Defining the role!of microRNA-122 in the early detection of chemotherapy- induced hepatotoxicity in the neo- adjuvant treatment of advanced colorectal cancer

摘要

! Colorectal! cancer! remains! one! of! the!most! common! cancers! in! the!United! Kingdom!with!around!40,000!new!cases!being!diagnosed!each!year.!Around! 25%!of!patients!will!have!liver!metastases!at!the!time!of!presentation,!with! up! to! 50%! developing!metastases! at! some! point! in! their! life.! Advances! in! surgical! technique! and!developments! in! chemotherapy!have! increased! the! number! of! patients!with! advanced! disease! for!whom! potentially! curative! treatment! is! possible.! The! use! of! chemotherapy! in! a! neo2adjuvant! setting! has! improved! the! outcome! for! patients! with! liver! metastases! who! have! initially! irresectable! or! borderline! disease.! Chemotherapy2induced! hepatotoxicity! affects! up! to! 78%! of! patients! receiving! standard! chemotherapy!for!colorectal!cancer!and!can!lead!to!increased!morbidity!and! mortality.!Current!gold! standard! serum2based!biomarkers!of!drug2induced! hepatotoxicity! have! their! limitations! and! there! remains! a! need! for! more! sensitive!and!specific!novel!biomarkers!to!detect!early!hepatotoxicity.!! The!use!of!serum2based!microRNAs,!in!particular!microRNA2122!(miR2122),! a!hepatocyte2specific!molecule!has!been!proposed!as!a!possible!biomarker! for!chemotherapy2induced!hepatotoxicity.! ! The!work!described!in!this!thesis!assessed!the!characteristics!of!serum!miR2 122!in!a!healthy!human!population.!It!also!assessed!serum!levels!of!miR2122! in!different!diseases! including!primary! liver! cancer.! In!order! to! assess! the! role! of! serum! miR2122! in! chemotherapy2induced! hepatotoxicity,! a! pilot! study! was! carried! out! in! patients! receiving! chemotherapy! for! advanced! colorectal!cancer.! ! In! a! healthy! human! population! (n=129)! serum! levels! of! miR2122! were! measured! to! investigate! the! degree! of! variation! and! define! a! normal! reference!range!that!could!be!used!to!assess!changes!found!in!patients!with! hepatic! injury! and! disease.! In! addition! to! miR2122,! two! endogenous! (U6snRNA/let27d)! and! one! exogenous! controls! (c.lin24)! were! measured.! Inter2individual!variation!was!low!for!miR2122!(CV%!5.21)!and!also!for!all! three!controls!(CV%!