Morgan and Mendel Genomics, Inc. — Department of Health and Human Services STTR Phase I: 102

Description

Summary At leastpeople in the United States are at high risk for Lynch syndromebased on inheritance of a genetic mutation in the mismatch repairMMRor double strand breakDSBrepair pathwayMore than half of them are unaware of their riskbecause their family history is uninformative or unknownGenetic testing is important for identifying mutations in this pathwaybut in a large number of cases no mutation or a variant of uncertain significance will be identifiedleading to ambiguousunsatisfactory resultsAs more people are seeking testing to identify their risk of Lynch syndromeaccurate alternatives to sequencing are needed to predict the molecular phenotypic effects of mutations in genes in colon cancer and endometrial cancerpredisposing pathwaysRisk classification scores based on flow variant assaysFVAsare a new technology that can accurately identify people with heterozygous germline mutations in these pathwaysIn response to treatment with chemical agentsFVAs identify decreased nuclear localization of repair proteins and decreased phosphorylation of damage sensing proteins in cells that bear mutations in these genesFVAs are rapidinexpensive and highly reproducible and can be performed on circulating and cultured human blood cellsthus lending themselves to becoming a Next Generationnon sequencingstandalone test for assessing cancer risksThe goal of this STTR project is to develop asimplerapid and inexpensive clinical test that will accurately identify those at high risk for Lynch syndromePhase I hypothesisThe standalone FVA test using whole blood samples will identify those at high risk withaccuracySpecific aimAchieve MMR pathway risk classification score forof subjects with at leastaccuracy onsubjects from well characterized risk groupsSpecific AimAchieve risk classification score results for all subjects from Aimwith comparable accuracy using an automated gating and analysis protocol and a newly created commercial kitHaving demonstrated analytical validity in Phase IMMG will demonstrate clinical utility in Phase II by calculating and validatingyear hazard ratios for colon cancer by age decade forpeople followed by up toyears by the NCI s Colon Cancer Family RegistryThis product will be sold to clinical laboratories in collaboration with a designated good manufacturing practices facility commercial partnerinitially as a laboratory developed test and then as an FDA approved testSeveral factors will drive this commercialization into the $ B market cancer risk assessment marketlow entry and performance costsgreater accuracy than sequencingandapplication to understanding risks for endometrialgastricovariansmall bowelpancreaticurinary tractkidneybile duct and brain cancersThe creation of simplifiedcommercial FVA kits will change risk assessment for Lynch syndrome Project narrative Robust predictive risk scores based on FVA analysis to identify theAmericans at risk for Lynch syndrome would be a Next Generation high throughput improvement over the current standard of cancer gene panel sequencingThe increased sensitivity and specificitylower cost and shortened time to reporting would make testing those even without a significant family history practicalEven when a mutation could not be found by sequencingindividuals with defects in the MMR pathway would be faithfully identifiedDirect testing of the molecular phenotypes associated with genetic defectsinitiation of repair of mismatch repair defects in response to treatment with chemical agents will circumvent the need to annotate the very frequent variants of uncertainly significance in the many genes in this pathwayThe robust assays and risk scores are meant to benefit health care providers and their at risk patientsbut these tools would be of considerable use for preclinical and clinical researchers who may want to investigate the effects of exposures on increasing the risks for those with MMR deficiencies