750 Identification of Inherited Predisposition to Colonic Neoplasia Through Partial Wave Spectroscopic Analysis of the Microscopically Normal Colonic Epithelium

Abstract

While familial risk comprises ~20-30% of all colorectal cancers (CRC), in most cases the genetic etiology is not readily identifiable. Thus, counselling CRC-prone families members is not based on individized risk assessment (e.g. one size fits all approach). Our group has developed novel light scattering technologies such as partial wave spectroscopy (PWS)to quantitate nanoscale architecture. We have noted that pre-dysplastic mucosal optical signatures provided a highly sensitive means of detecting CRC risk in experimental models(Gastro 2004, CEBP 2005, Clin Cancer Res 2006). Moreover, the PWS parameter, disorder strength (Ld), was markedly elevated in the endoscopically normal rectal mucosa of patients harboring adenomas (i.e. “field effect”). We now explore whether colonic Ld could detect a genetic predisposition to CRC. Methods: Animal studies: MIN (murine model of FAP with APC gene mutation) or age-matched wildtype mice were euthanized and had intestinal brushings taken of neoplasia-free areas Human Studies 35 patients with HNPCC mutation-confirmed (hMLH-1&hMSH-2),adenoma-free or controls (age-matched but no personal/family history) had rectal brushings taken during colonoscopy. PWS analysis: Ld and standard deviation of Ld (SDLd) were calculated by investigator blinded to clinical findings Results Ld was markedly elevated in the normal mucosa of germline carriers when compared to controls (figure). This, coupled with SDLd, allowed clear descrimination between cases and controls(both murine and human model. Conclusions: Ld and SDLd from the visually normal mucosa identified APC and hMLH1/hMSH2 mutations prior to phenotype development. Thus, probing nanoscale perturbations from readily accessible mucosa (e.g. rectum) may provide a modality for determing both the carriage of these syndromic mutations and possibly allow detection of the more common lower penetrant CRC risk genes.