Estudio genético del metabolismo tumoral en pacientes con cáncer de mama y cáncer colorectal. ADN mitocondrial, PI3K y células tumorales circulantes como biomarcadores

Résumé

The identification of mutations in genes that are part of the signaling pathways involved in tumorigenesis is still a critical point in cancer research. However, some properties acquired by cancer cells cannot be explained by the occurrence of mutations in classical cancer genes. In this context the metabolic reprogramming emerges as a new field of research that analyzes the energy metabolism of tumor cells. In recent years, numerous studies have reported mitochondrial alterations associated with various cancers and its relationship with conventional cancer genes. In our study we have analyzed variants and mitochondrial haplogroups associated with familial breast cancer (BC). We found association between the control group, the variant 12308G and haplogroup U, suggesting a protective effect against familial BC. We also study the haplotypes of BRCA1 nuclear gene (associated with hereditary CB) finding no association with disease. In patients with sporadic BC and patients with metastatic colorectal cancer (mCRC) we have analyzed the mitochondrial DNA (mtDNA) copy number in tumor tissue and its relationship with clinicopathological variables without finding any association. Going further in the analysis we thought it could be interesting to study the interaction with other cellular signaling pathways involved in mitochondrial biogenesis, such as PI3K/AKT and RAS pathways. Therefore we analyzed the mutational status of KRAS and PI3KCA in these patients and its relationship to the mtDNA copy number. We found that mutations in PI3KCA are frequent events in BC and mCRC. This result, together with the relationship described between PI3KCA mutations and treatment resistance in these cancers, the analysis of mutations PI3KCA is a recommended analysis within the context of personalized therapy in cancer. Furthermore, the relationship between clinicopathologic variables and PI3KCA mutations and/or KRAS suggests that these are an early event in cancer and corroborating the hypothesis that they are driver mutations. In BC we have found association between PI3KCA mutations and high mtDNA copy number, suggesting that quantification of mtDNA could be a PI3KCA mutation marker. This result can also be considered as a starting point for investigate the relationship of alterations of the PI3K/AKT pathway and mitochondrial biogenesis in the BC metabolic reprogramming. In addition to new cancer biomarkers search, both in cancer classical signaling pathways and pathways related to energy metabolism, identify these mutations in peripheral blood is a challenge. This will allow real time monitoring of the disease course, identifying mechanisms of therapeutic resistance and better representing tumor biology. In mCRC and BC we found higher mtDNA copy number in peripheral blood of cancer patients, suggesting that it may be useful as a potential biomarker in cancer. In mCRC we developed a protocol for isolation and analysis of circulating tumor cells (CTCs). Moreover we analyzed the mutational status of KRAS, showing that the genetic characterization of CTCs is an alternative to the analysis of biomarkers through invasive procedures.