Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-09-28
2001-06-19
Zitomer, Stephanie (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200, C536S023100
Reexamination Certificate
active
06248524
ABSTRACT:
BACKGROUND
This invention relates to the field of genetic markers for disease.
In most cases the complex genetic contribution to cancer and other disease susceptibility remains to be elucidated. Efforts have focused on identification of potentially pathogenetic allelic variants of individual candidate loci. To increase the probability of identifying such variants, this invention focuses on interaction of candidate loci. According to this invention, it is a candidate locus interaction, rather than simply a candidate gene inquiry, that serves as the principal means of discovery.
SUMMARY OF THE INVENTION
Our invention is a method for rapidly identifying pathogenetic allele variants present in the population-at-large that predispose to a disease or that are relevant to diagnosis, prognosis or treatment of a disease such as cancer. Our method initially relies on allele-sharing stratification of affected sib pairs to identify subgroups of cases bearing potentially pathogenetic alleles of that candidate locus. To increase the probability of identifying such variants, we further stratify the sib pairs by allele-sharing status at a second candidate locus that may demonstrate an epistatic interaction with the first candidate locus. If desired, the sib pairs may be further stratified by allele-sharing status at one or more additional candidate loci that may demonstrate an epistatic interaction with one or more of the other candidate loci. We refer to our method as disease association by locus stratification.
Using this method, a pathogenetic variant of the ATM locus which is associated with a 4.5 fold relative risk of breast cancer has been identified. This variant has a G for C substitution in exon 24 at the nucleotide which is numbered 3349 in Genbank accession no. U33841. (This is nucleotide number 3060 if numbering begins at the first nucleotide of the atg start codon, which is numbered 190 in Genbank accession no. U33841.) We refer to this pathogenetic variant as the ATM exon 24 variant.
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Flanagan Steven D.
Krontiris Theodore G.
Larson Garry P.
City of Hope
Rothwell Figg Ernst & Manbeck
Wilder Cynthia B.
Zitomer Stephanie
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