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.

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 Clinical, Pathological and Molecular Characteristics of Chilean Patients with Early-, Intermediate- and Late-Onset Colorectal Cancer

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 631
Author(s):  
Karin Alvarez ◽  
Alessandra Cassana ◽  
Marjorie De La Fuente ◽  
Tamara Canales ◽  
Mario Abedrapo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Age Of Onset ◽  
Late Onset ◽  
Molecular Characteristics ◽  
Family History Of Cancer ◽  
Molecular Features ◽  
Age Of Diagnosis ◽  
History Of ◽  
History Of Cancer

Colorectal cancer (CRC) is the second most frequent neoplasm in Chile and its mortality rate is rising in all ages. However, studies characterizing CRC according to the age of onset are still lacking. This study aimed to identify clinical, pathological, and molecular features of CRC in Chilean patients according to the age of diagnosis: early- (≤50 years; EOCRC), intermediate- (51–69 years; IOCRC), and late-onset (≥70 years; LOCRC). The study included 426 CRC patients from Clinica Las Condes, between 2007 and 2019. A chi-square test was applied to explore associations between age of onset and clinicopathological characteristics. Body Mass Index (BMI) differences according to age of diagnosis was evaluated through t-test. Overall (OS) and cancer-specific survival (CSS) were estimated by the Kaplan–Meier method. We found significant differences between the age of onset, and gender, BMI, family history of cancer, TNM Classification of Malignant Tumors stage, OS, and CSS. EOCRC category was characterized by a family history of cancer, left-sided tumors with a more advanced stage of the disease but better survival at 10 years, and lower microsatellite instability (MSI), with predominant germline mutations. IOCRC has shown clinical similarities with the EOCRC and molecular similarities to the LOCRC, which agrees with other reports.

Molecular characteristics of complete PTEN loss in metastatic colorectal cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 389-389
Author(s):  
Zhi-Qin Jiang ◽  
Laurel Deaton ◽  
Nastaran Neishaboori ◽  
Jean-Nicolas Vauthey ◽  
Michael J. Overman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cpg Island ◽  
Pik3ca Mutation ◽  
The Cancer Genome Atlas ◽  
Akt Pathway ◽  
Molecular Characteristics ◽  
Braf Mutations ◽  
Pik3ca Mutations ◽  
Pten Loss

389 Background: Loss of expression of phosphatase and tensin homolog (PTEN) is associated with activation of the PI3K/AKT pathway, and has been identified as a potential modulator of response to targeted therapies in metastatic colorectal cancer (mCRC). The association of PTEN loss with other molecular characteristics and outcomes has not been described for mCRC. Methods: Tumor from 229 mCRC patients (pts) were included for analysis of PTEN staining by IHC from whole-mounts, across two cohorts of unresectable mCRC or resectable liver-limited disease. PTEN loss was defined as complete loss of staining with preservation of expression of stromal components. Mutation status was defined using mass-spectroscopy or next-generation sequencing platforms. CpG island methylation (CIMP) status was determined using a previously defined 6-marker panel, with methylation of ≥3 markers denoting CIMP-High. Methylation findings where confirmed in 193 pts from the Cancer Genome Atlas (TCGA) database, using previously defined classifications. Results: The overall frequency of complete PTEN loss was 12% in the primary tumor and 15% when assayed from metastatic sites (P=NS). There was no difference in clinical characteristics in patients with PTEN-loss tumors. Complete PTEN loss and PIK3CA mutations were not mutually exclusive, with PIK3CA mutation rate of 24% and 14% in PTEN loss and intact, respectively (p=0.3). There was no association of PTEN loss with KRAS mutations (p=0.3), although there were non-significant trends toward higher rates of CIMP-High, BRAF mutations, and R-sided tumors (OR 3.2, 2.7, and 1.6, respectively; p<0.2), consistent with an association with the serrated adenoma pathway and epigenetic inactivation. In the TCGA, PTEN protein loss (defined by the lowest 12% of expression) was associated with increased AKT signaling (77% increase in pAKT/AKT, p<0.01) and a similar trend with CIMP-H tumors (OR 3.1, p=0.13). Conclusions: In patient samples, PTEN loss is independent of KRAS and PIK3CA mutations, associated with robust AKT pathway activation, and may be more prominent in tumors with hypermethylation and BRAF mutations.

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 Colorectal Cancer in Iran: A Retrospective, Comparative Study of Early-onset and Late-onset Cases in north-eastern Iran based on the Iranian Hereditary Colorectal Cancer Registry

2021 ◽  
Author(s):  
Benyamin Hoseini ◽  
Zahra Rahmatinejad ◽  
Ladan Goshayeshi ◽  
Robert Bergquist ◽  
Fatemeh Rahmatinejad ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Onset ◽  
Age Of Onset ◽  
Late Onset ◽  
Young Patients ◽  
City Hospital ◽  
Genetic Characteristics ◽  
Eastern Iran ◽  
North Eastern ◽  
Tumour Location

Abstract Background: Generally, the incidence rate of colorectal cancer (CRC) is increasing among young patients (aged <49 years), while the reasons for the rising incidence are unclear. Indicative variables, such as tumour location, gender preference and genetic preponderance have not been followed up in a consistent manner. The current study was primarily conducted to improve the hereditary CRC screening programme by assessing the demographic and pathological characteristics of early-onset CRC compared to late-onset CRC in northeast Iran. Methods: This retrospective study was carried out over a three-year follow-up period (2014-2017) and included 562 CRC patients in three Mashhad City hospital laboratories in north-eastern Iran. We applied comparative analysis of pathological and familial features together with information on the presence of genetic mismatch repair-deficiency in relation to final patient status (surviving versus deceased cases). Analyses using R studio software were performed on early-onset CRC (n=222) and late-onset CRC (n=340) groups produced by division at the age of 50 years. Results: From an age-of-onset point of view, the distribution between the genders differed with females showing a higher proportion of early-onset CRC compared to men (56% vs. 44 %) , while the late-onset CRC disparity was less pronounced (48% vs. 52%). The mean age of all participants was 55.6 ± 14.8 years, while it was 40.3 ± 7.3 years for early-onset CRC and 65.1 ± 9.3 years for late-onset CRC. With respect to anatomical tumour location (distal, rectal, and proximal), the frequencies were 61%, 28% and 11%, respectively, but the variation did not reach statically significance. There was a dramatic difference with regard to the history of CRC in second-degree relatives (SDR) and that of the combination of first-degree relatives and SDR (p=0.001 and p=0.03, respectively). Expression of the MLH1 and PMS2 genes were significantly different between survivors and deceased, however this finding was not observed with regard to the MSH6 and the MSH2 genes. Conclusion: The variation of demographic, pathological and genetic characteristics of CRC between early-onset and late-onset cancers of this kind emphasizes the need for a well-defined algorithm to identify high-risk patients.

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 Recent developments in the treatment of metastatic colorectal cancer

2017 ◽  
Vol 9 (8) ◽  
pp. 551-564 ◽  
Author(s):  
Jonathan M. Loree ◽  
Scott Kopetz
Keyword(s):  
Colorectal Cancer ◽  
Decision Making ◽  
Clinical Decision Making ◽  
Growth Factor Receptor ◽  
Low Frequency ◽  
Clinical Decision ◽  
Tumor Location ◽  
Targeted Agents ◽  
Braf Mutations ◽  
Exon 2

Over the past decade there have been significant advances in the molecular characterization of colorectal cancer (CRC) that are driving treatment decisions. Expanded RAS testing beyond KRAS exon 2 was established as crucial for identifying patients who will respond to anti-epidermal growth factor receptor (EGFR) therapies and low-frequency mutations in RAS/tumor heterogeneity are gaining recognition as potential mechanisms of resistance. Despite this progress, the fact that we do not understand why left-sided but not right-sided tumors have improved outcomes following anti-EGFR therapy highlights our superficial understanding of this disease. Even with few new targeted agents receiving approval in CRC, the incorporation of next-generation sequencing into clinical decision making represents an important step forward. Biomarkers such as BRAF mutations, microsatellite instability, and HER2 amplification represent promising molecular aberrations with therapies in various stages of development, and highlight the importance of companion diagnostics in supporting targeted agents. In this review, we will discuss the importance of incorporating biomarkers into clinical decision making and regimen selection in CRC. We will particularly focus on the recent evidence suggesting an important role for tumor location in selecting first-line therapy, the importance of recent advances in biomarker development and molecular subtyping, as well as recently approved agents (regorafenib and TAS-102) and promising targeted agents that have the potential to change the standard of care.

scholarly journals DNA methylation signatures and the contribution of age-associated methylomic drift to carcinogenesis in early-onset colorectal cancer

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

AbstractBackgroundThe role of DNA methylation (DNAm) in the carcinogenesis of colorectal cancer (CRC) diagnosed <50years of age (early-onset CRC or EOCRC) is currently unknown. We investigated aberrant DNAm changes and the contribution of ageing-associated methylomic drift, and age acceleration to EOCRC carcinogenesis.MethodsGenome-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.ResultsCommon 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. 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).ConclusionEOCRC 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. We found accelerated ageing in normal mucosa from people with EOCRC, as evidenced by a faster stem-cell division rate, potentially contributing to EOCRC carcinogenesis.

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 Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci

2010 ◽  
Vol 9 (1) ◽  
pp. 100 ◽  
Author(s):  
Marianne Berg ◽  
Trude H Agesen ◽  
Espen Thiis-Evensen ◽  
INFAC-study group [infac] ◽  
Marianne A Merok ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
High Resolution ◽  
Gene Expression Data ◽  
Early Onset ◽  
Late Onset ◽  
Expression Data ◽  
Susceptibility Loci ◽  
Genome Profiles
Sign in / Sign up

Export Citation Format

Share Document