Colorectal cancer (CRC) is the third most frequently diagnosed cancer, the second leading cause of cancer-related mortality, and the most common gastrointestinal malignancy. CRC symptoms often emerge at advanced stage, with approximately 15-30% of patients presenting with metastatic disease (mCRC) at initial diagnosis. Among those diagnosed with localized CRC, an estimated 20-50% will eventually develop metastases. Combination of chemotherapy with targeted agents has significantly improved overall survival in mCRC, but prognosis remains poor with 5-year survival rates of only 10-15%.
CRC is a highly heterogeneous disease, resulting in variable clinical outcomes and treatment responses. Molecular characterization based on genomic alterations and gene expression profiles allows classification of CRC into distinct subtypes, each with prognostic and predictive implications for surgical and systemic therapies. For example, in mCRC, monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) are effective only in tumors without activating mutations in the RAS oncogene. Conversely, microsatellite instability (MSI) mCRC typically exhibits resistance to anti-EGFR therapy but represents the only mCRC subgroup with proven sensitivity to immune checkpoint inhibitors. Given the poor prognosis associated with mCRC, optimal deployment of targeted therapies is critical, underscoring the urgent need to discover novel predictive biomarkers.
Our primary objective is to identify histopathological, microenvironmental, and genetic features associated with oncological treatment response in a mCRC trial population. We compare patients with a favorable treatment outcome to those with non-responsive disease and further stratify analyses by oncogene mutation status and treatment regimen.
Pseudomyxoma peritonei (PMP) is a rare malignant disease (3-4 cases per million per year) that most often originates from the appendix and presents as a mucinous adenocarcinoma growing in the peritoneal cavity. The abundance of mucinous ascites secreted by the more common low-grade subtype of PMP leads to progressive obstruction, which is eventually fatal. In addition to mucin production, the high-grade subtype of PMP is able to invade surrounding tissues and organs, thereby shortening the survival time when compared to the low-grade disease.
We have analyzed the mutational profile of PMP and found KRAS mutation to be frequent and nearly always combined with mutated GNAS, or some other component of the cAMP-PKA signaling pathway (Nummela et al., 2015; Saarinen et al., 2017). Further, we have identified CEA and EpCAM proteins to be ubiquitously expressed in PMP cells, thus serving as immunohistochemistry markers to detect disseminated PMP cells (Nummela et al., 2016). Using glycomics, we have demonstrated that the N-glycans of PMP cells exhibit structural features that may contribute to increased mucus production, peritoneal dissemination, and disease progression (Saarinen et al., 2018; Nummela et al., 2021). In PMP research, we participated in the COST Action CA17101, European Network on Pseudomyxoma Peritonei, years 2018-23.