Colorectal cancer genomic biomarkers in the clinical management of patients with metastatic colorectal carcinoma

Abstract

Colorectal carcinoma (CRC) is an heterogeneous disease in which different genetic alterations play a role in its pathogenesis and progression and offer potential for therapeutic intervention. The research on predictive biomarkers in metastatic CRC (mCRC) mainly focused on the identification of biomarkers of response or resistance to anti-epidermal growth factor receptor monoclonal antibodies. In this respect, international guidelines suggest testing mCRC patients only for KRAS, NRAS and BRAF mutations and for microsatellite instability. However, the use of novel testing methods is raising relevant issue related to these biomarkers, such as the presence of sub-clonal RAS mutations or the clinical interpretation of rare no-V600 BRAF variants. In addition, a number of novel biomarkers is emerging from recent studies including amplification of ERBB2, mutations in ERBB2, MAP2K1 and NF1 and rearrangements of ALK, ROS1, NTRK and RET. Mutations in POLE and the levels of tumor mutation burden also appear as possible biomarkers of response to immunotherapy in CRC. Finally, the consensus molecular subtypes classification of CRC based on gene expression profiling has prognostic and predictive implications. Integration of all these information will be likely necessary in the next future in order to improve precision/personalized medicine in mCRC patients.

Genomic and Transcriptomic Research in the Discovery and Application of Colorectal Cancer Circulating Markers

“…The somatic mutations detectable in cfDNA could be instrumental in the rational assignment of immunotherapy and assessment of its effectiveness. For CRC, the total number of somatic mutations, also known as tumor mutation burden (TMB), could be one of the parameters to assess the response to immunotherapy [41,42] A high level of TMB (≥20 mutations/Mb) was found to be associated with microsatellite instability (MSI) or mutations in the two DNA polymerases (POLD and POLE) [42,43]. In a phase II trial, ctDNA was shown to be helpful in assessing the variant allele frequencies (VAFs) as a predictive biomarker for the immunotherapy of patients with solid tumors treated with an anti-PD1 agent.…”

Mass Spectrometry-Based Pipeline for Identifying RNA Modifications Involved in a Functional Process: Application to Cancer Cell Adaptation

“…Cancer onset and evolution typically result from the accumulation of various molecular aberrations comprising genetic and epigenetic alterations. , The identification of genomic, transcriptomic, and epigenomic abnormalities is critical for precision oncology in many cancers, both to establish molecular subtypes and to offer appropriate treatment. − Likewise, the RNA mark landscape evolves along with tumor progression and represents a novel source of biomarkers for personalized medicine . To illustrate this principle, our group has recently uncovered “epitranscriptomic signatures” from glioma patients’ cohorts that could be exploited to guide glioma/glioblastoma diagnosis with unmet accuracy .…”

Dynamics of RAS/BRAF Mutations in cfDNA from Metastatic Colorectal Carcinoma Patients Treated with Polychemotherapy and Anti-EGFR Monoclonal Antibodies

“…In this respect, the addition of anti-EGFR monoclonal antibodies to first-line polychemotherapy increases the overall response rate (ORR) and prolongs the progression-free survival (PFS) and overall survival (OS), as compared with chemotherapy alone, in metastatic CRC (mCRC) patients who do not carry either KRAS or NRAS mutations [ 3 , 4 , 5 ]. In fact, the presence of RAS mutations leads to constitutive activation of signaling pathways downstream the EGFR, thus leading to primary resistance to EGFR blockade [ 6 ]. The role of BRAF mutations in the resistance to anti-EGFR antibodies is less defined.…”