Frequency of Common and Uncommon Alterations among Colorectal and Non-Colorectal Gastrointestinal Malignancies.

BACKGROUND

The predictive and prognostic role of alterations has been evaluated in colorectal cancer (CRC); however, alterations have not been fully characterized in non-CRC gastrointestinal (GI) malignancies. In the present study, we report the frequency and spectrum of alterations among patients with non-CRC GI malignancies.

METHODS

Patients with CRC and non-CRC GI malignancies who underwent somatic tumor profiling via a tissue-based or liquid-based assay were included in this study. Gain-of-function alterations were defined as pathogenic/likely pathogenic somatic short variants (SVs), copy number amplifications ≥8, or fusions (RNA or DNA).

RESULTS

Among 51,560 patients with somatic profiling, 40% had CRC and 60% had non-CRC GI malignancies. GOF alterations were seen more frequently in CRC (8.9%) compared to non-CRC GI malignancies (2.2%) ( < 0.001). Non-CRC GI malignancies with the highest prevalence of GOF alterations were bile duct cancers (4.1%) and small intestine cancers (4.0%). Among GOF alterations, class II (28% vs. 6.8%, < 0.001) and class III (23% vs. 14%, < 0.001) were more common in non-CRC GI malignancies. Among class II alterations, rates of amplifications (3.1% vs. 0.3%, < 0.001) and fusions (12% vs. 2.2%, < 0.001) were higher in non-CRC GI malignancies compared to CRC.

CONCLUSIONS

Non-CRC GI malignancies demonstrate a distinct alteration profile compared to CRC, with a higher frequency of class II and III mutations, and more specifically, a higher incidence of fusions. Future studies should evaluate clinical implications for the management of non-CRC GI patients with alterations, especially BRAF fusions.