Genetics and genomics of BNCT among basics and perspectives

Risultato della ricerca: Conference contribution


The Boron neutron capture therapy (BNCT) bases its therapeutic action on the selective ability to induce DNA damage of tumor cells with the aim to cause their death by apoptosis or necrosis, preserving as much as possible the normal cells. The genetic variability is an evolutionary mechanism of species survival and improvement according to which diversity in genetic configurations exists among individuals of a population, revealed also in different tolerance to insults and reparative ability of DNA damage induced by physical and chemical agents.A tumor, due to its intrinsic genomic instability, acquires the mutator phenotype and may, during the cell duplications, generate in the same individual neoplastic cells with different mutations which, by clonal selection and expansion, may change some characteristics of the tumor, for example, the aggressiveness and the over-capability to repair DNA breaks to withstand therapies DNA damage-based, such as BNCT.It follows that we must also take account of genetic / genomic parameters of every patient in order to give greater success to BNCT. It would be desirable to act on at least two fronts.1-Improve boric carriers to give less systemic toxicity (Imperio et al., 2017), greater specificity to the delivery (Wang et al., 2017) and avoid that even a few genomic insult can trigger oncogenic mutations in normal cells, especially in subjects with a risk-genotype(s).2-Associate genetic studies to determine the preventive patients genotype for some key-genes, the so called ”genome guardians” as TP53 (Seki et al., 2015), BRCA, P16, etc and add this genetic data for an evaluation of the risk / benefit of BNCT cycles. In fact, a patient with a constitutionally heterozygous genotype for some of these key-genes has certainly more risk to have greater genomic instability, BNCT-induced, in normal cells and to generate other secondary tumors. It would also be necessary, when logistically possible, to have serial data from tumor biopsies taken with cyclical time, to detect the genetic / genomic evolution of the tumor, in terms of silencing of certain genes involved in the DNA repair capability. Two recent in vitro studies, in fact, show that deficient cells for gene for DNA ligase IV (LIG4 - / -) are much more sensitive to the effects of BNCT of other proficient cells for this gene (Kondo et al., 2016) and that, on the other hand, may exist apparently healthy subjects, carriers of mutations for LIG4 but totally asymptomatic for cancer or related syndromes (Felgentreff et al., 2016). The first study opens hopeful scenarios in terms of efficacy of BNCT to cancer cells while the second raises the possibility that predict cycles of BNCT on subjects which are constitutionally and asymptomatically carriers of LIG4 mutations can expose them to develop secondary tumors in tissue districts unrelated to the primary tumor.In conclusion today it is necessary to apply also to the BNCT the principles of Pharmacogenetics and Pharmacogenomics that now are spreading in oncology therapy thanks to the massive DNA sequencing techniques. These sciences personalize treatment strategies with the help of genetics and genomics to maximize their curative effects and minimize those unpleasant.
Lingua originaleEnglish
Titolo della pubblicazione ospiteAtti delle IX Giornate Argentine del Consorzio Universitario Italiano per l'Argentina (CUIA) 2017. Workshop Terapia por Captura Neutrónica en Boro (BNCT). Neutrones para la Salud.
Numero di pagine2
Stato di pubblicazionePublished - 2017

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