Incidence of RSPO3 rearrangements in advanced colorectal cancer patients detected by NGS and their relationship with disease characteristics

Colorectal cancer (CRC) is the second most frequent cause of cancer-related deaths. Mortality is largely due to limited treatment options for patients who present with advanced disease. Genomic abnormalities that are potentially characteristic of such advanced stages of the disease are complex and are not yet fully understood. In fact, only 30% of cases with advanced disease benefit from targeted treatments. The molecular heterogeneity of primary advanced CRC (aCRC) tumor samples was evaluated by next-generation sequencing (NGS) in 53 consecutive patients (pT4a-b). The genetic abnormalities found in primary tumors were most frequently mutations in TP53 (57% of cases), KRAS (45%), PI3KCA (27%), BRAF (15%) and RET (10%), as well as RSP03 fusions (8%). Alterations in the TP53 and NRAS genes were more commonly observed in the left colon, while BRAF mutations and RSPO3 fusions were more frequently detected in the right or transverse colon. We also show a strong association between the presence of RSPO3 rearrangements and patients with small, low histological grade tumors, with normal CEA levels, preferentially located on the right side of the colon. Furthermore, aCRC patients with PTPRK::RSPO3 fusions showed a higher frequency of deaths, and RSPO3 gene expression levels had an adverse impact on overall survival in two large, independent series of patients with CRC. We show that RSPO3 rearrangements occur very frequently in advanced disease, making it a promising therapeutic target for this subtype of patient.