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.

Clinical features and survival among patients with standard-onset versus early-onset colorectal cancer by age groups.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3614-3614
Author(s):  
Ana Acuna Villaorduna ◽  
Nishi Shah ◽  
Sanjay Goel
Keyword(s):  
Colorectal Cancer ◽  
Clinical Features ◽  
Early Onset ◽  
Task Force ◽  
Age Groups ◽  
Stage Iv ◽  
Early Screening ◽  
Cancer Society ◽  
Crc Screening ◽  
Early Onset Colorectal Cancer

3614 Background: Colorectal cancer (CRC) incidence is increasing in patients younger than 50 years old. Currently, there are discordant recommendations regarding CRC screening: while the American Cancer Society favors to start at age 45, the National Comprehensive Cancer Network and the US Preventive Task Force suggest starting at age 50. This study is aimed to compare the incidence, clinical characteristics and survival of patients diagnosed with standard-onset CRC (SO) versus early-onset colorectal cancer by age-groups. Methods: Patients diagnosed with CRC at ages older than 35 were identified using the SEER registry and categorized into four groups based on age at diagnosis. EO1 (35-39), EO2 (40-44), EO3 (45-49) and SO (>50) years, respectively. Incidence, clinical features and survival were compared among groups. Results: 178 678 patients were identified. 9.2% were diagnosed before 50 years. Of these, 1.4%, 2.8% and 5.1% were EO1, EO2 and EO3; respectively. Patients with early-onset CRC (EO) had higher frequency of Hispanics (13.9% vs. 8.4%, p<0.01), stage IV (24.8% vs. 17.3%, p<0.01), left-sided tumors (74.1% vs. 56.9%, p<0.01) and better survival compared to SO. Among EO groups, the frequency of poor/anaplastic grade was inversely proportional to age; stage IV was similar between EO2 and EO3 and lower in EO1. Black race, grade and stage were predictors of mortality for all EO groups; laterality was a mortality predictor in EO2 and EO3. Conclusions: EO-CRC and SO-CRC have different pathological features that should be considered for CRC screening. Higher rates of stage IV disease are encountered in patients between 40-49 years old; hence early screening should be considered. Given higher rates of left-sided tumors, sigmoidoscopy might be an adequate tool for most patients with EO-CRC. [Table: see text]

scholarly journals Incident Crohn’s Disease as a Risk Factor for Colorectal Cancer in the First 10 Years after Diagnosis: A Nationwide Population-Based Study

2021 ◽  
Vol 10 (20) ◽  
pp. 4663
Author(s):  
Hyunil Kim ◽  
Ji Hoon Kim ◽  
Jung Kuk Lee ◽  
Dae Ryong Kang ◽  
Su Young Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Early Onset ◽  
Late Onset ◽  
Age Groups ◽  
Population Based ◽  
Hazard Ratios ◽  
Increased Risk ◽  
Cox Proportional Hazard Regression

We investigated the risk of colorectal cancer (CRC) in patients with Crohn’s disease (CD) using the claims data of the Korean National Health Insurance during 2006–2015. The data of 13,739 and 40,495 individuals with and without CD, respectively, were analyzed. Hazard ratios (HRs) were calculated using multivariate Cox proportional hazard regression tests. CRC developed in 25 patients (0.18%) and 42 patients (0.1%) of the CD and non-CD groups, respectively. The HR of CRC in the CD group was 2.07 (95% confidence interval (CI), 1.25–3.41). The HRs of CRC among men and women were 2.02 (95% CI 1.06–3.87) and 2.10 (95% CI, 0.96–4.62), respectively. The HRs of CRC in the age groups 0–19, 20–39, 40–59, and ≥60 years were 0.07, 4.86, 2.32, and 0.66, respectively. The HR of patients with late-onset CD (≥40 years) was significantly higher than that of those with early-onset CD (<40 years). CD patients were highly likely to develop CRC. Early-onset CD patients were significantly associated with an increased risk of CRC than matched individuals without CD. However, among CD patients, late-onset CD was significantly associated with an increased risk of CRC.

scholarly journals Early-onset colorectal cancer: more than one side to the story

2020 ◽  
Vol 9 (3) ◽  
pp. CRC28
Author(s):  
Nina N Sanford ◽  
Pooja Dharwadkar ◽  
Caitlin C Murphy
Keyword(s):  
Colorectal Cancer ◽  
Early Onset ◽  
Age Groups ◽  
Younger Adults ◽  
Risk Of Death ◽  
Colon Cancers ◽  
All Cause Mortality ◽  
Colon And Rectum ◽  
The Impact ◽  
Early Onset Colorectal Cancer

Aim: To determine the impact of tumor sidedness on all-cause mortality for early- (age 18–49 years) and older-onset (age ≥50 years) colorectal cancer (CRC). Materials & methods: We conducted a retrospective study of 650,382 patients diagnosed with CRC between 2000 and 2016. We examined the associations of age, tumor sidedness (right colon, left colon and rectum) and all-cause mortality. Results: For early-onset CRC (n = 66,186), mortality was highest in the youngest age group (18–29 years), driven by left-sided colon cancers (vs 50–59 years, hazard ratio: 1.18; 95% CI: 1.03–1.34). 5-year risk of death among 18–29-year-olds with left-sided colon cancer (0.42, 95% CI: 0.38, 0.46) was higher than all other age groups. Conclusion: Left-sided colon cancers are enriched in younger adults and may be disproportionately fatal.

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 Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ismael A. Vergara ◽  
Christopher P. Mintoff ◽  
Shahneen Sandhu ◽  
Lachlan McIntosh ◽  
Richard J. Young ◽  
...  
Keyword(s):  
Large Scale ◽  
Point Mutations ◽  
Whole Genome ◽  
Sequencing Data ◽  
Genetic Changes ◽  
Genome Doubling ◽  
Whole Exome ◽  
Whole Genome Doubling ◽  
Treatment Naïve ◽  
Key Driver

AbstractAlthough melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.

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 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 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.

Characteristics and survival among early onset and standard onset colorectal cancer by race.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 522-522 ◽  
Author(s):  
Ana Acuna Villaorduna ◽  
Sanjay Goel
Keyword(s):  
Colorectal Cancer ◽  
Clinical Features ◽  
Early Onset ◽  
Minority Groups ◽  
Age Groups ◽  
Screening Colonoscopy ◽  
Racial Groups ◽  
Early Screening ◽  
Race Ethnicity ◽  
Early Onset Colorectal Cancer

522 Background: The incidence of early-onset colorectal cancer (EO) is increasing. Guidelines recommend to start screening colonoscopy at 45 yo in Non-Hispanic Black (NHB). We compare the clinical features and outcomes between EO and standard-onset (SO) colorectal cancer (CRC) among racial groups. Methods: Patients with CRC adenocarcinoma; available race/ethnicity and stage were identified using the SEER registry. Clinical features and 5 year-overall survival (OS) is described by racial and age groups. Results: 190 670 patients were identified. EO rates were higher for minorities than NHW. Median age at diagnosis in EO was 44 and was similar among racial groups; while it was 71 in SO, being lower among minorities compared to NHW (67 vs. 72 years, p < 0.01). Left-sided tumors accounted for 77.4% of tumors in EO while it was 60.8% in SO for minorities versus NHW. The most common CRC location for EO was the rectum and sigmoid colon for SO. EO was most commonly diagnosed as stage III. Surgery and radiation rates were higher for EO for all stages. OS was higher in all stages of EO compared to SO. Conclusions: EO frequency is higher in all minority groups and most commonly located in the rectum. Despite higher stage and grade, OS is higher for EO which might be due to higher treatment rates. Early screening should be extended to all minority groups. [Table: see text]

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.

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