• Lynch syndrome
• gastric cancer
• genetic screening
• germline mutation
• microsatellite instability

• cancer
• colorectal cancer

• 50 Years
• Clinical
• Colorectal Cancer
• Recommendation
• Young

• Humans
• Endoscopy
• Genetic Testing
• Colorectal Neoplasms/diagnosis

• I01 BX004455 BLRD VA
• I01 CX001146 CSRD VA
• P30 CA047904 NCI NIH HHS
• R01 CA220329 NCI NIH HHS

• bundled genomic screening
• implementation
• population screening
• principlist ethics
• utilitarian ethics

• R01 HG009694 NHGRI NIH HHS
• National Human Genome Research Institute

• pediatric polyps
• polyposis syndromes

• ethics
• health policy
• medical ethics
• genetic counselling

• Colorectal cancer
• Cost-effectiveness analysis
• Lynch syndrome
• Population screening

• Colorectal Neoplasms, Hereditary Nonpolyposis/therapy
• Female
• Humans
• Male
• Neoadjuvant Therapy
• Neoplasm Staging
• Prognosis
• Rare Diseases
• Rectal Neoplasms/pathology
• Retrospective Studies

DNA methylation (DNAm) age metrics have been widely accepted as an epigenetic biomarker for biological aging and disease. The purpose of this study is to assess whether or not individuals carrying Lynch Syndrome-associated mutations are affected in their rate of biological aging, as measured by the epigenetic clock.

Genome-wide bisulfite DNA sequencing data were generated using DNA from CD4 + T-cells obtained from peripheral blood using 27 patient samples from Lynch syndrome families. Horvath’s DNAm age model based on penalized linear regression was applied to estimate DNAm age from patient samples with distinct clinical and genetic characteristics to investigate cancer mutation-related aging effects.

Both Lynch mutation carriers and controls exhibited high variability in their estimated DNAm age, but regression analysis showed steeper slope for the Lynch mutation carriers. Remarkably, six Lynch Syndrome-associated mutation carriers showed a strong correlation to the control group, and two sisters carrying Lynch Syndrome-associated mutations, with no significant difference in lifestyle and similar chronological age, were assigned very different DNAm age.

Future studies will be required to explore, in larger patient populations, whether specific epigenetic age acceleration is predictive of time-to-cancer development, treatment response, and survival. Epigenetic clock DNAm metrics may be affected by the presence of cancer mutations in the germline, and thus show promise of potential clinical utility for stratified surveillance strategies based on the relative risk for imminent emergence of tumor lesions in otherwise healthy Lynch Syndrome-associated mutation carriers.

• DNA methylation
• Epigenetic clock
• Lynch syndrome

• Colorectal cancer
• prognostic factors
• young patients

• Adenocarcinoma/epidemiology
• Adenocarcinoma/genetics
• Adenocarcinoma/pathology
• Adult
• Age of Onset
• Australia/epidemiology
• Biomarkers, Tumor/genetics
• Canada/epidemiology
• Colorectal Neoplasms/epidemiology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Computer Simulation
• Cross-Sectional Studies
• DNA Glycosylases/genetics
• DNA Mismatch Repair
• DNA Mutational Analysis
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• Germ-Line Mutation
• Heredity
• Humans
• Li-Fraumeni Syndrome/epidemiology
• Li-Fraumeni Syndrome/genetics
• Male
• Models, Genetic
• New Zealand/epidemiology
• Pedigree
• Phenotype
• Predictive Value of Tests
• Registries
• Risk Assessment
• Risk Factors
• Tumor Suppressor Protein p53/genetics
• United States/epidemiology
• Young Adult

• K24 CA113433 NCI NIH HHS
• U01 CA074799 NCI NIH HHS
• U24 CA074783 NCI NIH HHS
• U24 CA074794 NCI NIH HHS
• U24 CA074806 NCI NIH HHS
• U24 CA097735 NCI NIH HHS
• U01 CA074794 NCI NIH HHS
• P30 CA015083 NCI NIH HHS
• U01 CA097735 NCI NIH HHS
• UM1 CA167551 NCI NIH HHS
• CA-95-011 NCI NIH HHS
• U01 CA074783 NCI NIH HHS
• U24 CA074799 NCI NIH HHS
• U01 CA074806 NCI NIH HHS
• K24CA113433 NCI NIH HHS
• U24 CA074800 NCI NIH HHS
• U01 CA074800 NCI NIH HHS

• Chromosomal instability
• CpG island methylator phenotype
• Early-onset colorectal cancer
• Lynch syndrome
• Microsatellite instability

• Biomarkers, Tumor/genetics
• Colorectal Neoplasms/classification
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Disease Progression
• Genetic Predisposition to Disease
• Humans
• Molecular Diagnostic Techniques
• Neoplasm Staging
• Pedigree
• Phenotype
• Predictive Value of Tests
• Risk Factors

Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a “sporadic” subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the “sporadic” subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this “sporadic” early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.

• Early-onset colorectal cancer
• Epidemiology
• Hereditary syndrome
• Lynch syndrome
• MUTYH-associated polyposis

• Adult
• Age of Onset
• Colorectal Neoplasms/epidemiology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Female
• Genetic Predisposition to Disease
• Genetic Variation
• Heredity
• Humans
• Male
• Middle Aged
• Neoplastic Syndromes, Hereditary/epidemiology
• Neoplastic Syndromes, Hereditary/genetics
• Neoplastic Syndromes, Hereditary/pathology
• Pedigree
• Peutz-Jeghers Syndrome/epidemiology
• Peutz-Jeghers Syndrome/genetics
• Phenotype
• Prevalence
• Prognosis
• Risk Factors
• Young Adult

Several studies evaluated the prevalence of Lynch Syndrome (LS) in young onset colorectal cancer (CRC) patients and the results were extremely variable (5%-20%). Immunohistochemistry (IHC) for MMR proteins and/or MSI analysis are screening tests that are done, either by themselves or in conjunction, on colon cancer tissue to identify individuals at risk for LS. The primary aim of our study was to evaluate the prevalence of LS in a large series of early-onset CRC without family history compared with those with family history. The secondary aim was to assess the diagnostic accuracy of IHC and MSI analysis as pre-screening tools for LS.

Early-onset CRC patients (≤ 50 years) were prospectively recruited in the study. IHC and MSI analysis were performed in all the patients. Germ-line mutation analysis (GMA) was carried out in all MMR deficient tumors. A logistic regression model was performed to identify clinical features predictive of MSI-H.

117 early onset CRC cases were categorized in three groups (A, B, C) according with family history of CRC. IHC and MSI analysis showed MMR deficiency in 6/70 patients (8.6%) of group A, 24/40 patients (60%) of group B and none of group C. GMA showed a deleterious mutation in 19 (47.5%) patients of group B. MSI analysis had a diagnostic accuracy of 95.7% (CI 92.1-99.4) and IHC of 83.8% (CI 77.1-90.4). The logistic regression model revealed that by using a combination of the two features “No Amsterdam Criteria” and ”left sided CRC” to exclude MSI-H, accuracy was 89.7% (84.2-95.2).

Early-onset CRC patients, with left sided CRC and without family history are “at very low risk” for Lynch syndrome. The two simple criteria of family history and CRC site could be used as a pre-screening tool to evaluate whether or not patients should undergo tissue molecular screening. In the few cases of suspected LS (right sided CRC and/or Amsterdam Criteria), a reasonable approach could be to perform MSI analysis first and IHC afterwards only in MSI-H patients.

• Adult
• Age of Onset
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• DNA Glycosylases/deficiency
• DNA Glycosylases/genetics
• DNA Mismatch Repair
• DNA-Binding Proteins/deficiency
• DNA-Binding Proteins/genetics
• Female
• Humans
• Immunohistochemistry
• Male
• Microsatellite Instability
• Retrospective Studies

• R01 CA072851 NCI NIH HHS
• R01 CA072851-15 NCI NIH HHS