Publications by authors named "Andreana N Holowatyj"

39 Publications

The Use of Human Serum Samples to Study Malignant Transformation: A Pilot Study.

Cells 2021 10 6;10(10). Epub 2021 Oct 6.

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48823, USA.

Obesity and excess adiposity account for approximately 20% of all cancer cases; however, biomarkers of risk remain to be elucidated. While fibroblast growth factor-2 (FGF2) is emerging as an attractive candidate biomarker for visceral adipose tissue mass, the role of circulating FGF2 in malignant transformation remains unknown. Moreover, functional assays for biomarker discovery are limited. We sought to determine if human serum could stimulate the 3D growth of a non-tumorigenic cell line. This type of anchorage-independent 3D growth in soft agar is a surrogate marker for acquired tumorigenicity of cell lines. We found that human serum from cancer-free men and women has the potential to stimulate growth in soft agar of non-tumorigenic epithelial JB6 P cells. We examined circulating levels of FGF2 in humans in malignant transformation in vitro in a pilot study of = 33 men and women. Serum FGF2 levels were not associated with colony formation in epithelial cells ( = 0.05, = 0.80); however, a fibroblast growth factor receptor-1 (FGFR1) selective inhibitor significantly blocked serum-stimulated transformation, suggesting that FGF2 activation of FGFR1 may be necessary, but not sufficient for the transforming effects of human serum. This pilot study indicates that the FGF2/FGFR1 axis plays a role in JB6 P malignant transformation and describes an assay to determine critical serum factors that have the potential to promote tumorigenesis.
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http://dx.doi.org/10.3390/cells10102670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534413PMC
October 2021

Incorporating Reproductive Health in the Clinical Management of Early-Onset Colorectal Cancer.

JCO Oncol Pract 2021 Sep 23:OP2100525. Epub 2021 Sep 23.

Intermountain Healthcare, Murray, UT.

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http://dx.doi.org/10.1200/OP.21.00525DOI Listing
September 2021

Surgical resection and survival outcomes in metastatic young adult colorectal cancer patients.

Cancer Med 2021 07 16;10(13):4269-4281. Epub 2021 Jun 16.

Division of Hematology and Oncology, Department of Internal Medicine, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.

Background: The incidence of colorectal cancer in adults younger than age 50 has increased with rates expected to continue to increase over the next decade. The objective of this study is to examine the survival benefit of surgical resection (primary and/or metastatic) versus palliative therapy in this patient population.

Methods: We identified 6708 young adults aged 18-45 years diagnosed with metastatic colorectal cancer (mCRC) from 2004 to 2015 from the SEER database. Overall survival (OS) was analyzed using Kaplan-Meier estimation, log rank test, and multivariate Cox proportional hazards model.

Results: Sixty-three percent of patients in our study underwent primary tumor resection (PTR), with 40% undergoing PTR alone and 23% undergoing both resection of primary disease and metastasectomy. The median OS for patients who underwent both PTR and metastasectomy was 36 months, compared to 13 months for those who did not receive any surgical intervention. The multivariate analysis showed significant OS benefit of receiving both PTR and metastasectomy (HR 0.34, 95% CI: 0.31-0.37, p < 0.001) compared to palliative therapy. Undergoing PTR only and metastasectomy only were also associated with improved OS (HR 0.46, 95% CI: 0.43-0.49, p < 0.001 and HR 0.64, 95% CI: 0.55-0.76, p < 0.001, respectively).

Conclusion: This is the largest observational study to evaluate survival outcomes in young-onset mCRC patients and the role of surgical intervention of the primary and/or metastatic site. Our study provides evidence of statistically significant increase in OS for young mCRC patients who undergo surgical intervention of the primary and/or metastatic site.
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http://dx.doi.org/10.1002/cam4.3940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267130PMC
July 2021

Understanding the Prevalence of Prediabetes and Diabetes in Patients With Cancer in Clinical Practice: A Real-World Cohort Study.

J Natl Compr Canc Netw 2021 Mar 10;19(6):709-718. Epub 2021 Mar 10.

2Huntsman Cancer Institute, and.

Background: This study aimed to understand the prevalence of prediabetes (preDM) and diabetes mellitus (DM) in patients with cancer overall and by tumor site, cancer treatment, and time point in the cancer continuum.

Methods: This cohort study was conducted at Huntsman Cancer Institute at the University of Utah. Patients with a first primary invasive cancer enrolled in the Total Cancer Care protocol between July 2016 and July 2018 were eligible. Prevalence of preDM and DM was based on ICD code, laboratory tests for hemoglobin A1c, fasting plasma glucose, nonfasting blood glucose, or insulin prescription.

Results: The final cohort comprised 3,512 patients with cancer, with a mean age of 57.8 years at cancer diagnosis. Of all patients, 49.1% (n=1,724) were female. At cancer diagnosis, the prevalence of preDM and DM was 6.0% (95% CI, 5.3%-6.8%) and 12.2% (95% CI, 11.2%-13.3%), respectively. One year after diagnosis the prevalence was 16.6% (95% CI, 15.4%-17.9%) and 25.0% (95% CI, 23.6%-26.4%), respectively. At the end of the observation period, the prevalence of preDM and DM was 21.2% (95% CI, 19.9%-22.6%) and 32.6% (95% CI, 31.1%-34.2%), respectively. Patients with myeloma (39.2%; 95% CI, 32.6%-46.2%) had the highest prevalence of preDM, and those with pancreatic cancer had the highest prevalence of DM (65.1%; 95% CI, 57.0%-72.3%). Patients who underwent chemotherapy, radiotherapy, or immunotherapy had a higher prevalence of preDM and DM compared with those who did not undergo these therapies.

Conclusions: Every second patient with cancer experiences preDM or DM. It is essential to foster interprofessional collaboration and to develop evidence-based practice guidelines. A better understanding of the impact of cancer treatment on the development of preDM and DM remains critical.
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http://dx.doi.org/10.6004/jnccn.2020.7653DOI Listing
March 2021

Fusobacterium nucleatum and Clinicopathologic Features of Colorectal Cancer: Results From the ColoCare Study.

Clin Colorectal Cancer 2021 09 27;20(3):e165-e172. Epub 2021 Feb 27.

Huntsman Cancer Institute, Salt Lake City, UT; Department of Population Health Sciences, University of Utah, Salt Lake City, UT.

Background: Fusobacterium nucleatum (Fn), a bacterium associated with a wide spectrum of infections, has emerged as a key microbe in colorectal carcinogenesis. However, the underlying mechanisms and clinical relevance of Fn in colorectal cancer (CRC) remain incompletely understood.

Patients And Methods: We examined associations between Fn abundance and clinicopathologic characteristics among 105 treatment-naïve CRC patients enrolled in the international, prospective ColoCare Study. Electronic medical charts, including pathological reports, were reviewed to document clinicopathologic features. Quantitative real-time polymerase chain reaction (PCR) was used to amplify/detect Fn DNA in preoperative fecal samples. Multinomial logistic regression was used to analyze associations between Fn abundance and patient sex, age, tumor stage, grade, site, microsatellite instability, body mass index (BMI), alcohol consumption, and smoking history. Cox proportional hazards models were used to investigate associations of Fn abundance with overall survival in adjusted models.

Results: Compared to patients with undetectable or low Fn abundance, patients with high Fn abundance (n = 22) were 3-fold more likely to be diagnosed with rectal versus colon cancer (odds ratio [OR] = 3.01; 95% confidence interval [CI], 1.06-8.57; P = .04) after adjustment for patient sex, age, BMI, and study site. Patients with high Fn abundance also had a 5-fold increased risk of being diagnosed with rectal cancer versus right-sided colon cancer (OR = 5.32; 95% CI, 1.23-22.98; P = .03). There was no statistically significant association between Fn abundance and overall survival.

Conclusion: Our findings suggest that Fn abundance in fecal samples collected prior to surgery varies by tumor site among treatment-naïve CRC patients. Overall, fecal Fn abundance may have diagnostic and prognostic significance in the clinical management of CRC.
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http://dx.doi.org/10.1016/j.clcc.2021.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390557PMC
September 2021

Gut instinct: a call to study the biology of early-onset colorectal cancer disparities.

Nat Rev Cancer 2021 06;21(6):339-340

University of Colorado Denver, Aurora, CO, USA.

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http://dx.doi.org/10.1038/s41568-021-00356-yDOI Listing
June 2021

Histologic and Racial/Ethnic Patterns of Appendiceal Cancer among Young Patients.

Cancer Epidemiol Biomarkers Prev 2021 06 1;30(6):1149-1155. Epub 2021 Apr 1.

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

Background: Appendiceal cancer incidence among individuals age < 50 years (early-onset appendiceal cancer) is rising with unknown etiologies. Distinct clinicopathologic/demographic features of early-onset appendiceal cancer remain unexplored. We compared patterns of appendiceal cancer among individuals by age of disease-onset.

Methods: Using the NIH/NCI's Surveillance, Epidemiology, and End Results program data, we identified individuals age 20+ years diagnosed with appendiceal cancer from 2007 to 2016. Cochran-Armitage trend tests and multinomial logistic regression models were used to examine age-related differences in clinicopathologic/demographic features of appendiceal cancer.

Results: We identified 8,851 patients with appendiceal cancer during the 10-year study period. Histologic subtype, tumor grade, stage, sex and race/ethnicity all significantly differed by age of appendiceal cancer diagnosis. After adjustment for race/ethnicity, sex, stage, insurance status, and tumor grade, young patients were 82% more likely to be Hispanic [OR, 1.82; 95% confidence interval (CI), 1.48-2.25; < 0.001] and 4-fold more likely to be American Indian or Alaska Native (OR, 4.02; 95% CI, 1.77-9.16; = 0.0009) compared with late-onset cases. Patients with early-onset appendiceal cancer were also 2- to 3.5-fold more likely to be diagnosed with neuroendocrine tumors of the appendix (goblet cell carcinoid: OR, 1.96; 95% CI, 1.59-2.41; < 0.0001; carcinoid: OR, 3.52; 95% CI, 2.80-4.42; < 0.0001) compared with patients with late-onset appendiceal cancer. Among patients with neuroendocrine tumors, early-onset cases were also 45% to 61% less likely to present with high-grade (III-IV) tumors.

Conclusions: Approximately one in every three patients with appendiceal cancer is diagnosed before age 50 years in the United States. Appendiceal cancer in young patients is classified by distinct histologic and demographic features.

Impact: Early-onset appendiceal cancer determinants can inform discovery of risk factors and molecular biomarkers of appendiceal cancer in young patients, with implications for appendiceal cancer prevention, detection, and treatment.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1505DOI Listing
June 2021

Targeted Plasma Metabolic Profiles and Risk of Recurrence in Stage II and III Colorectal Cancer Patients: Results from an International Cohort Consortium.

Metabolites 2021 Feb 24;11(3). Epub 2021 Feb 24.

Huntsman Cancer Institute Salt Lake City, Salt Lake City, UT 84112, USA.

The identification of patients at high-risk for colorectal cancer (CRC) recurrence remains an unmet clinical need. The aim of this study was to investigate associations of metabolites with risk of recurrence in stage II/III CRC patients. A targeted metabolomics assay (128 metabolites measured) was performed on pre-surgery collected EDTA plasma samples from n = 440 newly diagnosed stage II/III CRC patients. Patients have been recruited from four prospective cohort studies as part of an international consortium: Metabolomic profiles throughout the continuum of CRC (MetaboCCC). Cox proportional hazard models were computed to investigate associations of metabolites with recurrence, adjusted for age, sex, tumor stage, tumor site, body mass index, and cohort; false discovery rate (FDR) was used to account for multiple testing. Sixty-nine patients (15%) had a recurrence after a median follow-up time of 20 months. We identified 13 metabolites that were nominally associated with a reduced risk of recurrence. None of the associations were statistically significant after controlling for multiple testing. Pathway topology analyses did not reveal statistically significant associations between recurrence and alterations in metabolic pathways (e.g., sphingolipid metabolism = 0.04; p = 1.00). To conclude, we did not observe statistically significant associations between metabolites and CRC recurrence using a well-established metabolomics assay. The observed results require follow-up in larger studies.
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http://dx.doi.org/10.3390/metabo11030129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996362PMC
February 2021

Circulating B-vitamin biomarkers and B-vitamin supplement use in relation to quality of life in patients with colorectal cancer: results from the FOCUS consortium.

Am J Clin Nutr 2021 06;113(6):1468-1481

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

Background: B vitamins have been associated with the risk and progression of colorectal cancer (CRC), given their central roles in nucleotide synthesis and methylation, yet their association with quality of life in established CRC is unclear.

Objectives: To investigate whether quality of life 6 months postdiagnosis is associated with: 1) circulating concentrations of B vitamins and related biomarkers 6 months postdiagnosis; 2) changes in these concentrations between diagnosis and 6 months postdiagnosis; 3) B-vitamin supplement use 6 months postdiagnosis; and 4) changes in B-vitamin supplement use between diagnosis and 6 months postdiagnosis.

Methods: We included 1676 newly diagnosed stage I-III CRC patients from 3 prospective European cohorts. Circulating concentrations of 9 biomarkers related to the B vitamins folate, riboflavin, vitamin B6, and cobalamin were measured at diagnosis and 6 months postdiagnosis. Information on dietary supplement use was collected at both time points. Health-related quality of life (global quality of life, functioning scales, and fatigue) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 6 months postdiagnosis. Confounder-adjusted linear regression analyses were performed, adjusted for multiple testing.

Results: Higher pyridoxal 5'-phosphate (PLP) was cross-sectionally associated with better physical, role, and social functioning, as well as reduced fatigue, 6 months postdiagnosis. Associations were observed for a doubling in the hydroxykynurenine ratio [3-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3-hydroxyanthranilic acid + anthranilic acid); an inverse marker of vitamin B6] and both reduced global quality of life (β = -3.62; 95% CI: -5.88, -1.36) and worse physical functioning (β = -5.01; 95% CI: -7.09, -2.94). Dose-response relations were observed for PLP and quality of life. No associations were observed for changes in biomarker concentrations between diagnosis and 6 months. Participants who stopped using B-vitamin supplements after diagnosis reported higher fatigue than nonusers.

Conclusions: Higher vitamin B6 status was associated with better quality of life, yet limited associations were observed for the use of B-vitamin supplements. Vitamin B6 needs further study to clarify its role in relation to quality of life.
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http://dx.doi.org/10.1093/ajcn/nqaa422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168355PMC
June 2021

Community Health Behaviors and Geographic Variation in Early-Onset Colorectal Cancer Survival Among Women.

Clin Transl Gastroenterol 2020 12;11(12):e00266

Division of Epidemiology, Augusta University at the Medical College of Georgia, Augusta, Georgia, USA.

Introduction: Despite overall reductions in colorectal cancer (CRC) morbidity and mortality, survival disparities by sex persist among young patients (age <50 years). Our study sought to quantify variance in early-onset CRC survival accounted for by individual/community-level characteristics among a population-based cohort of US women.

Methods: Geographic hot spots-counties with high early-onset CRC mortality rates among women-were derived using 3 geospatial autocorrelation approaches with Centers for Disease Control and Prevention national mortality data. We identified women (age: 15-49 years) diagnosed with CRC from 1999 to 2016 in the National Institutes of Health/National Cancer Institute's Surveillance, Epidemiology, and End Results program. Patterns of community health behaviors by hot spot classification were assessed by Spearman correlation (ρ). Generalized R values were used to evaluate variance in survival attributed to individual/community-level features.

Results: Approximately 1 in every 16 contiguous US counties identified as hot spots (191 of 3,108), and 52.9% of hot spot counties (n = 101) were located in the South. Among 28,790 women with early-onset CRC, 13.7% of cases (n = 3,954) resided in hot spot counties. Physical inactivity and fertility were community health behaviors that modestly correlated with hot spot residence among women with early-onset CRC (ρ = 0.21 and ρ = -0.23, respectively; P < 0.01). Together, individual/community-level features accounted for distinct variance patterns in early-onset CRC survival among women (hot spot counties: 33.8%; non-hot spot counties: 34.1%).

Discussion: Individual/community-level features accounted for approximately one-third of variation in early-onset CRC survival among women and differed between hot spot vs non-hot spot counties. Understanding the impact of community health behaviors-particularly in regions with high early-onset CRC mortality rates-is critical for tailoring strategies to reduce early-onset CRC disparities.
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http://dx.doi.org/10.14309/ctg.0000000000000266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678794PMC
December 2020

Spectrum of Somatic Cancer Gene Variations Among Adults With Appendiceal Cancer by Age at Disease Onset.

JAMA Netw Open 2020 12 1;3(12):e2028644. Epub 2020 Dec 1.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: The incidence of appendiceal cancer (AC) is rising, particularly among individuals younger than 50 years (early-onset AC), with unexplained etiologies. The unique spectrum of somatic cancer gene variations among patients with early-onset AC is largely undetermined.

Objective: To characterize the frequency of somatic variations and genomic patterns among patients with early-onset (age <50 years) vs late-onset (age ≥50 years) AC.

Design, Setting, And Participants: This cohort study included individuals aged 18 years and older diagnosed with pathologically verified AC. Cases with clinical-grade targeted sequencing data from January 1, 2011, to December 31, 2019, were identified from the international clinicogenomic data-sharing consortium American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE). Data analysis was conducted from May to September 2020.

Exposures: Age at disease onset.

Main Outcomes And Measures: Somatic variation prevalence and spectrum in AC patients was determined. Variation comparisons between early-onset and late-onset AC were evaluated using multivariable logistic regression with adjustment for sex, race/ethnicity, histological subtype, sequencing center, and sample type.

Results: In total 385 individuals (mean [SD] age at diagnosis, 56.0 [12.4] years; 187 [48.6%] men; 306 [79.5%] non-Hispanic White individuals) with AC were included in this study, and 109 patients (28.3%) were diagnosed with early-onset AC. Race/ethnicity differed by age at disease onset; non-Hispanic Black individuals accounted for a larger proportion of early-onset vs late-onset cases (9 of 109 [8.3%] vs 11 of 276 [4.0%]; P = 0.04). Compared with patients aged 50 years or older at diagnosis, patients with early-onset AC had significantly higher odds of presenting with nonsilent variations in PIK3CA, SMAD3, and TSC2 (PIK3CA: odds ratio [OR], 4.58; 95% CI, 1.72-12.21; P = .002; SMAD3: OR, 7.37; 95% CI, 1.24-43.87; P = .03; TSC2: OR, 12.43; 95% CI, 1.03-149.59; P = .047). In contrast, patients with early-onset AC had a 60% decreased odds of presenting with GNAS nonsilent variations compared with patients with late-onset AC (OR, 0.40; 95% CI, 0.21-0.76, P = .006). By histological subtype, young patients with mucinous adenocarcinomas of the appendix had 65% decreased odds of variations in GNAS compared with late-onset cases in adjusted models (OR, 0.35; 95% CI, 0.15-0.79; P = .01). Similarly, patients with early-onset nonmucinous appendiceal adenocarcinomas had 72% decreased odds of presenting with GNAS variations vs late-onset cases, although these findings did not reach significance (OR, 0.28; 95% CI, 0.07-1.14; P = .08). GNAS and TP53 variations were mutually exclusive in ACs among early-onset and late-onset cases (P < .05).

Conclusions And Relevance: In the study, AC diagnosed among younger individuals harbored a distinct genomic landscape compared with AC diagnosed among older individuals. Development of therapeutic modalities that target these unique molecular features may yield clinical implications specifically for younger patients.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.28644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726634PMC
December 2020

Copy neutral loss of heterozygosity (cnLOH) patterns in synchronous colorectal cancer.

Eur J Hum Genet 2021 04 2;29(4):709-713. Epub 2020 Dec 2.

Surgery Department, Fundación Jiménez Díaz University Hospital, Madrid, Spain.

Copy neutral loss of heterozygosity (cnLOH) is a common event in several human malignancies-positing this as a mechanism of carcinogenesis. However, the role of cnLOH in synchronous colorectal cancer (SCRC), a unique CRC subtype, is not well understood. The aim of this study was to establish a cnLOH profile of SCRC using a single-nucleotide polymorphism array (SNP-A), and to explore associations between cnLOH and the genomic landscape of frequently mutated genes in SCRC. Among 74 paired SCRC cases, the most frequently altered regions were 16p11.2-p11.1 (59.5%) and 11p11.2-p11.12 (28.4%). Notably, the 6q11.21-q11.22 region altered by cnLOH was uniquely associated with polyclonal SCRCs (p = 0.038). Together, our analysis suggests that inactivation of tumor suppressor genes and cnLOH are rare events among SCRC cases. This study defines distinct patterns of cnLOH in SCRC, and provides initial evidence of a role for cnLOH in SCRC etiology.
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http://dx.doi.org/10.1038/s41431-020-00774-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115567PMC
April 2021

Patterns of Early-Onset Colorectal Cancer Among Nigerians and African Americans.

JCO Glob Oncol 2020 10;6:1647-1655

University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA.

Purpose: Colorectal cancer (CRC) incidence rates are increasing among individuals < 50 years of age (early-onset CRC) globally with causes unknown. Racial/ethnic disparities in early-onset CRC have also grown more pronounced, because Black individuals have higher early-onset CRC incidence and poorer survival compared with White individuals. We describe the prevalence and burden of early-onset CRC among Africans in Nigeria and African Americans (AAs) in the United States.

Patients And Methods: We identified Black individuals diagnosed with a first primary CRC ages 18 to 49 years between 1989 and 2017 at Ahmadu Bello University Teaching Hospital in Zaria, Nigeria (Nigerians), and in the United States (AAs) using the National Institutes of Health/National Cancer Institute's SEER program of cancer registries. Multivariable logistic regression models were used to investigate clinical and demographic differences between Nigerians and AAs with early-onset CRC, adjusted for age, sex, tumor site, and histology.

Results: A total of 5,019 Black individuals were diagnosed with early-onset CRC over the study period (379 Nigerians; 4,640 AAs). Overall, approximately one third of young Black patients were diagnosed with rectal tumors (35.8%). Nigerian individuals with early-onset CRC were eight-fold more likely to be diagnosed with rectal tumors (odds ratio [OR], 8.14; 95% CI, 6.23 to 10.62; < .0001) and more likely to be diagnosed at younger ages (OR, 0.87; 95% CI, 0.86 to 0.89; < .0001) compared with young African Americans in adjusted models.

Conclusion: Compared with AA individuals diagnosed with early-onset CRC, Nigerian individuals harbor distinct features of early-onset CRC. Additional investigation of the histopathologic and biologic heterogeneity of early-onset CRCs among Black individuals is critical for understanding racial disparities in susceptibility and outcomes, which may have implications for tailored early-onset CRC prevention, detection, and treatment strategies.
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http://dx.doi.org/10.1200/GO.20.00272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713583PMC
October 2020

Circulating Folate and Folic Acid Concentrations: Associations With Colorectal Cancer Recurrence and Survival.

JNCI Cancer Spectr 2020 Oct 7;4(5):pkaa051. Epub 2020 Jul 7.

Department of Surgery, Hospital Group Twente ZGT, Almelo, the Netherlands.

Background: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown.

Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival.

Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n = 296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival.

Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.
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http://dx.doi.org/10.1093/jncics/pkaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583160PMC
October 2020

Diabetes, Body Fatness, and Insulin Prescription Among Adolescents and Young Adults with Cancer.

J Adolesc Young Adult Oncol 2021 04 29;10(2):217-225. Epub 2020 Jul 29.

Huntsman Cancer Institute, Salt Lake City, Utah, USA.

Rates of obesity and obesity-related health consequences, including type 2 diabetes (T2D) and cancer, continue to rise. While cancer patients are at an increased risk of developing T2D, the prevalence of T2D and insulin prescription among young patients with cancer remains unknown. Using the Total Cancer Care Study cohort at Huntsman Cancer Institute (Salt Lake City, UT), we identified individuals age 18-39 years at cancer diagnosis between 2009 and 2019. Multivariable logistic regression was used to investigate associations between body mass index (BMI) with insulin prescription within 1 year of cancer diagnosis. In total, 344 adolescents and young adults (AYAs) were diagnosed with primary invasive cancer. Within this cohort, 19 patients (5.5%) were ever diagnosed with T2D, 48 AYAs ever received an insulin prescription (14.0%), and 197 were overweight or obese (BMI: 25+ kg/m) at cancer diagnosis. Each kg/m unit increase in BMI was associated with 6% increased odds of first insulin prescription within 1 year of cancer diagnosis among AYAs, even after adjustment for age, sex, smoking history, marital status, glucocorticoid prescription, and cancer treatments (odds ratio = 1.06, 95% confidence interval 1.02-1.11;  = 0.005). One in every 18 AYAs with cancer ever had T2D, 1 in 7 AYA patients with cancer ever received an insulin prescription, and higher BMI was associated with increased risk of insulin prescription within a year of cancer diagnosis among AYAs. Understanding the incidence of T2D and insulin prescription/use is critical for short-term and long-term clinical management of AYAs with cancer.
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http://dx.doi.org/10.1089/jayao.2020.0071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064923PMC
April 2021

Multi-omics Analysis Reveals Adipose-tumor Crosstalk in Patients with Colorectal Cancer.

Cancer Prev Res (Phila) 2020 10 12;13(10):817-828. Epub 2020 Jul 12.

International Agency for Research on Cancer (IARC), Lyon, France.

Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte-colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumor-adjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer. We report that high peroxisome proliferator-activated receptor gamma () visceral adipose tissue expression is associated with glycoprotein VI (GPVI) signaling-the major signaling receptor for collagen-as well as fibrosis and adipogenesis pathway signaling in colorectal tumors. These associations were supported by correlations between visceral adipose tissue expression and circulating levels of plasma 4-hydroxyproline and serum intercellular adhesion molecule 1 (ICAM1), as well as gene set enrichment analysis and joint gene-metabolite pathway results integration that yielded significant enrichment of genes defining epithelial-to-mesenchymal transition-as in fibrosis and metastasis-and genes involved in glycolytic metabolism, confirmed this association. We also reveal that elevated prostaglandin-endoperoxide synthase 2 () colorectal tumor expression is associated with a fibrotic signature in adipose-tumor crosstalk via GPVI signaling and dendritic cell maturation in visceral adipose tissue. Systemic metabolite and biomarker profiling confirmed that high expression in colorectal tumors is significantly associated with higher concentrations of serum amyloid A and glycine, and lower concentrations of sphingomyelin, in patients with colorectal cancer. This multi-omics study suggests that adipose-tumor crosstalk in patients with colorectal cancer is a critical microenvironment interaction that could be therapeutically targeted..
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877796PMC
October 2020

Early-Onset Appendiceal Cancer Survival by Race or Ethnicity in the United States.

Gastroenterology 2020 10 13;159(4):1605-1608. Epub 2020 Jun 13.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

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http://dx.doi.org/10.1053/j.gastro.2020.06.011DOI Listing
October 2020

Examining factors underlying geographic disparities in early-onset colorectal cancer survival among men in the United States.

Am J Cancer Res 2020 1;10(5):1592-1607. Epub 2020 May 1.

Vanderbilt University Medical Center 2525 West End Ave., Nashville, Tennessee, USA.

Despite overall incidence reduction in colorectal cancer (CRC) the past 32 years, unexplained incidence and mortality rates have increased significantly in younger adults ages 20-49. To improve understanding of sex-specific differences among this population, we aimed to determine the variance in early-onset CRC (EOCRC) survival among US men diagnosed with CRC before age 50, while considering individual- and county-level CRC outcome determinants. Hotspots (i.e., counties with high EOCRC mortality rates) were derived from Centers for Disease Control and Prevention data from 1999-2017, and linked to SEER data for men aged 15-49 years with CRC. Cox proportional hazards models were used to compare CRC-specific survival probability and hazard in hotspots versus non-significant counties. A generalized R was used to estimate the total variance in EOCRC survival explained by clinicodemographic and county-level determinants. We identified 232 hotspot counties for EOCRC-214 (92%) of which were in the South. In hotspots, 1,009 men were diagnosed with EOCRC and 31,438 in non-significant counties. After adjusting for age, race, tumor stage and grade, surgery, chemotherapy, radiation therapy, and marital status, men residing in hotspot counties had higher hazard of CRC-specific death (HR 1.24, 95% CI, 1.12-1.36). Individual/county-level factors explained nearly 35% of the variation in survival, and adult smoking served as the strongest county-level determinant of EOCRC survival. Distinct geographic patterns of EOCRC were predominantly located in the southern US. Survival after EOCRC diagnosis was significantly worse among men residing in hotspot counties.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269786PMC
May 2020

Impact of Pre-blood Collection Factors on Plasma Metabolomic Profiles.

Metabolites 2020 May 21;10(5). Epub 2020 May 21.

Population Sciences, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.

Demographic, lifestyle and biospecimen-related factors at the time of blood collection can influence metabolite levels in epidemiological studies. Identifying the major influences on metabolite concentrations is critical to designing appropriate sample collection protocols and considering covariate adjustment in metabolomics analyses. We examined the association of age, sex, and other short-term pre-blood collection factors (time of day, season, fasting duration, physical activity, NSAID use, smoking and alcohol consumption in the days prior to collection) with 133 targeted plasma metabolites (acylcarnitines, amino acids, biogenic amines, sphingolipids, glycerophospholipids, and hexoses) among 108 individuals that reported exposures within 48 h before collection. The differences in mean metabolite concentrations were assessed between groups based on pre-collection factors using two-sided -tests and ANOVA with FDR correction. Percent differences in metabolite concentrations were negligible across season, time of day of collection, fasting status or lifestyle behaviors at the time of collection, including physical activity or the use of tobacco, alcohol or NSAIDs. The metabolites differed in concentration between the age and sex categories for 21.8% and 14.3% metabolites, respectively. In conclusion, extrinsic factors in the short period prior to collection were not meaningfully associated with concentrations of selected endogenous metabolites in a cross-sectional sample, though metabolite concentrations differed by age and sex. Larger studies with more coverage of the human metabolome are warranted.
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http://dx.doi.org/10.3390/metabo10050213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281389PMC
May 2020

Metabolomics profiling of visceral and abdominal subcutaneous adipose tissue in colorectal cancer patients: results from the ColoCare study.

Cancer Causes Control 2020 Aug 19;31(8):723-735. Epub 2020 May 19.

Huntsman Cancer Institute, Salt Lake City, UT, USA.

Purpose: Underlying mechanisms of the relationship between body fatness and colorectal cancer remain unclear. This study investigated associations of circulating metabolites with visceral (VFA), abdominal subcutaneous (SFA), and total fat area (TFA) in colorectal cancer patients.

Methods: Pre-surgery plasma samples from 212 patients (stage I-IV) from the ColoCare Study were used to perform targeted metabolomics. VFA, SFA, and TFA were quantified by computed tomography scans. Partial correlation and linear regression analyses of VFA, SFA, and TFA with metabolites were computed and corrected for multiple testing. Cox proportional hazards were used to assess 2-year survival.

Results: In patients with metastatic tumors, SFA and TFA were statistically significantly inversely associated with 16 glycerophospholipids (SFA: p range 0.017-0.049; TFA: p range 0.029-0.048), while VFA was not. Doubling of ten of the aforementioned glycerophospholipids was associated with increased risk of death in patients with metastatic tumors, but not in patients with non-metastatic tumors (p range: 0.00044-0.049). Doubling of PC ae C34:0 was associated with ninefold increased risk of death in metastatic tumors (Hazard Ratio [HR], 9.05; 95% confidence interval [CI] 2.17-37.80); an inverse association was observed in non-metastatic tumors (HR 0.17; 95% CI 0.04-0.87; p = 0.00044).

Conclusion: These data provide initial evidence that glycerophospholipids in metastatic colorectal cancer are uniquely associated with subcutaneous adiposity, and may impact overall survival.
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http://dx.doi.org/10.1007/s10552-020-01312-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425810PMC
August 2020

One-carbon metabolites, B vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients: results from the ColoCare Study.

Br J Nutr 2020 05 5;123(10):1187-1200. Epub 2020 Feb 5.

Division of Cancer Control and Population Sciences, Huntsman Cancer Institute, Salt Lake City, UT, USA.

B vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- and angiogenesis-related chronic diseases, such as colorectal cancer (CRC). Yet, the role of one-carbon metabolism in inflammation and angiogenesis among CRC patients remains unclear. The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed CRC patients (n 238) in the prospective ColoCare Study, Heidelberg. We cross-sectionally analysed associations between twelve B vitamins and one-carbon metabolites and ten inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesised that pyridoxal-5'-phosphate (PLP) is inversely associated with inflammatory biomarkers. We observed that PLP was inversely associated with C-reactive protein (CRP) (r -0·33, Plinear < 0·0001), serum amyloid A (SAA) (r -0·23, Plinear = 0·003), IL-6 (r -0·39, Plinear < 0·0001), IL-8 (r -0·20, Plinear = 0·02) and TNFα (r -0·12, Plinear = 0·045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r -0·14), SAA (r -0·14) and TNFα (r -0·15) among CRC patients. Folate catabolite acetyl-para-aminobenzoylglutamic acid (pABG) was positively correlated with IL-6 (r 0·27, Plinear < 0·0001), and pABG was positively correlated with IL-8 (r 0·21, Plinear < 0·0001), indicating higher folate utilisation during inflammation. Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among CRC patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for CRC patients.
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http://dx.doi.org/10.1017/S0007114520000422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425811PMC
May 2020

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

Gastroenterology 2020 04 19;158(5):1274-1286.e12. Epub 2019 Dec 19.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.

Background & Aims: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.

Methods: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.

Results: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.

Conclusions: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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http://dx.doi.org/10.1053/j.gastro.2019.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103489PMC
April 2020

Expression Patterns of Xenobiotic-Metabolizing Enzymes in Tumor and Adjacent Normal Mucosa Tissues among Patients with Colorectal Cancer: The ColoCare Study.

Cancer Epidemiol Biomarkers Prev 2020 02 18;29(2):460-469. Epub 2019 Nov 18.

Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.

Background: Xenobiotic-metabolizing enzymes (XME) play a critical role in the activation and detoxification of several carcinogens. However, the role of XMEs in colorectal carcinogenesis is unclear.

Methods: We investigated the expression of XMEs in human colorectal tissues among patients with stage I-IV colorectal cancer ( = 71) from the ColoCare Study. Transcriptomic profiling using paired colorectal tumor and adjacent normal mucosa tissues of XMEs (, , and ) by RNA microarray was compared using Wilcoxon rank-sum tests. We assessed associations between clinicopathologic, dietary, and lifestyle factors and XME expression with linear regression models.

Results: , and were all statistically significantly downregulated in colorectal tumor relative to normal mucosa tissues (all ≤ 0.03). Women had significantly higher expression of in normal tissues compared with men (β = 0.37, = 0.02). By tumor site, expression was lower in normal mucosa among patients with rectal cancer versus colon cancer cases (β = -0.21, = 0.0005). Smokers demonstrated higher expression levels in normal mucosa (β = 0.17, = 0.02) when compared with nonsmokers. Individuals who used NSAIDs had higher tumor expression compared with non-NSAID users (β = 0.17, = 0.03). Higher consumption of cooked vegetables (>1×/week) was associated with higher expression in colorectal tumor tissues (β = 0.14, = 0.007).

Conclusions: XMEs have lower expression in colorectal tumor relative to normal mucosa tissues and may modify colorectal carcinogenesis via associations with clinicopathologic, lifestyle, and dietary factors.

Impact: Better understanding into the role of drug-metabolizing enzymes in colorectal cancer may reveal biological differences that contribute to cancer development, as well as treatment response, leading to clinical implications in colorectal cancer prevention and management.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007332PMC
February 2020

Distinct Molecular Phenotype of Sporadic Colorectal Cancers Among Young Patients Based on Multiomics Analysis.

Gastroenterology 2020 03 13;158(4):1155-1158.e2. Epub 2019 Nov 13.

Huntsman Cancer Institute, Salt Lake City, Utah; University of Utah, Salt Lake City, Utah. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2019.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291587PMC
March 2020

Plasma metabolites associated with colorectal cancer stage: Findings from an international consortium.

Int J Cancer 2020 06 10;146(12):3256-3266. Epub 2019 Oct 10.

Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.

Colorectal cancer is the second most common cause of cancer-related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I-IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography-mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I-IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (p  < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl-alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (p  < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression.
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http://dx.doi.org/10.1002/ijc.32666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216900PMC
June 2020

Racial/Ethnic Patterns of Young-Onset Noncardia Gastric Cancer.

Cancer Prev Res (Phila) 2019 11 16;12(11):771-780. Epub 2019 Aug 16.

Department of Internal Medicine, Intermountain Healthcare, Murray, Utah.

Increasing noncardia gastric cancer incidence rates among individuals age younger than 50 years have gained much attention, particularly as causes remain unknown. Using population-based NIH/NCI's Surveillance, Epidemiology, and End Results (SEER) program data from 2007 to 2015, multivariable logistic regression was used to quantify associations between race/ethnicity and clinicodemographic features among young-onset noncardia gastric cancer patients. A total of 2,872 individuals ages 20 to 49 years were diagnosed with primary noncardia gastric cancer. Age at diagnosis, insurance status, anatomic subsite, American Joint Committee on Cancer (AJCC) clinical stage, histologic type, tumor grade, surgery, and county-level smoking prevalence differed by race/ethnicity (all ≤ 0.003). Compared with non-Hispanic whites, Hispanics were more likely to be diagnosed at younger ages [odds ratio (OR) = 0.97; 95% confidence intervals (CI), 0.95-0.99], on Medicaid/uninsured (OR = 3.83; 95% CI, 2.89-5.08), diagnosed with higher grade tumors (OR = 1.93; 95% CI, 1.32-2.84), and less likely to undergo surgery (OR = 0.62; 95% CI, 0.44-0.88) or to reside in counties with higher smoking prevalence (OR = 0.15; 95% CI, 0.11-0.21) after adjustment for sex, subsite, and histologic type. Asian/Pacific Islanders were more likely to be female (OR = 1.40; 95% CI, 1.04-1.88), and less likely to be diagnosed with metastatic disease (OR = 0.59; 95% CI, 0.37-0.95) or to reside in counties with higher smoking prevalence (OR = 0.13; 95% CI, 0.08-0.19). Approximately two in every five patients with young-onset noncardia gastric cancer are Hispanic. Further investigation into the molecular heterogeneity of young-onset noncardia gastric cancers by race/ethnicity to understand etiologies underlying this rising disease epidemic is warranted. This population-based cohort study sheds light that biological and environmental factors may partly underlie race/ethnicity-related differences in young-onset noncardia gastric cancer susceptibility and outcomes.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825562PMC
November 2019

Clinicopathologic and Racial/Ethnic Differences of Colorectal Cancer Among Adolescents and Young Adults.

Clin Transl Gastroenterol 2019 07;10(7):e00059

Huntsman Cancer Institute, Salt Lake City, Utah, USA.

Objectives: Despite overall reductions in colorectal cancer burden, incidence rates continue to rise among younger patients, and causes remain unknown. We examined differences in clinicopathologic and racial/ethnic characteristics within the adolescent and young adult (AYA) population diagnosed with colorectal cancer in the United States.

Methods: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results program data, we identified individuals diagnosed with first primary colorectal cancer between ages 15 and 39 years from 2010 to 2015. Adjusted multivariable logistic regression models were used to quantify clinicopathologic and racial/ethnic differences across age at onset subgroups (15-19, 20-24, 25-29, 30-34, and 35-39 years).

Results: We identified 5,350 AYA patients diagnosed with colorectal cancer. Of note, 28.6% of AYA cases were diagnosed with right-sided tumors (cecum to transverse colon). The proportion of right-sided colorectal cancers differed significantly by age group at diagnosis (38.3% vs 27.3% of AYAs aged 15-19 vs 35-39 years, respectively; P trend = 0.01). Proportions of cases with mucinous adenocarcinoma and signet ring cell carcinoma histopathologic subtypes significantly increased with younger age at onset (P trends = 0.01 and 0.03, respectively). Differences in clinical stage were observed across AYA age groups, with stage II disease increasing with younger age (P trend = 0.01). The proportion of Hispanic AYAs was higher within younger patients, accounting for 21.0% of the AYA population aged 35-39 years up to 28.3% of 15-19-year-old individuals (P trend = 0.003).

Discussion: Within the AYA population, colorectal cancers differ by clinicopathologic and racial/ethnic characteristics. Further investigation of the clinical and biologic diversity of colorectal cancers that partially underlie age- and race-related differences in cancer susceptibility and outcomes is warranted.
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http://dx.doi.org/10.14309/ctg.0000000000000059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708666PMC
July 2019

Transcriptome Profiling of Adipose Tissue Reveals Depot-Specific Metabolic Alterations Among Patients with Colorectal Cancer.

J Clin Endocrinol Metab 2019 11;104(11):5225-5237

Division of Preventive Oncology, National Center for Tumor Diseases Heidelberg and German Cancer Research Center, Heidelberg, Germany.

Context: Adipose tissue inflammation and dysregulated energy homeostasis are key mechanisms linking obesity and cancer. Distinct adipose tissue depots strongly differ in their metabolic profiles; however, comprehensive studies of depot-specific perturbations among patients with cancer are lacking.

Objective: We compared transcriptome profiles of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from patients with colorectal cancer and assessed the associations of different anthropometric measures with depot-specific gene expression.

Design: Whole transcriptomes of VAT and SAT were measured in 233 patients from the ColoCare Study, and visceral and subcutaneous fat area were quantified via CT.

Results: VAT compared with SAT showed elevated gene expression of cytokines, cell adhesion molecules, and key regulators of metabolic homeostasis. Increased fat area was associated with downregulated lipid and small molecule metabolism and upregulated inflammatory pathways in both compartments. Comparing these patterns between depots proved specific and more pronounced gene expression alterations in SAT and identified unique associations of integrins and lipid metabolism-related enzymes. VAT gene expression patterns that were associated with visceral fat area poorly overlapped with patterns associated with self-reported body mass index (BMI). However, subcutaneous fat area and BMI showed similar associations with SAT gene expression.

Conclusions: This large-scale human study demonstrates pronounced disparities between distinct adipose tissue depots and reveals that BMI poorly correlates with fat mass-associated changes in VAT. Taken together, these results provide crucial evidence for the necessity to differentiate between distinct adipose tissue depots for a correct characterization of gene expression profiles that may affect metabolic health of patients with colorectal cancer.
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http://dx.doi.org/10.1210/jc.2019-00461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763280PMC
November 2019

Tumor suppressive autophagy in intestinal stem cells controls gut homeostasis.

Autophagy 2019 09 20;15(9):1668-1670. Epub 2019 Jun 20.

a Huntsman Cancer Institute and Department of Oncological Sciences, University of Utah , Salt Lake City , UT , USA.

We recently found that re-routing intracellular vesicle traffic by suppressing macroautophagy/autophagy or endocytosis genes drastically deregulates intestinal stem cell (ISC) proliferation, leading to massive gut hyperplasia that has a negative impact upon lifespan. Beginning with the poorly characterized (sorting nexin) genes, we surveyed a broad set of genes in the endocytosis-autophagy network and found that most of them have this effect. We then discovered that deregulated Egfr-Ras85D/Ras1-mitogen-activated protein kinase signaling is the primary trigger for ISC proliferation upon disruption of this network and determined that in the mutants, ligand-activated receptors were stabilized and recycled to the cell surface via Rab11-dependent endosomes, rather than being degraded via autophagosomes. We profiled the mutational landscape for orthologous network genes in human cancers using The Cancer Genome Atlas (TCGA), and revealed strong, novel associations with distinct genomic and epigenomic subtypes of colorectal cancer.
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http://dx.doi.org/10.1080/15548627.2019.1633863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693466PMC
September 2019

An SH3PX1-Dependent Endocytosis-Autophagy Network Restrains Intestinal Stem Cell Proliferation by Counteracting EGFR-ERK Signaling.

Dev Cell 2019 05 18;49(4):574-589.e5. Epub 2019 Apr 18.

Huntsman Cancer Institute and Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA. Electronic address:

The effect of intracellular vesicle trafficking on stem-cell behavior is largely unexplored. We screened the Drosophila sorting nexins (SNXs) and discovered that one, SH3PX1, profoundly affects gut homeostasis and lifespan. SH3PX1 restrains intestinal stem cell (ISC) division through an endocytosis-autophagy network that includes Dynamin, Rab5, Rab7, Atg1, 5, 6, 7, 8a, 9, 12, 16, and Syx17. Blockages in this network stabilize ligand-activated EGFRs, recycling them via Rab11-dependent endosomes to the plasma membrane. This hyperactivated ERK, calcium signaling, and ER stress, autonomously stimulating ISC proliferation. The excess divisions induced epithelial stress, Yki activity, and Upd3 and Rhomboid production in enterocytes, catalyzing feedforward ISC hyperplasia. Similarly, blocking autophagy increased ERK activity in human cells. Many endocytosis-autophagy genes are mutated in cancers, most notably those enriched in microsatellite instable-high and KRAS-wild-type colorectal cancers. Disruptions in endocytosis and autophagy may provide an alternative route to RAS-ERK activation, resulting in EGFR-dependent cancers.
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http://dx.doi.org/10.1016/j.devcel.2019.03.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542281PMC
May 2019
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