Germline Cancer Risk Profiles of Patients With Young-Onset Colorectal Cancer: Findings From a Prospective Universal Germline Testing and Telegenetics Program

BACKGROUND: Colorectal cancer is being increasingly diagnosed in people younger than 50 years. An inheritable cancer predisposition has been reported in 22% of the young-onset cases. Assessment of germline risk is critical for personalized cancer care. OBJECTIVE: The study aimed to implement universal germline cancer risk assessment and testing and to define the germline cancer risk profiles of patients presenting with young-onset disease.DESIGN: This is a prospective cohort study.SETTINGS: This study was conducted at a tertiary-referral academic medical center.PATIENTS: This study included newly diagnosed patients presenting to surgical clinics between September 2019 and February 2021 who were treated on a standardized care pathway including the universal germline risk assessment.INTERVENTIONS: Patients received educational material on young-onset disease, genetic testing, and insurance coverage followed by genetic counseling (either remotely by telegenetics or in person). Consenting patients were assessed on a 47-gene common hereditary cancer panel.MAIN OUTCOME MEASURES: The primary outcome was a proportion of patients with identifiable germline cancer predisposition.RESULTS: Among 500 patients with colorectal cancer, 185 (37%) were 50 years of age or younger (median: 44). A family history was absent for the majority of patients (123; 67%), and in 15 patients, tumors (8.1%) were deficient in DNA mismatch repair. Germline testing was completed in 130 patients (70%); the remainder were pending (7%), deceased (1%), or declined (22%). Pathogenic germline mutations were identified in 25 of 130 (19%) patients: 12 in mismatch repair genes and 13 in other genes. A variant of uncertain significance was found in 23 (18%) patients. Importantly, a pathogenic germline mutation was identified in 12% of the patients without a family history (versus 32% with; p = 0.015) and in 13% of those with proficient mismatch repair colorectal cancers (versus 71% if deficient; p < 0.001).LIMITATIONS: The study is limited by its implementation at a single tertiary academic institution.CONCLUSIONS: One in 5 patients with young-onset disease harbored germline cancer predisposition. This detection rate, coupled with a high level of interest and acceptance from patients and feasibility of implementation, supports universal germline cancer risk assessment in this patient population.

Automated summary

This study aimed to implement universal germline cancer risk assessment and testing and define the germline cancer risk profiles of patients with young-onset disease. Among 500 patients with colorectal cancer, 185 were age 50 or younger and 25 of them had pathogenic germline mutations. The results support universal germline cancer risk assessment in this patient population.