian Sean V , Goldgar David E , Horton Carolyn 
Published: January 2023

19 Background: The burden of early-onset colorectal cancer (CRC diagnosed before age 50 years) differs across racial/ethnic groups. Yet the distinct prevalence and spectrum of germline pathogenic variants associated with early-onset CRC by race/ethnicity is uncharacterized. Methods: We identified 3,980 early-onset CRC patients unselected for family CRC history who underwent clinical multi-gene panel testing of 14 CRC susceptibility genes ( MLH1, MSH2, MSH6, PMS2, SMAD4, APC, BMPR1, CHEK2, EPCAM, MUTYH, PTEN, STK11, CDH1, and TP53) performed by a nationwide clinical testing laboratory from 2012 to 2016 and identified as Ashkenazi Jewish, Asian, Black, Hispanic, or White. Multi-gene panel testing was performed by targeted custom capture and sequencing and chromosome rearrangement analysis. Clinical and individual/family histories were ascertained from clinician-completed test requisition forms. Germline variant prevalence and spectrum in early-onset CRC was determined by race/ethnicity. Pathogenic variant comparisons by race/ethnicity were evaluated using chi-square tests and multivariable logistic regression adjusted for sex, age, CRC site and sequence. Results: Among 3,980 early-onset CRC patients, a total of 503 germline genetic variants were identified in 481 individuals (12.1%). By race/ethnicity, 12.7% of Ashkenazi Jewish, 8.6% of Asian, 10.3% of Black, 14.0% of Hispanic, and 12.3% of White individuals presented with a pathogenic variant in a CRC susceptibility gene. Nearly 7% of early-onset CRC patients (n = 268) presented with a germline pathogenic mutation in a mismatch repair gene—with the prevalence of Lynch Syndrome in early-onset CRC differing across racial/ethnic groups ( P= 0.037). The prevalence of germline APC, CHEK2, MLH1, monoallelic MUTYH, and PTEN variants also varied by race/ethnicity (all P< 0.02). Overall, Asian individuals with early-onset CRC had 49% lower odds of carrying a pathogenic germline variant in a CRC susceptibility gene versus White individuals in adjusted models (Odds Ratio [OR] = 0.51, 95% Confidence Interval [CI]: 0.26-0.99, P= 0.046). Ashkenazim and Hispanic individuals had higher odds of presenting with pathogenic APC and MLH1 variants, respectively, compared with White individuals in adjusted models ( APC: OR = 8.69, 95% CI: 2.68-28.21, P= 0.0003; MLH1: OR = 2.67, 95% CI: 1.30-5.49, P= 0.007). Conclusions: Of 3,980 patients with early-onset CRC unselected for family history, the prevalence and spectrum of pathogenic germline variants differed across racial/ethnic populations. Beyond multigene panel testing for all early-onset CRC patients, further study is needed to optimize genes selected for germline genetic testing in early-onset CRC across diverse groups—which would have clinical implications for disease surveillance and intervention.
Metagenomic analysis of gut microbiota of patients with colorectal cancer at the Federal Medical Centre (FMC), Abeokuta, Ogun State, Nigeria.
Authors: Sulaimon Lateef Adegboyega , Joel Ireoluwa Yinka , Sanusi Olalekan Sabur , Olanipekun Quadri Arise-kola , Haliru Amatullah Mahe , Ajanaku Zainab Adedolapo , Hassan Aaliyah Eniola , Zakariyah Ikimot Fehintola , Ajibade Faidat Bukola , Olajide Monsurat , Lawal Modinat Olasunkanmi , Ajibare Abosede Christiana 
Published: January 2023

195 Background: It has been suggested that the intestinal microbiome plays a vital role in the development of colorectal cancer (CRC), but the changes in intestinal bacteria in healthy and CRC subjects have not yet been examined in the Nigerian population. The study sought to investigate changes in intestinal bacteria in healthy subjects and patients with CRC. Methods: Fecal samples were collected from healthy and CRC subjects at the Federal Medical Centre, Abeokuta with the study ethical approval number FMCA/47O/HREC/01/2021/23. We extracted genomic DNA with magnetic bead extraction and sequenced the whole genome using a Nanopore MinION sequencer. We performed metagenomic analysis on fecal samples from 20 healthy subjects and 20 patients with colorectal cancer (CRC) to study the bacterial community structure, relative abundance, differentially abundant bacteria, association networks, taxonomic profiling, and specialty gene expression. Results: CRC patients have significantly different bacterial community structures compared to healthy subjects. Compared to healthy subjects, CRC patients had low intestinal bacterial diversity. Only CRCs contain Gammaproteobacteria at the phylum level. Compared to CRC, Bacteroidia and Actinobacteria were significantly more abundant in healthy subjects, while Bacilli and Negativicutes were significantly less abundant. Bacteroides and Prevotella are more abundant in healthy subjects than in CRC at the genus level. There was a greater abundance of Escherichia and Pseudomonas in CRC as compared with healthy subjects. It is noteworthy that Escherichia coli, which co-occurred in both healthy and CRC subjects, was significantly elevated only in CRC, while Pseudomonas aeruginosa only occurs in CRC. Based on phylogenetic analysis, there were notable relationships between six strains of E. coli and four strains of Shigella sp. identified in CRC. There were several pathogenic-associated virulent and antimicrobial resistant genes expressed in these strains. These genes conferred resistance via antibiotic inactivation, efflux pump activity, alteration of cell wall proteins, and regulation of antibiotic permeability. Conclusions: The present study demonstrated that the taxonomic composition and functional genes of intestinal bacteria were significantly altered in CRC. Also, E. coli and P. aeruginosa are at least partially involved in the pathogenesis of CRC.
Tumor mutations associated with outcomes in colorectal peritoneal metastases.
Authors: Uppal Abhineet , White Michael , Chang George J. , Zeineddine Fadl A. , Zeineddine Mohammad A. , Yousef Abdelrahman M.G. , Scally Christopher , Fournier Keith F. , Newhook Timothy E. , You Y. Nancy , Willis Jason , Kopetz Scott , Shen John Paul Y.C. 
Published: January 2023

196 Background: The association between tumor mutations beyond KRAS and BRAF for patients with peritoneal metastases (PM) from colorectal cancer (CRC) are poorly understood. Here we describe these associations with survival after diagnosis of PM. Methods: CRC patients with PM with or without synchronous liver or lung metastases treated at a single institution from 2016 to 2020 were retrospectively studied. Standard of care next-generation sequencing was performed on tissue specimens with a targeted panel of genes frequently mutated in cancer. Clinical data, including survival and last contact, were obtained from medical records. Multivariate Cox regression was used to identify associations between overall survival after diagnosis of PM (OS) with clinical, histopathologic and somatic mutation data. Results: Of 526 PM patients, 179 (34.2%) also had synchronous liver metastases, and these patients had worse OS compared to PM alone (HR 1.67, [1.26-2.22], p=0.0003). Lung metastases were identified in 57 (10.8%) and were not associated with worse OS (HR 1.34, [0.90-1.97], p=0.15). Poorly differentiated grade (HR 2.08, [1.42-3.04], p=0.0002), mucinous histology (HR 1.44, [1.07-1.94], p=0.016), male gender (HR 1.37, [1.05-1.78), p=0.019), and age (HR 1.02, [1.01-1.04], p=0.004) were independently associated with OS. Tumor sequencing data was available for 442 (87%) patients. TP53 was the most common mutation (61.5% of patients) and was associated with decreased OS (HR=1.51 [1.12-2.02], p=0.005). BRAF mutation (85% of which were V600E) was identified in 9.7% of patients and was also associated with decreased OS (HR=1.88 [1.23-2.86], p=0.003). In contrast, PTEN mutation (4.3%) was associated with improved OS (0.41 (0.17-0.99), p=0.049), while both KRAS (51.4%) and SMAD4 mutations (16%) were not (KRAS: HR 0.94, [0.72-1.24], p=0.68; SMAD4: HR 0.78, [0.53-1.16], p=0.21). Conclusions: Mutational data for PM patients has a distinct profile and unique associations with OS when compared to other sites of metastatic disease. TP53 and BRAF mutations were associated with worse survival, while PTEN mutation was associated with improved OS. KRAS mutation was more prevalent than expected in an unselected cohort, and not associated with OS. A better understanding of PM-specific associations with survival may influence treatment strategies for this difficult disease site.
Concordance of genomic alterations in anal cancer by next-generation sequencing in tissue and circulating tumor DNA.
Authors: LaPelusa Michael Brian , Cann Christopher G , Eng Cathy 
Published: January 2023

2 Background: The feasibility of identifying genomic alterations via next-generation sequencing (NGS) of peripheral blood (PB) to spare patients an invasive biopsy is an active area of investigation. High concordance of mutations between tissue and PB has been observed in several cancer types. However, the concordance between tissue and PB in patients with SCCA is unknown. Methods: We identified 11 patients with SCCA who had NGS (TEMPUS) performed on tissue and PB between 2017 - 2022. The IRB at Vanderbilt-Ingram Cancer Center approved this study. Results: See Table. Conclusions: In 6 of the 11 patients, concordant genomic alterations found in tissue were also identified in PB. More patients with anal cancer should be studied to better understand this phenomenon and the impact of therapy on ctDNA kinetics.[Table: see text]
Comparison between interval and sporadic colon cancer in terms of clinicopathologic and molecular features.
Authors: Huh Kyu Chan , Kim Dae Sung , Shin Jeong Eun , Lee Yoo Jin , Kim Kyeong Ok , Kim Jae Hyun , Kang Gyeong Hoon 
Published: January 2023

205 Background: Interval colon cancer occurs due to either limitations of colonoscopy or rapidly developing new tumors, possibly reflecting molecular and environmental differences in tumorigenesis. This study aimed to compare the clinicopathologic and molecular features of interval colon cancer with those of sporadic colon cancer in Asia. Methods: This prospective, multicenter, cross‐sectional study was conducted from May 2017 to December 2021 at six university hospitals in South Korea. Interval colon cancer was defined as colon cancer diagnosed within 5 years of complete colonoscopy. We compared the clinicopathologic and molecular biological characteristics, including CpG island methylator phenotype (CIMP), KRAS, BRAF, and microsatellite instability (MSI), between patients with interval and sporadic colon cancers. Results: We compared and analyzed 28 patients with interval colon cancer and 72 patients with sporadic cancer. There was no difference in terms of sex, BMI, underlying disease, and family history in the clinical comparison between the interval and sporadic cancer groups. There was no difference in the location, shape, or stage of cancer including metastasis, between the two groups. In molecular biological analysis, CIMP was 5.1% positive for sporadic cancer and 17.9% positive for interval colon cancer, indicating an approximately 13% greater frequency in interval colon cancer (p = .036). KRAR mutation was observed in 36.7% of patients with sporadic cancers and 17.9% of those with interval colon, which was about 18% higher in sporadic cancer, but there was no statistically significant difference (p = .066). There was no difference between MSI and BRAF genotype between the sporadic and interval cancer groups. Conclusions: Unlike the findings of western studies, there was no clinical difference between sporadic and interval colon cancer. In molecular biological comparison, the CIMP positivity rate was significantly higher in patients with interval colon cancer.
Differences in tumor-associated T cell receptor repertoires between young-onset and average-onset colorectal cancer.
Authors: Schmit Stephanie , Tsai Ya-Yu , Nair Kanika G. , Barot Shimoli V , Xiang Shao , Kamath Suneel Deepak , Melas Marilena , Walker Christopher P , Srivastava Raghvendra , Chan Timothy An-thy , Bonner Joseph D. , McDonnell Kevin , Idos Gregory , Greenson Joel K , Rennert Hedy S , Rennert Gad , Gruber Stephen B. , Khorana Alok A. , Liska David 
Published: January 2023

207 Background: The incidence of colorectal cancer (CRC) among individuals younger than age 50 (young-onset CRC; YOCRC) has increased, yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. Some studies suggest that YOCRCs have more aggressive biology. Here, we compare tumor-associated T cell repertoires between patients with YOCRC and average-onset CRC (AOCRC). A robust, focused T cell response is a positive prognostic indicator; therefore, we hypothesized that YOCRCs demonstrate lower T cell abundance and greater T cell diversity than AOCRCs. Methods: The discovery cohort included 242 patients with histologically confirmed Stage I-IV CRC who underwent surgical resection at Cleveland Clinic from 2000 to 2020 and consented to a biorepository. YOCRC was defined as < 50 years at diagnosis (N = 126), and AOCRC as > 60 years (N = 116). DNA was extracted from frozen tumors, and T Cell Receptor (TCR) abundance and clonality were measured using immunoSEQ (Adaptive Biotechnologies). Following quality control, logistic regression models were used to evaluate the associations between TCR repertoire features and age of onset, adjusting for sex, race, tumor location, and stage. Findings were replicated in 152 YOCRC and 1,984 AOCRC cases from the Molecular Epidemiology of Colorectal Cancer Study with adjustment for sex, Jewish ethnicity, tumor location, and stage. Results: YOCRC patients were more likely to have left-sided tumors and be diagnosed at advanced stages in both cohorts. In the discovery cohort, YOCRC tumors had significantly lower TCR clonality (higher T cell diversity) compared to AOCRC tumors in a multivariable model adjusting for sex, race, tumor location and stage (OR: 0.38, 95% Confidence Interval (CI): 0.25-0.56, p < 0.0001). This association was also observed in the replication cohort (OR: 0.74, 95% CI: 0.62-0.89, p = 0.0013). In the replication cohort, further adjustment for microsatellite instability status did not substantially change the association (OR: 0.73, 95% CI: 0.61-0.88 p = 0.0012). When restricting to microsatellite stable tumors, clonality remained statistically significant in both the discovery and replication cohorts. No significant difference in TCR abundance was observed between YOCRC and AOCRC in either cohort. Conclusions: Higher T cell repertoire diversity, indicating a less focused intratumoral T cell response, is more frequently observed in YOCRC. Further studies are warranted to investigate the role of T cell diversity in the etiology and outcomes of YOCRC.
Clinical outcomes and healthcare utilization among young adults with colon cancer on Medicaid vs private insurance.
Authors: Deenadayalan Vaishali , Solipuram Vinod , Sequeira Gross Harry Guillermo , Gupta Shweta 
Published: January 2023

22 Background: The incidence of colon cancer in young adults has been increasing. The role of insurance on the outcomes of young adults diagnosed with colon cancer is unclear. In this study we sought to study the impact of Private insurance vs Medicaid on the outcomes of colon cancer in young adults (<50 years). Methods: Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS) 2016-2019 was queried to identify young adult patients (Age <50 years) admitted for colon cancer using the ICD-10 (International Classification of Diseases) codes. Study population was stratified based on the insurance (private vs Medicaid). Primary outcomes included mortality, length of stay (LOS), and total hospitalization charges (THC). Secondary outcomes included prevalence of pulmonary embolism (PE), ICU admission, acute kidney injury (AKI), acute respiratory failure (ARF), blood transfusion, and sepsis. Statistics were performed using multivariate linear and logistic regression using STATA v17. Results: 59,065 young adult admissions were identified with a principal diagnosis of colon cancer between 2016-2019. Among them 36,765 (62.2%) were on private insurance while 13,480 (22.8%) were on Medicaid. Medicaid patients were significantly younger, female, Black and Hispanic with a higher Charlson comorbidity index (p<0.05). Of the 870 (1.5%) patients that died during the admission, 46.5% (N= 405) had private insurance whereas 26.4% (N= 230) had Medicaid. There was no significant difference in the odds of mortality between private insurance and Medicaid (adjusted OR 1.07, 95% CI 0.69-1.67; p=0.77). The LOS was increased by 1.5 days for Medicaid patients compared to private insurance (95% CI 1.15-1.90; p<0.001). There was no significant difference in total hospitalization charges among both groups. Medicaid patients had higher odds of sepsis (OR 1.5, 95% CI 1.09-1.94; p=0.012), requiring blood transfusion (OR 1.6, 95% CI 1.32-1.83; p<0.000) and less likely to undergo colectomy (OR 0.61, 95% CI 0.55-0.67; p<0.000). There were no significant differences in ICU admission, AKI and ARF. Conclusions: Compared to private insurance, Medicaid patients had similar healthcare outcomes and hospital charges despite a longer LOS. In an era where the country explores options for healthcare reform including single payor system, our study provides insight into similar effectiveness of Medicaid in caring for young colon cancer patients compared to Private Insurance despite higher comorbidities in Medicaid patients.
Tumor mutation burden in colorectal cancers with POLE exonuclease and non-exonuclease domain variants.
Authors: Ringenbach Salena , Shah Shreya M. , Demidova Elena , Faezov Bulat , Andrake Mark D. , Mur Pilar , Xiu Joanne , Korn Wolfgang Michael , Goel Sanjay , Lenz Heinz-Josef , Marshall John , Shields Anthony Frank , Oberley Matthew James , Spetzler David , Valle Laura , Dunbrack Roland , Hall Michael J. , Arora Sanjeevani 
Published: January 2023

224 Background: Driver mutations in the exonuclease domain (ExoD) of DNA polymerase epsilon ( POLE) have been associated with high tumor mutation burden (TMB). High TMB is an important marker for immunotherapy, and thus understanding the mechanisms that lead to high TMB is an area of active investigation. Many tumors with POLE ExoD driver mutations have additional POLE variants of uncertain significance (VUS). Some of these VUS lie within the ExoD, while most lie outside the ExoD. This study investigates the role of such POLE VUS on TMB and POLE functionality of ExoD-mutated tumors. Methods: Retrospective colorectal cancer (CRC) genomic profiles from Caris Life Sciences (n=1,870) were separated into groups based on the presence of POLE ExoD mutations and the TMB status. Groups were defined as: ‘TMB-high (TMB-H) POLE ExoD driver without additional POLE VUS’, ‘TMB-H POLE ExoD driver plus POLE VUS’, and ‘TMB-low (TMB-L) POLE variant(s) without ExoD driver’. An additional group with ‘TMB-H POLE variant(s) without ExoD driver’ was identified as potentially novel drivers for future study. The microsatellite instability status (MSI or MSS) was also considered. The level of TMB, the presence of polymerase proofreading-associated mutational signatures and POLE stability/functionality analyzed using AlphaFold2 models and Rosetta Molecular Modeling Suite, were evaluated. Results: POLE variants were identified in 4.9% of the CRCs studied (92/1870). In all, 52.2% (48/92) of those tumors were TMB-H, and 38.0% (35/92) of them contained POLE ExoD drivers. The highest median TMB (mTMB) was found in the ‘TMB-H POLE ExoD driver plus POLE VUS’ group, and this was significantly different from the ‘TMB-H POLE ExoD driver without additional POLE VUS’ and the ‘TMB-L POLE variant without ExoD driver’ group, even when MSI tumors were excluded (p<0.001, Mann-Whitney). These results were validated in TCGA CRC tumors and in other tumor types. Within the ‘TMB-H POLE ExoD driver plus POLE VUS’ group, the mTMB increased with the number of accumulated POLE VUS (p<0.001, Mann Whitney). The nucleotide sequence context of 77.8% of the POLE VUS matched mutational spectra associated with POLE ExoD defects, suggesting that most of the POLE VUS are secondary to the ExoD driver mutation. Finally, the majority of POLE VUS within ‘TMB-H POLE ExoD driver plus POLE VUS’ group have a predicted effect on POLE stability and/or function. Conclusions: Our results suggest that the presence of secondary POLE non-driver variants increase TMB in POLE ExoD-mutated tumors. Although still preliminary, these data could impact prognosis and response to immune checkpoint inhibitors in patients. [Table: see text]