Germline genomic profiling of patients with early-onset colorectal cancer

The incidence of early-onset colorectal cancer (EO-CRC) is rising. While most cases of EO-CRC are sporadic, the prevalence of hereditary cancer predisposition syndromes remains a subject of debate. Moreover, genes not traditionally associated with EO-CRC development are rarely included in germline testing panels.

Germline profiling data of patients with EO-CRC presenting to our clinics were collected at two Italian university institutions: IRCCS San Raffaele Scientific Institute and Grande Ospedale Metropolitano Niguarda. Multigene germline profiling analysis was carried out using next-generation sequencing and multiplex ligation probe amplification. Associations between germline alterations and clinicopathological variables were analyzed.

A total of 130 patients with EO-CRC were screened. The median age at EO-CRC diagnosis was 42 years (range 22-49 years). Germline pathogenic or likely pathogenic variants (PVs/LPVs) associated with hereditary cancer predisposition syndromes were identified in 23 (18%) patients, while germline variants of unknown significance were found in 47 (36%) patients. No alterations in high-penetrance genes associated with cancer susceptibility were observed in 67 (52%) patients. No patients with microsatellite stable BRAF-mutant (n = 5) or signet ring cell CRC (n = 2) exhibited germline PVs/LPVs. No clinicopathological features were significantly enriched in hereditary compared with sporadic EO-CRC. Germline PVs in FLCN and SDHAF2 were identified in two patients with EO-CRC.

While most EO-CRC cases are sporadic, approximately one-fifth arises within the context of hereditary cancer predisposition syndromes. As FLCN and SDH are not currently included in the current guidelines for EO-CRC, PVs/LPVs in these genes may be underestimated. To better understand their significance, we recommend including their assessment in all patients with EO-CRC.