scholarly journals Innate immune genes distinguish the immune microenvironment of early onset colorectal cancer

2020 ◽  
Author(s):  
Ivy H. Gardner ◽  
Ragavan Siddharthan ◽  
Katherine Watson ◽  
Elizabeth Dewey ◽  
Rebecca Ruhl ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Onset ◽  
Late Onset ◽  
Progression Free Survival ◽  
Tumor Location ◽  
Immune Microenvironment ◽  
Immune Genes ◽  
Genetic Features ◽  
Innate Immune Genes ◽  
Early Onset Colorectal Cancer

AbstractDespite a decrease in the incidence of colorectal cancer (CRC) over the last 40 years, the incidence of CRC in people under 50 years old is increasing around the globe. Early onset (≤50 years old) and late onset (≥65 years old) CRC appear to have differences in their clinicopathological and genetic features, but it is unclear if there are differences in the tumor microenvironment. We hypothesized that the immune microenvironment of early onset CRC is distinct from late onset CRC and promotes tumor progression. We used Nanostring immune profiling to analyze mRNA expression of immune genes in FFPE surgical specimens from patients with early (N=40) and late onset (N=39) CRC. We found three genes, SAA1, C7, and CFD, have increased expression in early onset colorectal cancer and distinct immune signatures based on the tumor location. After adjusting for clinicopathological features, increased expression of CFD and SAA1 were associated with worse progression free survival and increased expression of C7 was associated with worse overall survival. Our data demonstrate that the immune microenvironment in early onset CRC is unique, location dependent, and associated with worse outcomes.

scholarly journals Clinicopathological and Molecular Characteristics of Early-Onset vs Late-onset Colorectal Cancer according to Tumor Location

2021 ◽  
Author(s):  
Yongle Chen ◽  
Zexian Chen ◽  
Juanni Huang ◽  
Jiancong Hu ◽  
Xiaowen He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Onset ◽  
Odds Ratio ◽  
Late Onset ◽  
Tumor Location ◽  
Molecular Characteristics ◽  
Molecular Features ◽  
Significant Difference ◽  
The Right ◽  
Early Onset Colorectal Cancer

Abstract BackgroundThe incidence of early-onset colorectal cancer (EOCRC) is rapidly increasing worldwide in decade when screening of colorectal cancer (CRC) is more prevalent. The clinicopathological and molecular characteristics of EOCRC have not yet been clarified. This study aims to evaluate clinicopathological and molecular features including status of deficiencies of mismatch repair (dMMR), mutation of PIK3CA, BRAF and KRAS among EOCRC and late-onset colorectal cancer (LOCRC) patients according to different tumor locations.MethodsWe identified CRC patients from a prospectively maintained CRC database between January 2015 and December 2018 at the Sixth Affiliated Hospital of Sun Yat-sen University. The clinicopathological and molecular characteristics including dMMR, mutation of PIK3CA, BRAF and KRAS were compared between EOCRC and LOCRC. The relationships according to different tumor locations were assessed.ResultsTotally 4468 patients, including 947 EOCRC patients and 3521 LOCRC patients, were analyzed in this study. Compared with LOCRC patients, EOCRC patients were more likely to have status of dMMR (odds ratio [OR], 2.52; 95% confidence interval [CI], 2.05-3.10; P<0.001), regardless of tumor location, so were loss of MSH2 and MSH6 (OR, 4.31; 95% CI, 2.86-6.48; P<0.001; OR, 3.40; 95% CI, 2.42-4.76; P<0.001, respectively). Loss of MLH1 and PMS2 were detected more frequently in EOCRC overall (OR, 2.11; 95% CI, 1.55-2.87; P<0.001; OR, 1.83; 95% CI, 1.42-2.35; P<0.001, respectively), but only in left-side and right-side colon rather than in rectum. EOCRC patients were more likely to be detected with mutation of PIK3CA (OR, 1.24; 95% CI, 1.01-1.53; P=0.041), which only trended to exist in the left-side colon (OR, 1.51; CI, 0.98-2.33; P=0.06), but not in the right-side colon or rectum. No significant difference was found for BRAF or KRAS mutation, but mutation of KRAS was more frequently found in left-side colon (OR, 1.34; CI, 1.02-1.77; P=0.04) among EOCRC patients.ConclusionsStatus of dMMR, mutation of PIK3CA, BRAF and KRAS were different between EOCRC and LOCRC patients according to different tumor locations, which implied that EOCRC might be a unique subgroup of CRC patients. Further investigations of molecular and genetic differences should be performed to help define new diagnosing and therapeutical strategies for EOCRC patients.

scholarly journals High prevalence of TP53 loss and whole-genome doubling in early-onset colorectal cancer

2021 ◽  
Author(s):  
Jeong Eun Kim ◽  
Jaeyong Choi ◽  
Chang-Ohk Sung ◽  
Yong Sang Hong ◽  
Sun Young Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Onset ◽  
Large Scale ◽  
Late Onset ◽  
Age Groups ◽  
The Cancer Genome Atlas ◽  
Whole Genome ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Early Onset Colorectal Cancer

AbstractThe global incidence of early-onset colorectal cancer (EO-CRC) is rapidly rising. However, the reason for this rise in incidence as well as the genomic characteristics of EO-CRC remain largely unknown. We performed whole-exome sequencing in 47 cases of EO-CRC and targeted deep sequencing in 833 cases of CRC. Mutational profiles of EO-CRC were compared with previously published large-scale studies. EO-CRC and The Cancer Genome Atlas (TCGA) data were further investigated according to copy number profiles and mutation timing. We classified colorectal cancer into three subgroups: the hypermutated group consisted of mutations in POLE and mismatch repair genes; the whole-genome doubling group had early functional loss of TP53 that led to whole-genome doubling and focal oncogene amplification; the genome-stable group had mutations in APC and KRAS, similar to conventional colon cancer. Among non-hypermutated samples, whole-genome doubling was more prevalent in early-onset than in late-onset disease (54% vs 38%, Fisher’s exact P = 0.04). More than half of non-hypermutated EO-CRC cases involved early TP53 mutation and whole-genome doubling, which led to notable differences in mutation frequencies between age groups. Alternative carcinogenesis involving genomic instability via loss of TP53 may be related to the rise in EO-CRC.

scholarly journals Clinical and Molecular Comparative Study of Colorectal Cancer Based on Age-of-onset and Tumor Location: Two Main Criteria for Subclassifying Colorectal Cancer

2019 ◽  
Vol 20 (4) ◽  
pp. 968 ◽  
Author(s):  
Edurne Álvaro ◽  
Juana M. Cano ◽  
Juan L. García ◽  
Lorena Brandáriz ◽  
Susana Olmedillas-López ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Onset ◽  
Age Of Onset ◽  
Late Onset ◽  
Cpg Island ◽  
Low Frequency ◽  
Tumor Location ◽  
Molecular Characteristics ◽  
Braf Mutations ◽  
Rectal Cancers

Our aim was to characterize and validate that the location and age of onset of the tumor are both important criteria to classify colorectal cancer (CRC). We analyzed clinical and molecular characteristics of early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and we compared each tumor location between both ages-of-onset. In right-sided colon tumors, early-onset cases showed extensive Lynch syndrome (LS) features, with a relatively low frequency of chromosomal instability (CIN), but a high CpG island methylation phenotype. Nevertheless, late-onset cases showed predominantly sporadic features and microsatellite instability cases due to BRAF mutations. In left colon cancers, the most reliable clinical features were the tendency to develop polyps as well as multiple primary CRC associated with the late-onset subset. Apart from the higher degree of CIN in left-sided early-onset cancers, differential copy number alterations were also observed. Differences among rectal cancers showed that early-onset rectal cancers were diagnosed at later stages, had less association with polyps, and more than half of them were associated with a familial LS component. Stratifying CRC according to both location and age-of-onset criteria is meaningful, not only because it correlates the resulting categories with certain molecular bases, but with the confirmation across larger studies, new therapeutical algorithms could be defined according to this subclassification.

Risk factors and clinical characteristics of early-onset colorectal cancer vs. late-onset colorectal cancer

2020 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Milena Di Leo ◽  
Raffaella A. Zuppardo ◽  
Marta Puzzono ◽  
Ilaria Ditonno ◽  
Alessandro Mannucci ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Early Onset ◽  
Clinical Characteristics ◽  
Late Onset ◽  
Early Onset Colorectal Cancer

scholarly journals Clinical Characteristics and Outcomes of Colorectal Cancer in the ColoCare Study: Differences by Age of Onset

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3817
Author(s):  
Caroline Himbert ◽  
Jane C. Figueiredo ◽  
David Shibata ◽  
Jennifer Ose ◽  
Tengda Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Early Onset ◽  
Age Of Onset ◽  
Late Onset ◽  
Neoadjuvant Treatment ◽  
Standard Of Care ◽  
Patient Characteristics ◽  
Systemic Treatments ◽  
Early Onset Colorectal Cancer

Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (<50 years) vs. late-onset (≥50 years) disease in a large multinational cohort of colorectal cancer patients (n = 2193). We calculated descriptive statistics and assessed associations of clinicodemographic factors with age of onset using mutually-adjusted logistic regression models. Patients were on average 60 years old, with BMI of 29 kg/m2, 52% colon cancers, 21% early-onset, and presented with stage II or III (60%) disease. Early-onset patients presented with more advanced disease (stages III–IV: 63% vs. 51%, respectively), and received more neo and adjuvant treatment compared to late-onset patients, after controlling for stage (odds ratio (OR) (95% confidence interval (CI)) = 2.30 (1.82–3.83) and 2.00 (1.43–2.81), respectively). Early-onset rectal cancer patients across all stages more commonly received neoadjuvant treatment, even when not indicated as the standard of care, e.g., during stage I disease. The odds of early-onset disease were higher among never smokers and lower among overweight patients (1.55 (1.21–1.98) and 0.56 (0.41–0.76), respectively). Patients with early-onset colorectal cancer were more likely to be diagnosed with advanced stage disease, to have received systemic treatments regardless of stage at diagnosis, and were less likely to be ever smokers or overweight.

scholarly journals Early‑onset colorectal cancer: A distinct entity with unique genetic features

2020 ◽  
Author(s):  
Dan Jiang ◽  
Chang Shu ◽  
Chuanfen Lei ◽  
Ying Wan ◽  
Linyong Sun
Keyword(s):  
Colorectal Cancer ◽  
Early Onset ◽  
Distinct Entity ◽  
Genetic Features ◽  
Early Onset Colorectal Cancer

scholarly journals DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2589
Author(s):  
Jihoon E. Joo ◽  
Mark Clendenning ◽  
Ee Ming Wong ◽  
Christophe Rosty ◽  
Khalid Mahmood ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Early Onset ◽  
Late Onset ◽  
Normal Mucosa ◽  
Accelerated Ageing ◽  
Normal Colonic Mucosa ◽  
Age Related ◽  
Differentially Methylated Genes ◽  
Early Onset Colorectal Cancer

We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50–70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups (p = 3.7 × 10−16) and young people without CRC (p = 5.8 × 10−6). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis.

Differences in the immune microenvironment between early and late-onset colon and rectal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 214-214
Author(s):  
Ivy Hernandez Gardner ◽  
Ragavan Siddharthan ◽  
Kate Watson ◽  
Rebecca Ruhl ◽  
Sudarshan Anand ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Colon Cancer ◽  
Early Onset ◽  
Late Onset ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Immune Microenvironment ◽  
Colon And Rectal Cancer ◽  
Number Of Patients

214 Background: Over the past 35 years, there has been a significant increase in the number of patients below the recommended initial screening age (50 years old) diagnosed with colorectal cancer (CRC). Early onset colorectal cancer is more likely to occur in non-white patients, be located in the rectum, be diagnosed at a more advanced stage, and have concerning pathological features. The immune microenvironment in CRC is a key player in disease progression, therapy response, and overall survival. However, the role of the immune microenvironment in early onset CRC, particularly in rectal cancer has not been investigated. This study aims to characterize the immune microenvironment of early onset ( 50 years old) and late onset ( 65 years old) colon and rectal cancer patients. Methods: We used Nanostring immune profiling to analyze FFPE surgical specimens and identified genes that were differentially expressed between early and late onset colon and rectal cancer groups. We validate our results with qPCR. The differentially expressed genes in the rectal cancer cohort were compared to our analysis of a publically available database (GSE8721) of gene expression profiles for 203 rectal cancer and 160 matched normal mucosa samples. Immunohistochemistry (IHC) was performed on FFPE colorectal specimens for CXCL3. Results: Using Nanostring, we identified two genes that were differentially expressed between early and late onset colon cancer (IFITM1, CXCL3) and two genes in the rectal cancer cohort (FLT3, SAA1). CXCL3 has increased expression in late onset colon cancer utilizing qPCR and IHC. High expression of CXCL3 in both IHC and qPCR is associated with improved disease free survival. Analysis of the GSE8721 database also showed that FLT3 and SAA1 were differentially expressed in early versus late onset rectal cancer. Using qPCR, FLT3 is increased in early onset rectal cancer specimens compare to late onset rectal cancer, early and late onset colon cancer, and normal colon. Conclusions: There are distinct differences in the immune microenvironment between early and late onset colon and rectal cancer that may hold the potential for targeted therapeutics.

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