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 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.

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 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.

Related Heterogeneity in Pathologically Confirmed Sporadic Alzheimer Disease

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011772
Author(s):  
Denis S Smirnov ◽  
Douglas Galasko ◽  
Annie Hiniker ◽  
Steven Edland ◽  
David P. Salmon
Keyword(s):  
Early Onset ◽  
Age Of Onset ◽  
Late Onset ◽  
Functional Decline ◽  
Apoe Genotype ◽  
Executive Dysfunction ◽  
Bimodal Distribution ◽  
Cognitive Testing ◽  
Apoe Ε4 ◽  
Age Related

Objective:To characterize age-related clinical heterogeneity in Alzheimer’s disease (AD) and determine if it is modified by APOE genotype or concomitant non-AD pathology, we analyzed data from 1750 patients with sporadic, pathologically-confirmed severe AD.Methods:In this retrospective cohort study, regression and mixed effects models assessed effects of estimated age of onset, APOE genotype, and their interaction on standardized clinical, cognitive and pathologic outcome measures from the National Alzheimer’s Coordinating Center (NACC) database.Results:A bimodal distribution of age of onset frequency in APOE ε4- cases showed best separation at age 63. Using this age cut-off, cases were grouped as early onset (EO) AD ε4- (n=169), EOAD ε4+ (n=273), late onset (LO) AD ε4- (n=511), and LOAD ε4+ (n=797). EOAD were more likely than LOAD patients to present with non-cognitive behavioral or motor symptoms or non-memory cognitive complaints, and had more executive dysfunction, but less language impairment on objective cognitive testing. Age of onset and ε4- genotype were independently associated with lower baseline MMSE and greater functional impairment, and EOAD had faster cognitive and functional decline than LOAD regardless of APOE genotype. EOAD were more likely than LOAD patients to receive a non-AD clinical diagnosis even though they were more likely to have “pure” AD without concomitant vascular or other non-AD neurodegenerative pathology.Conclusions:Early onset sporadic AD is associated with a greater likelihood of an atypical, non-memory dominant clinical presentation, especially in the absence of the APOE ε4 allele, which may lead to misattribution to non-AD underlying pathology.

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 Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Zijian Chen ◽  
Zenghong Huang ◽  
Yanxin Luo ◽  
Qi Zou ◽  
Liangliang Bai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Promoter Methylation ◽  
Expression Profiles ◽  
Methylation Status ◽  
Gene Promoter ◽  
Normal Mucosa ◽  
Suppressor Gene ◽  
Survival Outcome ◽  
Prognostic Models

Abstract Background Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC). Methods An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP). Results The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma. Conclusions This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.

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, 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.

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

Age, Age of Onset and Course of Primary Depressive Illness in the Elderly*

1983 ◽  
Vol 28 (2) ◽  
pp. 102-104 ◽  
Author(s):  
Martin G. Cole
Keyword(s):  
Elderly Patients ◽  
Depressive Episode ◽  
Early Onset ◽  
Age Of Onset ◽  
Late Onset ◽  
The Elderly ◽  
Depressive Illness ◽  
Physical Illness ◽  
Course Of Illness

Thirty-eight elderly patients with primary depressive illness (Feighner criteria) were followed up for 7–31 months. In the absence of persistent organic signs and severe physical illness, age of onset (first depressive episode after 60) but not age was significantly related to course of illness. Compared to early onset depressives, late onset depressives were more likely to remain completely well during the follow-up period and less likely to have frequent or disabling relapses.

Sign in / Sign up

Export Citation Format

Share Document