Traditional Colorectal Cancer Research Articles

Decoding early-onset of colorectal cancer: Insights into SERPINA3 expression patterns

Early-onset colorectal cancer (EOCRC), recognized as a distinct subgroup with an increased incidence over the past two decades, characterized by its aggressive nature and potentially unique molecular factors that differentiate it from traditional colorectal cancer (CRC). In this study, we investigated differentially expressed genes in a young-CRC patient using paired-end mRNA-sequencing. Validation of target genes through qRT-PCR highlighted a significant increase in SERPINA3 levels in EOCRC, representing a novel finding. Epithelial expression of SERPINA3 demonstrated a strong association with disease progression, whereas stromal expression showed a negative correlation. Our findings reveal the distinct expression patterns and potential involvement of SERPINA3 in both the initiation and progression of CRC, suggesting that SERPINA3 could serve as a marker for distinguishing early-onset from late-onset cases.

A multi-center study for colorectal cancer early detection among patients with high-risk disease using a cell-free fragmentomics assay.

3613 Background: Colorectal cancer (CRC) is the third most prevalent and the second deadliest cancer globally, accounting for an estimated 1,926,000 new cases and 903,800 deaths in the year 2022 alone. It's also established that chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis, elevate the risk of developing CRC. Therefore, a timely CRC diagnosis for patients with colorectal disease can significantly improve their prognosis and therefore reduce cancer-related mortalities. Methods: In this study, we enrolled a total of 167 patients diagnosed with CRC (stages I: 43, II: 55, III: 56, IV: 13) and 217 patients with benign colorectal disease (BCD), from five participating hospitals. All participants underwent colonoscopy procedures, and their CRC or BCD status was pathologically confirmed. The development of the cancer detection model was based on a training cohort of 98 CRC patients and 131 BCD patients from three hospitals, and the evaluation of the model's performance was carried out on an independent test cohort comprising 69 CRC patients and 96 BCD patients from the remaining two hospitals. The predictive model leveraged cell-free fragmentomics profiling, employing low-pass whole-genome sequencing (WGS) on pre-operative plasma samples to identify CRC. Results: The early detection model exhibited remarkable efficacy in differentiating CRC patients from those with BCD, achieving an Area Under the Curve (AUC) of 0.930 in the training cohort and a nearly equivalent AUC of 0.926 in the independent test cohort. By applying the same cutoff determined in the training cohort, our model demonstrated a high sensitivity (91.8% in the training cohort and 91.3% in the test cohort) and a satisfactory specificity (78.6% in the training cohort and 82.3% in the test cohort). Notably, the model showed consistent and robust performance across various CRC characteristics, including tumor location, histology subtypes, grades, and mismatch repair deficiency status in both cohorts. Moreover, our model outperformed traditional CRC screening methods such as the fecal immunochemical test, carcinoembryonic antigen (CEA), and CA19-9, which achieved AUCs of 0.742, 0.720, and 0.543, respectively. Further validation was conducted using an additional cohort of 31 patients with advanced colorectal adenoma (advCRA), where the model achieved an AUC of 0.846 and a 66.7% sensitivity for distinguishing advCRA from BCD. Conclusions: The study introduces a non-invasive, cell-free fragmentomics assay that incorporates low-pass WGS and machine learning algorithms, demonstrating significant clinical potential in accurately distinguishing CRC and BCD patients. Our innovative approach offers a promising alternative to traditional screening methods that can improve early CRC detection, enhance CRC patient outcomes, and reduce mortality rates.

Identification of Aging and Young Subtypes for Predicting Colorectal Cancer Prognosis and Immunotherapy Responses.

Colorectal cancer (CRC) is critically related to aging and severely threatens human lives. To better explore the effects of aging on CRC progression and therapy outcome, a reliable aging subtypes identification of CRC is urgently desired. Here, 28 aging-related genes associated with the CRC prognosis were selected by univariate Cox analyses. Based on these 28 genes, CRC patients were divided into the aging subtype and young subtype by non-negative matrix factorization clustering. Aging subtype and young subtype of CRC were identified with distinct molecular features and clinical prognosis. The aging subtype was characterized by upregulation of senescence-associated secretory phenotype, higher frequencies of TP53 and immune checkpoint molecules, and high sensitivity to protein kinase and angiogenesis inhibitors. Furthermore, 14 genes were selected by LASSO penalized Cox regression analyses for aging-related risk signature construction. The constructed aging risk signature exhibited good prediction and the nomogram showed robust discrimination power over the traditional CRC staging system. In conclusion, this study successfully established aging subtype and young subtype of CRC, which is helpful to identify patients with aging characteristics to evaluate prognosis and treatment outcomes. Introducing aging-based subtypes into clinical concern and patient prognostication provides new opportunities for personalized CRC treatment.

Rationally Designed Oral DOX Gels for Colon-Specific Administration.

Colorectal cancer (CRC) is the third leading cause of death from cancer in both men and women. Traditional CRC dosage forms deliver the drug to both desired and unwanted sites of drug action, resulting in a number of negative side effects. Chemotherapeutic and chemopreventive agents are being targeted and delivered directly to the colon and rectum using targeted oral drug delivery systems. The main challenge in successfully targeting drugs to the colon via the oral route is avoiding drug absorption/degradation in the stomach and small intestine before the dosage form reaches the colon. In this study, we employed biocompatible chalk to adsorb DOX, then mixed pectin and cross-linked with calcium ions to form PC-DOX gels. The presence of cross-linked pectin and chalk can provide dual protection for the drug, significantly reducing drug leakage in gastric acid. In vitro release results showed that the designed PC-DOX could achieve 68% colon delivery efficiency. In the simulated colon environment, the released semi-degradable chalk did not affect the uptake of doxorubicin by colon cancer cells. Finally, in vivo simulation experiments in mice showed that rationally designed PC-DOX could achieve the highest colonic delivery efficiency. Our strategy has great potential for application in the treatment of colon cancer.

Young-Onset Colorectal Cancer in Serbia: Tertiary Cancer Center Experience.

Purpose: Early-onset colorectal cancer (CRC) is a growing problem. The aim of the study was to identify adolescent and young adult (AYA) patients with CRC in Serbia, treated in the single tertiary cancer center. Materials and Methods: This is a retrospective study that included only AYA patients (ages 18-39 years) with histologically confirmed CRC. In 11 year (2009-2019), 109 patients were identified from a single-institution database and their clinical variables and outcomes were analyzed. Results: The prevalence of a positive family history of CRC was 12.8%. Presenting symptoms were not different than traditional CRC. More than a quarter were diagnosed as an emergency. Left-sided tumors were diagnosed in 83.4% and mucinous tumors were recorded in one-third of the patients. Postoperatively patients mainly were in PS0-1 (97%). Patients presented as stages II (18.3%), III (47.7%), and IV (33.9%). The recurrence rate in local stages was 50%. Surgical treatment of localized metastatic disease was performed in almost half of the stage IV patients. Median disease-free survival for patients with the recurrent disease was 11.8 months. Median overall survival (OS) for the local and metastatic stage was 64.3 and 20.5 months, respectively. Survival analysis showed that performance status, bowel obstruction, N2 status, local invasions, disease stage, and surgery in stage IV had a statistically significant influence on OS. Conclusion: Serbian AYA CRC patients are of good general condition, with advanced left-sided tumors, common mucinous histology, and inverse histology features. Surgery in metastatic disease provided long-term survival. The outcome of the patient is influenced by a late diagnosis, inverse histological features, and treatment provided.

Short-term and long-term outcomes of natural orifice specimen extraction surgeries (NOSES) in rectal cancer: a comparison study of NOSES and non-NOSES.

BackgroundNatural orifice specimen extraction surgeries (NOSES) have been applied to colorectal cancer (CRC). Different types of NOSES have been proposed. Traditional laparoscopic CRC surgeries (non-NOSES) have been widely adopted in clinical practice. Therefore, the safety and feasibility of NOSES could be clarified by comparing with non-NOSES.MethodsConsecutive cases who underwent NOSE or non-NOSE rectal surgeries were retrospectively collected at the Second Affiliated Hospital of Harbin Medical University between 1 January 2013 and 31 December 2018. Other inclusion criteria included patients with adenocarcinoma of the rectum within 15 cm of the anal verge, over the age of 18 and undergoing primary laparoscopic rectal resection. Patients who were lost to follow-up or had incomplete information were excluded. Basic characteristics including gender, tumor location, age, staging, treatment, and Body Mass Index (BMI) were analyzed. Short-term outcomes including comorbidities, intra-operative blood loss, hospital stay, gas exhaust time were compared between different NOSES and non-NOSES groups. Long-term outcomes including overall survival (OS) and disease-free survival (DFS) were also analyzed. Patients were followed-up during the inpatient period, at an outpatient clinic, or by phone call.ResultsA total of 196 NOSES cases and 243 non-NOSES cases were included. There was a sex difference between the two groups and other factors were comparable. Cases were divided into NOSES groups [including extra-abdominal resection (EVER), specimen extraction and extra-abdominal resection (EXER), and intra-abdominal resection and specimen extraction (IREX)] and non-NOSES groups. Differences in sex (P=0.016), BMI (with mean of 22.08, 22.00, 22.53, and 23.26 kg/m2, P=0.003), and staging (P=0.008) were observed between the four groups. There was a difference in the intra-operative blood loss between NOSES and non-NOSES groups (57.05±62.78, 52.65±68.19, 36.52±43.99 vs. 76.12±90.11 mL, P=0.002), in which NOSES groups had less blood loss. Furthermore, NOSES groups showed a better post-operative gas exhaust time (54.68±37.80, 45.06±24.69, 47.91±28.93 vs. 56.94±27.69 hours, P=0.012). NOSES groups also had fewer ileostomies (17 vs. 37, P=0.003). There was no difference in the long-term DFS and OS between the two groups.ConclusionsNOSES in rectal cancer showed better short-term outcomes and had comparable long-term outcomes compared with non-NOSE surgeries.

Chemotherapy delivery in early-onset colorectal cancer is impacted by urban versus rural settings in Colorado.

19 Background: While colorectal cancer (CRC) incidence has been decreasing overall, incidence in adults under age 50 has been rising both nationally and across Colorado. National guidelines have adapted to recognize this trend, but knowledge gaps regarding early-onset CRC remain. This group has previously established rising early-onset CRC incidence in Colorado, as well as later stage at diagnosis and worse prognosis. This study examines demographics, treatment, survival, and concomitant disease among patients < 50 and diagnosed with CRC across a multicenter healthcare system in Colorado in order to better understand early-onset CRC. Methods: We analyzed 1,192 CRC cases in patients < 50 from the Colorado Health Data Compass database and cross-referenced these cases with the Colorado Central Cancer Registry to examine for association of gender, race/ethnicity, BMI, zip code, insurance type, stage, and concomitant medical conditions with overall survival and oncologic treatment modality. Logistic regressions were used to evaluate the relationships between chemotherapy and the important variables while adjusting for covariates, with 95% confidence intervals reported. Cox proportional hazard regressions were used to evaluate the relationships between overall survival and the important variables while adjusting for covariates, with 95% confidence intervals reported. Results: Overall, early-onset CRC in our population was 2.8% stage I, 6.3% stage II, 12.7% stage III, 18.5% stage IV, and 59.8% were unstageable or no stage recorded. Surgical treatment was associated with a 52% improvement in overall survival. Chemotherapy treatment was not associated with any survival changes in stage II disease. Radiation treatment, insurance type, number of concomitant conditions, geographic location, and race/ethnicity were not associated with overall survival. Upon exploring chemotherapy relationships, patients from urban areas were significantly more likely to receive chemotherapy than patients from rural areas, while adjusting for ethnicity, inpatient encounters, and stage (OR 5.55, p = 0.001). Conclusions: While less is known about CRC in patients < 50, trends are emerging that are not as well described in a traditional CRC population. The difference between urban and rural patients and their rates of chemotherapy points to a potential disparity in access to care, particularly when considering advanced stage CRC. This persisted through insurance type, indicating that distance from an infusion center, rather than ability to pay, is more likely to be driving this relationship. Further research is needed to determine if these findings are generalizable to the larger early-onset CRC population, and how access may be affecting care for this population.

Patient and Endoscopic Characteristics of Postcolonoscopy Colon Cancer-A Case-control Study.

Colonoscopy is imperfect for colorectal cancer (CRC) prevention. Postcolonoscopy CRC (PCCRC) is defined as CRC detected after a screening or surveillance colonoscopy. PCCRCs can be divided into noninterval CRC and interval CRC. We performed a case-control study to identify risk factors for PCCRCs and to compare risks between noninterval and interval PCCRCs. We designed a retrospective case-control study. Using a Vermont tumor registry data set, we identified all PCCRCs diagnosed at our medical center from January 2012 to September 2017. Cases were matched 1:3 with controls of the same age, sex, and index colonoscopy date. Fifty-four PCCRCs were matched with 162 controls and divided into noninterval (N= 27) and interval (N= 27) subsets. Overall PCCRC risk and noninterval PCCRC risk were significantly associated with history of polyps (odds ratio [OR] PCCRC= 2.71, OR noninterval= 4.41), sessile serrated polyps (OR PCCRC= 3.94, OR noninterval= 5.79), and high-risk adenoma (HRA) (OR PCCRC= 6.58, OR noninterval= 16.46) and with the index colonoscopy having a large polyp (OR PCCRC= 4.45, OR noninterval= 10.46) or having an HRA (OR PCCRC= 3.68, OR noninterval= 8.04). PCCRC risk and interval PCCRC risk were significantly associated with follow-up recommendations that did not correlate with American Gastroenterological Association surveillance guidelines (OR PCCRC= 3.30, OR interval= 4.85). Approximately 30% ofPCCRCs could be attributed to endoscopic quality. Overall PCCRC risk and noninterval PCCRC risk were significantly associated with traditional CRC risk factors including precancerous polyps and HRA on the index colonoscopy. Interval PCCRC was not associated with these risk factors. Many PCCRCs can be attributed to endoscopic quality, and nonadherence to CRC surveillance guidelines may be a novel risk factor.

Evaluation of diagnostic performances of leptin and vitamin D for colorectal cancer diagnosis and follow-up

Globally, colorectal cancer (CRC) is one of the most often diagnosed solid tumors, with a significant death and morbidity rate. CRC biomarkers are desperately needed for early detection. Traditional CRC tumor markers do not have the best diagnostic performance. The levels of leptin and vitamin D were evaluated. CRC patients before treatment (n=16), CRC patients after treatment (n=14), and 20 patients with benign tumors were included in this case-control study. ELISA was used to determine the levels of traditional tumor markers (CA19.9 and CEA) as well as candidate markers (leptin and vitamin D). Using area receiver-operating characteristic analysis (AUC), the diagnostic performance of single and combination markers was assessed (ROC). The levels of CEA and CA 19.9 in the three groups studied were not significantly different. Vitamin D and leptin were significantly decreased (p= 0.03 and p= 0.02; respectively) in CRC patients than after benign patients. A novel combination, based on the combination of vitamin D and leptin was developed for CRC diagnosis using stepwise multivariate discriminant analysis (MDA). The combination can be represented as = (4.65 – vitamin D ((ng/ml)) × 0.009 + Leptin (ng/ml) × 0.441). AUCs were reported when leptin was used as a single biomarker for distinguishing CRC from benign (0.78) and non-treated CRC from treated CRC (0.67). When leptin and vitamin D were combined, the AUCs increased to 0.84 and0.72, respectively. Conclusion: Leptin and vitamin D were shown to be promising diagnostic and follow-up indicators for CRC in our investigation.

Nongenetic Determinants of Risk forEarly-Onset Colorectal Cancer.

BackgroundIncidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite.MethodsUsing data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite.ResultsEarly-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27; P = .04).ConclusionIn this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease.

Clinicopathological and molecular biological characteristics of early-onset stage II/III colorectal adenocarcinoma: An analysis of 25 studies with 47,184 patients (pts) in the adjuvant colon cancer end points (ACCENT) database.

4099 Background: Colorectal cancer (CRC) incidence and mortality has decreased since the 1970s but the incidence is increasing in young adults (age 20-49). The incidence of early onset CRC (eoCRC) will keep increasing significantly based on the trends of the SEER CRC registry data. There is limited data suggesting eoCRC may have different behaviors compared to traditional CRC (tCRC, age ≥ 50). Methods: Individual pt data of 47184 stage II/III CRC pts from 25 randomized studies in the ACCENT database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and treatment-related data were summarized by age group. Overall survival (OS), disease-free survival (DFS), recurrence-free rate (RFR), and survival after recurrence (SAR) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for stage, performance status (PS), BMI and grade. Results: Using 5% difference between age groups as clinically meaningful cutoff, eoCRC had similar gender, race, ethnicity, PS, risk group, disease sidedness and T stage as tCRC. eoCRC were less likely overweight (30 vs 36%) and more pts had ≥ 12 lymph nodes resected (63 vs 51%). eoCRC had more frequent dMMR status (18 vs 12%), less BRAF mutations (5 vs 13%), and more dMMR/BRAF wild type (WT) status (17 vs 7%). Overall, eoCRC had better OS, DFS, and SAR, with the most significant differences between the < 30 and > = 70 age groups. Similar results were observed within pMMR pts. eoCRC experienced less hematological side effects, diarrhea, and stomatitis, but had more nausea and/or vomiting. Conclusions: eoCRC have unique characteristics; although statistically significant, the clinical differences in outcomes between eoCRC and tCRC are potentially due to the difference seen in extremely young and old pts. eoCRC have a different adverse events panel compared to tCRC. [Table: see text]

Smoking, alcohol consumption and colorectal cancer risk by molecular pathological subtypes and pathways

BackgroundSmoking and alcohol increase risk for colorectal malignancies. However, colorectal cancer (CRC) is a heterogenic disease and associations with the molecular pathological pathways are unclear.MethodsThis population-based case–control study includes 2444 cases with first-diagnosis CRC and 2475 controls. Tumour tissue was analysed for MSI (microsatellite instability), CIMP (CpG island methylator phenotype), BRAF (B-Raf proto-oncogene serine/threonine kinase gene) and KRAS (Kirsten rat sarcoma viral oncogene homologue gene) mutations. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for associations between alcohol and smoking and CRC molecular subtypes and pathways.ResultsCurrent smoking showed higher ORs for MSI-high (OR = 2.79, 95% CI: 1.86–4.18) compared to MSS (OR = 1.41, 1.14–1.75, p-heterogeneity (p-het) = 0.001), BRAF-mutated (mut) (OR = 2.40, 1.41–4.07) compared to BRAF-wild type (wt) (OR = 1.52, 1.24–1.88, p-het = 0.074), KRAS-wt (OR = 1.70, 1.36–2.13) compared to KRAS-mut (OR = 1.26, 0.95–1.68, p-het = 0.039) and CIMP-high (OR = 2.01, 1.40–2.88) compared to CIMP-low/negative CRC (OR = 1.50, 1.22–1.85, p-het=0.101). Current smoking seemed more strongly associated with sessile serrated pathway (CIMP-high + BRAF-mut; OR = 2.39, 1.27–4.52) than with traditional pathway CRC (MSS + CIMP-low/negative + BRAF-wt; OR = 1.50, 1.16–1.94) and no association was observed with alternate pathway CRC (MSS + CIMP-low/negative + KRAS-wt; OR = 1.08, 0.77–1.43). No heterogeneity was observed in alcohol consumption association by molecular subtypes.ConclusionsIn this large case–control study, smoking was more strongly associated with MSI-high and KRAS-wt CRC and with cases showing features of the sessile serrated pathway. Association patterns were less clear for alcohol consumption.

Clinicopathological features and prognosis of AFP-producing colorectal cancer: a single-center analysis of 20 cases.

Background: High serum levels of alpha-fetoprotein (AFP) are observed in some gastrointestinal cancers. However, primary AFP-producing colorectal cancer (CRC) is extremely rare and causes confusion among clinicians. In this study, we analyzed the clinicopathological features and clinical outcomes of AFP-producing CRC and provide a brief view of this rare carcinoma.Patients and methods: Twenty patients with AFP-producing CRC were enrolled at the Fudan University Shanghai Cancer Center from 2012 to 2015. Clinical information, including serum AFP and CEA levels, and outcomes were collected. Tumors were divided into three histologic types: the common adenocarcinoma (COM) type, mucinous adenocarcinoma type and hepatoid type (HPT). Immunohistochemical (IHC) staining of GPC3, Hepa-1, SALL4 and Arg-1 was performed. Additionally, mutations of the KRAS, NRAS and BRAF genes were examined. Finally, another 40 stage-matched patients with traditional CRC were enrolled as controls for survival analysis.Results: AFP-producing CRC was more likely to occur in males (60%) and arose mainly from the ascending (40%) and sigmoid (35%) colon. In addition, the majority of patients with AFP-producing CRC had poor differentiation (50%), advanced local invasion (80%) and lymph node (LN) metastasis (60%). Synchronous distant metastasis was commonly observed (35%). Interestingly, serum AFP levels were closely associated with LN metastasis. Histopathologically, the COM type was the most common pattern. In IHC staining, the HPT pattern was the most distinct due to high positivity rates of GPC3, Hepa-1 and Arg-1. One patient had mismatch repair deficiency, and another had a KRAS mutation. Patients with AFP-producing CRC had worse progression-free and overall survival than patients with traditional CRC.Conclusion: AFP-producing CRC has unique clinical and histopathological characteristics, showing an aggressive biological behavior and worse prognosis than traditional CRC.

Clinical and molecular characterization of early-onset colorectal cancer.

Colorectal cancer (CRC) incidence is increasing in adults younger than 50years. This study evaluated clinical and molecular features to identify those features unique to early-onset CRC that differentiate these patients from patients 50years old or older. Baseline characteristics were evaluated according to the CRC onset age with 3 independent cohorts. A fourth cohort was used to describe the impact of age on the consensus molecular subtype (CMS) prevalence. This retrospective review of more than 36,000 patients with CRC showed that early-onset patients were more likely to have microsatellite instability (P=.038), synchronous metastatic disease (P=.009), primary tumors in the distal colon or rectum (P<.0001), and fewer BRAF V600 mutations (P<.001) in comparison with patients 50years old or older. Patients aged 18 to 29years had fewer adenomatous polyposis coli (APC) mutations (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.35-0.90; P=.015) and an increased prevalence of signet ring histology (OR, 4.89; 95% CI, 3.23-7.39; P<.0001) in comparison with other patients younger than 50years. In patients younger than 40years, CMS1 was the most common subtype, whereas CMS3 and CMS4 were uncommon (P=.003). CMS2 was relatively stable across age groups. Early-onset patients with inflammatory bowel disease were more likely to have mucinous or signet ring histology (OR, 5.54; 95% CI, 2.24-13.74; P=.0004) and less likely to have APC mutations (OR, 0.24; 95% CI, 0.07-0.75; P=.019) in comparison with early-onset patients without predisposing conditions. Early-onset CRC is not only distinct from traditional CRC: special consideration should be given to and further investigations should be performed for both very young patients with CRC (18-29years) and those with predisposing conditions. The etiology of the high rate of CMS1 in patients younger than 40years deserves further exploration.

Dairy products and colorectal cancer in middle eastern and north African countries: a systematic review

BackgroundThis systematic review was conducted to explain the association between dairy products and colorectal cancer (CRC) risk in Middle Eastern and North African countries (MENA).MethodsThe database consulted were PubMed, Clinical Trials, and Cochrane to extract the relevant studies published till the 31stof December 2016, using inclusion and exclusion criteria according to Prisma Protocol. The characteristics of these studies comprised the consumption of all types of dairy products in relation to CRC risk.ResultsSeven studies were included in this review. For dairy products overall, no significant association was found. Regarding modern dairy products, included studies found controversial results with OR = 9.88 (95% CI: 3.80–24.65) and ORa = 0.14 (95% CI: 0.02–0.71). A positive association was reported between traditional dairy products and CRC risk, to OR = 18.66 (95% CI: 3.06–113.86) to OR = 24 (95% CI: 1.74–330.82) to ORa = 1.42 (95% CI: 0.62–3.25), ptrend = 0.03. Calcium was inversely associated with the CRC risk with ORa = 0.08 (95% CI: 0.04–0.17).ConclusionThis is the first systematic review which illustrated the association between dairy consumption and CRC risk in MENA region. The results were inconsistent and not always homogeneous. Further specified studies may be warranted to address the questions about the association between CRC and dairy products in a specific context of MENA region.

Abstract 274: Early-onset colorectal cancer is distinct from traditional colorectal cancer

Abstract Background &amp; Objective: Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide, responsible for over 700,000 deaths annually. Although CRC rates have declined 3.1%/year annually over the past decade, annual incidence rates of CRC among patients between 20-49 years old have increased by more than 1.4% per year over the same time period and these early-onset CRCs (E-CRC) now comprise 10-18% of newly diagnosed cases. Our hypothesis is that E-CRC represents a distinct subtype of CRC with unique drivers. To examine this, we analyzed national data sources such as the SEER database, the Behavioral Risk Factor Surveillance Survey (BRFSS), and the Cancer Genome Atlas (TCGA) to characterize the epidemiology and genetics differences between early onset CRC (E-CRC) and typical CRC (T-CRC). Methods: The SEER database was analyzed to characterize the clinical and pathological differences between E-CRC patients (20-49 years) and T-CRC group (&amp;gt; 50 years). We compared rates of age-adjusted CRC with known lifestyle risk factors using population data from the BRFSS. Based on differences in clinical presentation and anatomical location we hypothesized that there are underlying molecular differences between E-CRCs and T-CRC that may explain these differences. To investigate this we analyzed the TCGA CRC dataset for genomic markers that can distinguish between E-CRC and T-CRC tumors. Results: E-CRC incidence has risen at an annual rate of 1.4% per year from 2000-2011, whereas T-CRC incidence has declined by 3.1% per year among patients 50 years or older during the same period. Relative to T-CRC, E-CRC rates are significantly more prevalent in the Black population than the White or Hispanic populations. Anatomical location of E-CRC is significantly increased towards the distal colon when compared to T-CRC locations suggesting a distinct etiology. Analysis of risk factors confirmed that U.S counties with high rates of diabetes, obesity and smoking were significantly correlated with higher T-CRC rates. However, no such correlations were observed for E-CRC rates. Analysis of the limited number of E-CRC in the TCGA cohort identified a number of known oncogenes that are suggestive of distinct E-CRC tumorigenesis. Conclusions: Our results suggest that E-CRC appears to be distinct from T-CRC. Young patients with CRC represent a distinct patient group with unique epidemiology and mechanisms of disease development. The increase in left sided colon and rectal cancers is consistent with earlier reports and although the underlying reasons are unknown, they are suggestive of differences in tumor genesis and mutational characteristics. To follow up on this hypothesis we are performing additional genetic and epigenetic characterization of E-CRC and matching T-CRC samples collected at Weill Cornell. Citation Format: Doron Betel, Heather Yeo, Rhonda Yantiss, Xi E. Zheng, Jonathan S. Abelson, Manish A. Shah. Early-onset colorectal cancer is distinct from traditional colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 274. doi:10.1158/1538-7445.AM2017-274

Early-onset Colorectal Cancer is Distinct From Traditional Colorectal Cancer

BackgroundEarly-onset colorectal cancer (E-CRC) is increasing in incidence, unlike traditional CRC (T-CRC). We sought to characterize differences between E-CRC and T-CRC. Materials and MethodsData sources included the Surveillance, Epidemiology, and End Results database, the Behavioral Risk Factor Surveillance Survey, and The Cancer Genome Atlas (TCGA). We compared demographics, tumor characteristics, and incidence of CRC in subjects aged 20 to 49 years (E-CRC) with those aged ≥ 50 years (T-CRC). We correlated the incidence of E-CRC and T-CRC to CRC risk factors and age-dependent genomic characteristics of CRC using TCGA. ResultsA total of 369,796 CRCs were identified (2000-2011). E-CRC incidence has risen 1.4% per year, whereas T-CRC has declined 3.1% per year (P < .05). The incidence of E-CRC increases in a step-wise fashion from the ascending colon to rectum (P < 2.2e−16). E-CRC is more prevalent in male (53.7% vs. 46.4%; P < .001), Black (14.6% vs. 11.0%; P < .001), and Hispanic (14.7% vs. 8.3%; P < .001) patients. E-CRC presents with aggressive histology, including high-grade (1.5% vs. 1.3%; P < .001), signet ring cell (1.9% vs. 0.9%; P < .001), and mucinous carcinomas (8.9% vs. 8.1%; P < .001), and more often with distant disease (24.4% vs. 18.8%; P < .001). The geographic distribution of E-CRC mirrors United States counties with higher Black population densities. Unlike T-CRC, E-CRC prevalence is not correlated with known CRC risk factors. E-CRC is associated with a lower rate of mutations than traditional CRC. Limitations of this study include E-CRC sample size for the TCGA analysis, as well as lack of comorbidity information and family history. ConclusionE-CRC tumors are clinically, pathologically, and molecularly distinct from T-CRC. Further evaluation of genetic and molecular differences is necessary to understand the pathophysiology of E-CRC and to help target treatment/surveillance strategies.

Early-onset small bowel and colorectal cancer patients with BRCA mutations: Actionable variants in atypical presentations.

545 Background: The paradigm of genetic panel testing for hereditary colorectal cancer (CRC) continues to emerge. An association between Hereditary Breast and Ovarian Cancer (HBOC) syndrome and early onset CRC and has been reported, though only significantly associated with BRCA1 mutations. Guidelines do not include CRC in the HBOC spectrum. We describe nine early-onset ( &lt; 55 years) gastrointestinal (GI) cancer patients with germline mutations in BRCA1 or BRCA2 to highlight actionable findings that would have been missed by traditional CRC genetic testing. Methods: The nine affected patients underwent genetic testing using NGS-based multi-gene cancer panels. Genomic DNA variants were identified and classified according to ACMG criteria. Patient medical histories were obtained by referring clinician and documented on test requisition forms, and were de-identified for analysis. Results: Nine patients had a pathogenic (P) variant in BRCA1 (three cases) or BRCA2 (six cases). Four patients were under the age of 32 at the time of their CRC diagnosis. Of the nine cases, only one met NCCN testing criteria for HBOC syndrome. All patients were negative for P variants in the canonical CRC genes (APC, MUTYH, MLH1, MSH2, MSH6, PMS2, EPCAM). Conclusions: In this series, nine unrelated patients with early-onset CRC were found to carry a BRCA1 or BRCA2 mutation. The presence of BRCA mutations in these CRC patients is alone not strong evidence of causation; however, it suggests that clinicians should consider expanded panel testing in the presence of complex family histories, as these patients would have been found negative by traditional genetic tests. As the phenotypic spectrum of classical cancer syndromes is expanded by broad panel-based testing, it is important to identify patients that fall outside traditional diagnostic criteria, as some patients will have actionable findings in unexpected genes.

MG-115 Colorectal cancer patients with BRCA1 and BRCA2 mutations: Preparing for unexpected results

Background A new paradigm in genetic panel testing for hereditary colorectal cancer (CRC) has emerged. CRC association with BRCA1/2 has been suggested, but guidelines do not include CRC in Hereditary Breast and Ovarian Cancer syndrome (HBOC). Objectives We describe 6 patients with CRC and germline mutations in BRCA1 or BRCA2, detected by multi-gene panels, to highlight actionable findings that would have been missed by traditional CRC genetic testing. Design/method 585 patients with a personal history of CRC and/or gastrointestinal (GI) polyps were tested. Variants were identified using an NGS-based cancer gene panel with CRC genes and BRCA1/2. Germline variants were classified using a point-based system based on ACMG guidelines. Clinical histories from test request forms were de-identified for analysis. Results Hereditary cancer panel testing found Pathogenic (P) or Likely Pathogenic (LP) variants in 92 of 585 (15%) patients. Of the 92 mutation carriers, 69 (75%) had a P/LP variant in a CRC gene, while 6 (6%) had a P/LP variant in BRCA1/2. None of the patients with BRCA1/2 mutations reported Ashkenazi Jewish ancestry. The 4 male patients did not meet HBOC testing guidelines. Conclusions In this series, a substantial minority of P/LP variants were in non-canonical CRC genes. BRCA1/2 pathogenic variants’ prevalence in the general population is insufficiently elevated to account for these findings. More research is needed to link CRC and BRCA1/2, and clinicians need to prepare themselves and their patients to deal with unexpected, potentially actionable.

Targeted serum metabolite profiling and sequential metabolite ratio analysis for colorectal cancer progression monitoring.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and a major cause of human morbidity and mortality. In addition to early detection, close monitoring of disease progression in CRC can be critical for patient prognosis and treatment decisions. Efforts have been made to develop new methods for improved early detection and patient monitoring; however, research focused on CRC surveillance for treatment response and disease recurrence using metabolomics has yet to be reported. In this proof of concept study, we applied a targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) metabolic profiling approach focused on sequential metabolite ratio analysis of serial serum samples to monitor disease progression from 20 CRC patients. The use of serial samples reduces patient to patient metabolic variability. A partial least squares-discriminant analysis (PLS-DA) model using a panel of five metabolites (succinate, N2, N2-dimethylguanosine, adenine, citraconic acid, and 1-methylguanosine) was established, and excellent model performance (sensitivity = 0.83, specificity = 0.94, area under the receiver operator characteristic curve (AUROC) = 0.91 was obtained, which is superior to the traditional CRC monitoring marker carcinoembryonic antigen (sensitivity = 0.75, specificity = 0.76, AUROC = 0.80). Monte Carlo cross validation was applied, and the robustness of our model was clearly observed by the separation of true classification models from the random permutation models. Our results suggest the potential utility of metabolic profiling for CRC disease monitoring.