You are here
Robust Predictor of Colon Cancer Risk
Phone: (718) 430-8605
Email: harry.ostrer@einstein.yu.edu
Phone: (770) 350-8221
Email: apaul@morganandmendel.com
Address:
Type: Domestic Nonprofit Research Organization
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
* Information listed above is at the time of submission. *