Faculty Bibliography

BACKGROUND/UNASSIGNED:late-onset CRC (LOCRC). METHODS/UNASSIGNED:Using the National Inpatient Sample (NIS) (2016-2020), we identified hospitalizations with a primary diagnosis of CRC. Patients were categorized from a hospital-based classification of EOCRC (<50 years) or LOCRC (≥50 years). Multivariate logistic regression assessed associations between body mass index (BMI), demographics, and outcomes including inpatient mortality, length of stay (LOS), and chemotherapy use. RESULTS/UNASSIGNED:Among 246,231 CRC hospitalizations, 13.7% (n=33,662) were EOCRC. Compared to LOCRC, EOCRC patients were more likely to be female [odds ratio (OR): 1.09], Black (OR: 1.17), Hispanic (OR: 1.56), or Asian (OR: 1.29), and more often covered by Medicaid, private insurance, or have no coverage. EOCRC patients had higher rates of tobacco use disorder (OR: 1.26) and depression (OR: 1.13), but lower prevalence of diabetes, coronary artery disease (CAD), and alcohol use disorder. EOCRC hospitalizations had lower inpatient mortality (OR: 0.649). Inpatient chemotherapy was more common in EOCRC (OR: 1.78). Obesity was positively associated with EOCRC for BMI 30-39 (OR: 1.07) and BMI ≥40 (OR: 1.50), while LOCRC showed inverse associations for the same BMI groups. CONCLUSIONS/UNASSIGNED:EOCRC is associated with unique demographic and clinical profiles when compared to LOCRC, highlighting disparities by race, insurance status, and comorbidities. The higher rate of inpatient chemotherapy use in EOCRC warrants further study to evaluate its clinical necessity and outcomes. These findings reinforce the need for targeted screening and inpatient care strategies for younger and underserved patient populations.

The cancer-predisposing Lynch Syndrome (LS) arises from germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1, MSH2, MSH6, and PMS2. A major challenge for clinical diagnosis of LS is the frequent identification of variants of uncertain significance (VUS) in these genes, as it is often difficult to determine variant pathogenicity, particularly for missense variants. Generic programs such as SIFT and PolyPhen-2, and MMR gene-specific programs such as PON-MMR and MAPP-MMR, are often used to predict deleterious or neutral effects of VUS in MMR genes. We evaluated the performance of multiple predictive programs in the context of functional biologic data for 15 VUS in MLH1, MSH2, and PMS2. Using cell line models, we characterized VUS predicted to range from neutral to pathogenic on mRNA and protein expression, basal cellular viability, viability following treatment with a panel of DNA-damaging agents, and functionality in DNA damage response (DDR) signaling, benchmarking to wild-type MMR proteins. Our results suggest that the MMR gene-specific classifiers do not always align with the experimental phenotypes related to DDR. Our study highlights the importance of complementary experimental and computational assessment to develop future predictors for the assessment of VUS.