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The standard for cancer staging in the United States for all cancer sites, including primary carcinomas of the appendix, is the American Joint Committee on Cancer (AJCC) staging system. AJCC staging criteria undergo periodic revisions, led by a panel of site-specific experts, to maintain contemporary staging definitions through the evaluation of new evidence. Since its last revision, the AJCC has restructured its processes to include prospectively collected data because large data sets have become increasingly robust and available over time. Thus survival analyses using AJCC eighth edition staging criteria were used to inform stage group revisions in the version 9 AJCC staging system, including appendiceal cancer. Although the current AJCC staging definitions were maintained for appendiceal cancer, incorporating survival analysis into the version 9 staging system provided unique insight into the clinical challenges in staging rare malignancies. This article highlights the critical clinical components of the now published version 9 AJCC staging system for appendix cancer, which (1) justified the separation of three different histologies (non-mucinous, mucinous, signet-ring cell) in terms of prognostic variance, (2) demonstrated the clinical implications and challenges in staging heterogeneous and rare tumors, and (3) emphasized the influence of data limitations on survival analysis for low-grade appendiceal mucinous neoplasms.
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Neoplasias del Apéndice , Humanos , Estados Unidos , Neoplasias del Apéndice/patología , Estadificación de Neoplasias , Pronóstico , Análisis de SupervivenciaRESUMEN
Sporadic colorectal cancer has traditionally been viewed as a malignancy of older individuals. However, as the global prevalence of the disease diagnosed in younger individuals (<50 years) is expected to increase within the next decade, greater recognition is now being given to early-onset colorectal cancer. The cause of the predicted rise in prevalence is largely unknown and probably multifactorial. In this Series paper, we discuss the potential underlying causes of early-onset colorectal cancer, the role of energy balance, biological and genomic mechanisms (including microbiome aspects), and the treatment of early-onset colorectal cancer. We have specifically considered the psychosocial challenges of being diagnosed with colorectal cancer at younger age and the potential financial toxicity that might ensue. This Series paper brings a comprehensive review based on the existing data in the hopes of optimising the overall outcomes for patients with early-onset colorectal cancer.
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Neoplasias Colorrectales , Edad de Inicio , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Genómica , Humanos , PrevalenciaRESUMEN
BACKGROUND: Individuals with a non-syndromic family history of colorectal cancer are known to have an increased risk. There is an opportunity to prevent early-onset colorectal cancer (age less than 50 years) (EOCRC) in this population. The aim was to explore the proportion of EOCRC that is preventable due to family history of colorectal cancer. METHODS: This was a retrospective multicentre European study of patients with non-hereditary EOCRC. The impact of the European Society of Gastrointestinal Endoscopy (ESGE), U.S. Multi-Society Task Force (USMSTF), and National Comprehensive Cancer Network (NCCN) guidelines on prevention and early diagnosis was compared. Colorectal cancer was defined as potentially preventable if surveillance colonoscopy would have been performed at least 5 years before the age of diagnosis of colorectal cancer, and diagnosed early if colonoscopy was undertaken between 1 and 4 years before the diagnosis. RESULTS: Some 903 patients with EOCRC were included. Criteria for familial colorectal cancer risk in ESGE, USMSTF, and NCCN guidelines were met in 6.3, 9.4, and 30.4 per cent of patients respectively. Based on ESGE, USMSTF, and NCCN guidelines, colorectal cancer could potentially have been prevented in 41, 55, and 30.3 per cent of patients, and diagnosed earlier in 11, 14, and 21.1 per cent respectively. In ESGE guidelines, if surveillance had started 10 years before the youngest relative, there would be a significant increase in prevention (41 versus 55 per cent; P = 0.010). CONCLUSION: ESGE, USMSTF, and NCCN criteria for familial colorectal cancer were met in 6.3, 9.4, and 30.4 per cent of patients with EOCRC respectively. In these patients, early detection and/or prevention could be achieved in 52, 70, and 51.4 per cent respectively. Early and accurate identification of familial colorectal cancer risk and increase in the uptake of early colonoscopy are key to decreasing familial EOCRC.
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Neoplasias Colorrectales , Humanos , Persona de Mediana Edad , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Colonoscopía , Endoscopía GastrointestinalRESUMEN
Limited research has explored the mental health impact of coronavirus disease 2019 (COVID-19) in the U.S., especially among Black and low-income Americans who are disproportionately affected by COVID-19. To address this gap in the literature, we investigated factors associated with depressive and anxiety symptoms during the pandemic. From October to December 2020, over 4400 participants in the Southern Community Cohort Study (SCCS) completed a survey about the impact of the pandemic. The SCCS primarily enrolled adults with low income in 12 southeastern states. We used polytomous unconditional logistic regression to investigate factors associated with depressive and anxiety symptoms. About 28% of respondents reported mild or moderate/severe depressive symptoms and 30% reported mild or moderate/severe anxiety symptoms. Respondents in fair/poor health had significantly higher odds of moderate/severe depression and anxiety than those in very good/excellent health (depression: odds ratio (OR) = 4.72 [95% confidence interval (CI): 3.57-6.23]; anxiety: OR = 4.77 [95%CI: 3.63-6.28]). Similarly, living alone was associated with higher odds of moderate/severe depression and anxiety (depression: OR = 1.74 [95%CI: 1.38-2.18]; anxiety: OR = 1.57 [95%CI: 1.27-1.95]). Individuals whose physical activity or vegetable/fruit consumption decreased since the start of the pandemic also had higher odds of moderate/severe depression and anxiety. Results overall suggest that individuals in fair/poor health, living alone, and/or experiencing decreased physical activity and vegetable/fruit consumption have higher risk of depressive and anxiety symptoms. Clinical and public health interventions are needed to support individuals experiencing depression and anxiety during the pandemic.
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COVID-19 , Adulto , Ansiedad/epidemiología , Ansiedad/psicología , COVID-19/epidemiología , Estudios de Cohortes , Depresión/epidemiología , Depresión/psicología , Humanos , Pandemias , SARS-CoV-2 , Estados Unidos/epidemiologíaRESUMEN
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 × 10-5). 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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Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Edad de Inicio , Estudios de Casos y Controles , Estudios de Cohortes , Análisis Mutacional de ADN , Conjuntos de Datos como Asunto , Femenino , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Humanos , Estilo de Vida , Masculino , Anamnesis , Persona de Mediana Edad , Tasa de Mutación , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Secuenciación Completa del GenomaRESUMEN
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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Diabetes Mellitus , Neoplasias , Estado Prediabético , Estudios de Cohortes , Diabetes Mellitus/epidemiología , Diabetes Mellitus/terapia , Femenino , Humanos , Persona de Mediana Edad , Neoplasias/diagnóstico , Neoplasias/epidemiología , Neoplasias/terapia , Estado Prediabético/diagnóstico , Estado Prediabético/epidemiología , Estado Prediabético/terapia , PrevalenciaRESUMEN
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 (pFDR < 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 (pFDR < 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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Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/diagnóstico , Anciano , Biomarcadores de Tumor/metabolismo , Citrulina/sangre , Citrulina/metabolismo , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Femenino , Histidina/sangre , Histidina/metabolismo , Humanos , Modelos Logísticos , Masculino , Metabolómica , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Estadificación de Neoplasias , Estudios Observacionales como Asunto , Estudios Prospectivos , Esfingomielinas/sangre , Esfingomielinas/metabolismoRESUMEN
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: pFDR range 0.017-0.049; TFA: pFDR 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 (phet 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; phet = 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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Neoplasias Colorrectales/metabolismo , Grasa Intraabdominal/metabolismo , Grasa Subcutánea Abdominal/metabolismo , Adiposidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/patología , Femenino , Humanos , Grasa Intraabdominal/diagnóstico por imagen , Masculino , Metabolómica , Persona de Mediana Edad , Estadificación de Neoplasias , Grasa Subcutánea Abdominal/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
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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Carbono/sangre , Neoplasias Colorrectales/sangre , Mediadores de Inflamación/sangre , Neovascularización Patológica/sangre , Complejo Vitamínico B/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Amiloide/sangre , Biomarcadores de Tumor/sangre , Proteína C-Reactiva/metabolismo , Estudios Transversales , Femenino , Ácido Fólico/metabolismo , Glutamatos/sangre , Humanos , Inflamación , Interleucina-6/sangre , Interleucina-8/sangre , Intestinos/irrigación sanguínea , Modelos Lineales , Masculino , Persona de Mediana Edad , Monoéster Fosfórico Hidrolasas/sangre , Estudios Prospectivos , Estadísticas no Paramétricas , Tetrahidrofolatos/sangre , Factor de Necrosis Tumoral alfa/sangre , Adulto JovenRESUMEN
Colorectal cancer is known to arise from multiple tumorigenic pathways; however, the underlying mechanisms remain not completely understood. Metabolomics is becoming an increasingly popular tool in assessing biological processes. Previous metabolomics research focusing on colorectal cancer is limited by sample size and did not replicate findings in independent study populations to verify robustness of reported findings. Here, we performed a ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) screening on EDTA plasma from 268 colorectal cancer patients and 353 controls using independent discovery and replication sets from two European cohorts (ColoCare Study: n = 180 patients/n = 153 controls; the Colorectal Cancer Study of Austria (CORSA) n = 88 patients/n = 200 controls), aiming to identify circulating plasma metabolites associated with colorectal cancer and to improve knowledge regarding colorectal cancer etiology. Multiple logistic regression models were used to test the association between disease state and metabolic features. Statistically significant associated features in the discovery set were taken forward and tested in the replication set to assure robustness of our findings. All models were adjusted for sex, age, BMI and smoking status and corrected for multiple testing using False Discovery Rate. Demographic and clinical data were abstracted from questionnaires and medical records.
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Neoplasias Colorrectales/sangre , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Metabolómica/métodos , Persona de Mediana EdadAsunto(s)
Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Quimiocina CXCL12/metabolismo , Neoplasias Colorrectales/sangre , Femenino , Perfilación de la Expresión Génica , Glutatión/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Masculino , Metabolómica , Repeticiones de Microsatélite , Persona de Mediana Edad , Factor 2 Relacionado con NF-E2/metabolismo , Oxidación-Reducción , Estrés Oxidativo/genética , Fenotipo , Estudios Prospectivos , Proteómica , Receptores CXCR4/metabolismo , Transducción de Señal/genética , Adulto JovenAsunto(s)
Neoplasias del Apéndice/etnología , Neoplasias del Apéndice/mortalidad , Negro o Afroamericano/estadística & datos numéricos , Hispánicos o Latinos/estadística & datos numéricos , Población Blanca/estadística & datos numéricos , Adulto , Factores de Edad , Neoplasias del Apéndice/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
Overall, gastric adenocarcinoma (GC) incidence rates have declined in recent years, but racial/ethnic disparities persist. Individuals who identify as Hispanic/Spanish/Latino are diagnosed with GC at younger ages and have poorer outcomes than non-Hispanic individuals. However, our understanding of GC biology across racial/ethnic groups remains limited. We assessed tumor genomic patterns by race/ethnicity among 1019 patients with primary GC in the AACR Project GENIE Consortium. Hispanic individuals presented with significantly higher rates of ERBB2/HER2 amplification vs other racial/ethnic groups (Hispanic: 13.9% vs 9.8% non-Hispanic White, 8.1% non-Hispanic Asian, and 11.0% non-Hispanic Black; p < .001, FDR adjusted q < 0.001). Hispanic patients also had higher odds of an ERBB2 amplification vs non-Hispanic whites in adjusted models (OR = 2.52, 95%CI = 1.20-5.33, p = .015). These findings underscore the important role of genomic factors in GC disparities. Ensuring equitable access to genomic profiling and targeted therapies, such as trastuzumab for HER2-overexpressing GC, is a promising avenue to mitigate GC disparities and improve outcomes.
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Importance: Early-onset colorectal cancer (EOCRC), defined as a diagnosis at younger than age 50 years, is increasing, and so-called red flag signs and symptoms among these individuals are often missed, leading to diagnostic delays. Improved recognition of presenting signs and symptoms associated with EOCRC could facilitate more timely diagnosis and impact clinical outcomes. Objective: To report the frequency of presenting red flag signs and symptoms among individuals with EOCRC, to examine their association with EOCRC risk, and to measure variation in time to diagnosis from sign or symptom presentation. Data Sources: PubMed/MEDLINE, Embase, CINAHL, and Web of Science were searched from database inception through May 2023. Study Selection: Studies that reported on sign and symptom presentation or time from sign and symptom presentation to diagnosis for patients younger than age 50 years diagnosed with nonhereditary CRC were included. Data Extraction and Synthesis: Data extraction and quality assessment were performed independently in duplicate for all included studies using Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines. Joanna Briggs Institute Critical Appraisal tools were used to measure risk of bias. Data on frequency of signs and symptoms were pooled using a random-effects model. Main Outcomes and Measures: Outcomes of interest were pooled proportions of signs and symptoms in patients with EOCRC, estimates for association of signs and symptoms with EOCRC risk, and time from sign or symptom presentation to EOCRC diagnosis. Results: Of the 12â¯859 unique articles initially retrieved, 81 studies with 24â¯908â¯126 patients younger than 50 years were included. The most common presenting signs and symptoms, reported by 78 included studies, were hematochezia (pooled prevalence, 45% [95% CI, 40%-50%]), abdominal pain (pooled prevalence, 40% [95% CI, 35%-45%]), and altered bowel habits (pooled prevalence, 27% [95% CI, 22%-33%]). Hematochezia (estimate range, 5.2-54.0), abdominal pain (estimate range, 1.3-6.0), and anemia (estimate range, 2.1-10.8) were associated with higher EOCRC likelihood. Time from signs and symptoms presentation to EOCRC diagnosis was a mean (range) of 6.4 (1.8-13.7) months (23 studies) and a median (range) of 4 (2.0-8.7) months (16 studies). Conclusions and Relevance: In this systematic review and meta-analysis of patients with EOCRC, nearly half of individuals presented with hematochezia and abdominal pain and one-quarter with altered bowel habits. Hematochezia was associated with at least 5-fold increased EOCRC risk. Delays in diagnosis of 4 to 6 months were common. These findings highlight the need to identify concerning EOCRC signs and symptoms and complete timely diagnostic workup, particularly for individuals without an alternative diagnosis or sign or symptom resolution.
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Edad de Inicio , Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Persona de Mediana Edad , Detección Precoz del Cáncer/métodos , Femenino , Adulto , Masculino , Diagnóstico Tardío/estadística & datos numéricosRESUMEN
PURPOSE: The early-onset colorectal cancer (EOCRC) burden differs across racial/ethnic groups, yet the role of germline genetic predisposition in EOCRC disparities remains uncharacterized. We defined the prevalence and spectrum of inherited colorectal cancer (CRC) susceptibility gene variations among patients with EOCRC by race and ethnicity. PATIENTS AND METHODS: We included individuals diagnosed with a first primary CRC between age 15 and 49 years who identified as Ashkenazi Jewish, Asian, Black, Hispanic, or White and underwent germline genetic testing of 14 CRC susceptibility genes performed by a clinical testing laboratory. Variant comparisons by racial and ethnic groups were evaluated using chi-square tests and multivariable logistic regression adjusted for sex, age, CRC site, and number of primary colorectal tumors. RESULTS: Among 3,980 patients with EOCRC, a total of 530 germline pathogenic or likely pathogenic variants were identified in 485 individuals (12.2%). By race/ethnicity, 12.7% of Ashkenazim patients, 9.5% of Asian patients, 10.3% of Black patients, 14.0% of Hispanic patients, and 12.4% of White patients carried a germline variant. The prevalence of Lynch syndrome (P = .037), as well as APC, CHEK2, MLH1, monoallelic MUTYH, and PTEN variants, varied by race/ethnicity among patients with EOCRC (all P < .026). Ashkenazim and Hispanic patients had significantly higher odds of presenting with a pathogenic APC variant, which included p.I1307K (odds ratio [OR], 2.67; 95% CI, 1.30 to 5.49; P = .007) and MLH1 variant (OR, 8.69; 95% CI, 2.68 to 28.20; P = .0003), respectively, versus White patients in adjusted models. CONCLUSION: Germline genetic features differed by race/ethnicity in young patients with CRC, suggesting that current multigene panel tests may not be representative of EOCRC risk in diverse populations. Further study is needed to optimize genes selected for genetic testing in EOCRC via ancestry-specific gene and variant discovery to yield equitable clinical benefits for all patients and to mitigate inequities in disease burden.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Mutación de Línea Germinal , Pruebas Genéticas , Predisposición Genética a la EnfermedadRESUMEN
Molecular features underlying colorectal cancer disparities remain uncharacterized. Here, we investigated somatic mutation patterns by race/ethnicity and sex among 5,856 non-Hispanic white (NHW), 535 non-Hispanic Black (NHB), and 512 Asian/Pacific Islander (API) patients with colorectal cancer (2,016 early-onset colorectal cancer patients: sequencing age <50 years). NHB patients with early-onset nonhypermutated colorectal cancer, but not API patients, had higher adjusted tumor mutation rates than NHW patients. There were significant differences for LRP1B, FLT4, FBXW7, RNF43, ATRX, APC, and PIK3CA mutation frequencies in early-onset nonhypermutated colorectal cancers between racial/ethnic groups. Heterogeneities by race/ethnicity were observed for the effect of APC, FLT4, and FAT1 between early-onset and late-onset nonhypermutated colorectal cancer. By sex, heterogeneity was observed for the effect of EP300, BRAF, WRN, KRAS, AXIN2, and SMAD2. Males and females with nonhypermutated colorectal cancer had different trends in EP300 mutations by age group. These findings define genomic patterns of early-onset nonhypermutated colorectal cancer by race/ethnicity and sex, which yields novel biological clues into early-onset colorectal cancer disparities. SIGNIFICANCE: NHBs, but not APIs, with early-onset nonhypermutated colorectal cancer had higher adjusted tumor mutation rates versus NHWs. Differences for FLT4, FBXW7, RNF43, LRP1B, APC, PIK3CA, and ATRX mutation rates between racial/ethnic groups and EP300, KRAS, AXIN2, WRN, BRAF, and LRP1B mutation rates by sex were observed in tumors of young patients. See related commentary by Shen et al., p. 530 . This article is highlighted in the In This Issue feature, p. 517.
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Neoplasias Colorrectales , Proteínas Proto-Oncogénicas B-raf , Humanos , Masculino , Femenino , Persona de Mediana Edad , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Proteínas Proto-Oncogénicas B-raf/genética , Caracteres Sexuales , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Mutación , Genes Relacionados con las NeoplasiasRESUMEN
Colorectal cancer (CRC) is increasingly recognized as a heterogeneous disease. No studies have prospectively examined associations of blood metabolite concentrations with all-cause mortality in patients with colon and rectal cancer separately. Targeted metabolomics (Biocrates AbsoluteIDQ p180) and pathway analyses (MetaboAnalyst 4.0) were performed on pre-surgery collected plasma from 674 patients with non-metastasized (stage I-III) colon (n = 394) or rectal cancer (n = 283). Metabolomics data and covariate information were received from the international cohort consortium MetaboCCC. Cox proportional hazards models were computed to investigate associations of 148 metabolite levels with all-cause mortality adjusted for age, sex, tumor stage, tumor site (whenever applicable), and cohort; the false discovery rate (FDR) was used to account for multiple testing. A total of 93 patients (14%) were deceased after an average follow-up time of 4.4 years (60 patients with colon cancer and 33 patients with rectal cancer). After FDR adjustment, higher plasma creatinine was associated with a 39% increase in all-cause mortality in patients with rectal cancer. HR: 1.39, 95% CI 1.23-1.72, pFDR = 0.03; but not colon cancer: pFDR = 0.96. Creatinine is a breakdown product of creatine phosphate in muscle and may reflect changes in skeletal muscle mass. The starch and sucrose metabolisms were associated with increased all-cause mortality in colon cancer but not in rectal cancer. Genes in the starch and sucrose metabolism pathways were previously linked to worse clinical outcomes in CRC. In summary, our findings support the hypothesis that colon and rectal cancer have different etiological and clinical outcomes that need to be considered for targeted treatments.
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Understanding molecular features of colorectal cancer across diverse populations is an indispensable step toward reducing the pronounced disparities in this disease burden. Based on the findings that individuals of African ancestry have an observed increase in the frequency of KRAS, AOC, and PIK3CA mutations, Myer and colleagues suggest that patients of African ancestry should consider treatment and clinical trials specific to these mutations. See related article by Myer et al., p. 1282 (2).
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Neoplasias Colorrectales , Genómica , Neoplasias Colorrectales/genética , Humanos , MutaciónRESUMEN
Importance: Germline sequence variations in APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53 genes are associated with susceptibility to gastrointestinal cancers. As a rare cancer, the evaluation of appendiceal cancer (AC) predisposition has been limited. Objective: To assess the prevalence and spectrum of inherited cancer susceptibility gene sequence variations in patients with AC and the utility of germline genetic testing for this population. Design, Setting, and Participants: This cohort study included patients with AC who underwent germline genetic testing of 14 cancer susceptibility genes performed by a clinical testing laboratory between March 1, 2012, and December 31, 2016. Data were analyzed from March to August 2022. Clinical, individual, and family histories were obtained from clinician-completed test requisition forms. Multigene panel testing was performed by targeted custom capture and sequencing and chromosome rearrangement analysis. Main Outcomes and Measures: The main outcomes were germline sequence variation prevalence and spectrum in patients with AC. Results: Among the 131 patients with AC in the cohort (90 female [68.7%]), a total of 16 deleterious sequence variations were identified in 15 patients (11.5%). Similarly, when limited to the 74 patients with AC as the first and only primary tumor, a total of 8 patients (10.8%) had at least 1 deleterious sequence variation in a cancer susceptibility gene. Overall, 6 patients (4.6%) had a deleterious sequence variation observed in MUTYH (5 with monoallelic MUTYH and 1 with biallelic MUTYH). All 4 patients with Lynch syndrome (3.1%) had a sequence variation in the MLH1 gene, of whom 3 were aged 50 years or older at AC diagnosis. Five patients (3.8%) had deleterious sequence variations in other cancer predisposition genes (1 with APC [c.3920T>A, p.I1307K], 2 with CHEK2 [c.470T>C, p.I157T], 1 with SMAD4 [c.263 287dup, p.L98IFS*14], and 1 with TP53 [c.524G>A, p.R175H]). Conclusions and Relevance: In this cohort study, 1 in every 10 patients with AC who underwent testing for hereditary cancer predisposition carried an inherited gene sequence variation associated with cancer susceptibility. Given the high frequency and broad spectrum of germline gene sequence variations, these data suggest that genetic evaluation might be warranted for all patients diagnosed with this rare malignant tumor. A systemic sequencing effort for all patients with AC may also identify cancer vulnerabilities to exploit for therapeutic development in a cancer type for which clinical trials are limited.
RESUMEN
PURPOSE: The spectrum of somatic mutations among women with endometrial cancer (EC) younger than 50 years (early-onset EC) remains unknown. We investigated distinct somatic mutation patterns among early-onset and late-onset (age ≥ 50 years) EC patients. METHODS: This cohort study included individuals age 18+ years diagnosed with pathologically confirmed EC in the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE, v9.1) consortium. We explored tumor mutational burden (TMB) and genomic patterns of EC by age at clinical sequencing using multivariable regression models adjusted for race, ethnicity, histology, sequencing assay, sample type, and TMB. RESULTS: Among 2,425 women with EC, 176 (7.3%) had early-onset EC and 1,923 (79.3%) had nonhypermutated (< 17.78 mutations/Mb) tumors. TMB significantly differed across age and histology groups. Among nonhypermutated ECs, early-onset patients had significantly lower odds of presenting with nonsilent FGFR2 and PIK3R1 somatic mutations compared with late-onset EC patients in adjusted models (FGFR2: odds ratio [OR] = 0.18, 95% CI, 0.04 to 0.76; PIK3R1: OR = 0.54, 95% CI, 0.31 to 0.92). By contrast, early-onset EC patients had increased odds of presenting with nonsilent CTNNB1 and BRCA2 mutations compared with late-onset patients (CTNNB1: OR = 3.32, 95% CI, 2.14 to 5.16; BRCA2: OR = 4.01, 95% CI, 1.55 to 10.38). Subsequent analyses stratified by race, ethnicity, and tumor histology identified distinct patterns of APC, KMT2D, KMT2C, and KRAS by race, ethnicity, and PTEN and APC patterns by histologic subtypes. CONCLUSION: Early-onset EC harbors a unique genomic landscape compared with late-onset disease. A distinct molecular phenotype of early-onset EC provides novel insights into a unique etiology and may yield clinical implications for developing targeted treatment modalities for younger patients.