STABLE GENE TARGETS IN BREAST CANCER AND USE THEREOF FOR OPTIMIZING THERAPY

摘要

A method for determining genes in breast cancer that are stable in copy number, expression and sequence in tumors from nearly all patients. Certain stable genes are targets of standard chemotherapy. The effectiveness of therapies that act upon these targets depends on maintaining the stability and integrity of these genes in tumors. Mutations in these targets result in poor response to therapies that target these gene products. In the instant invention, ordinarily stable gene targets are characterized as either normal or mutant for the purpose of determining whether to include or exclude particular drugs as potential treatments.

主权项

1. A method for determining genes having stable copy number in the genomes of a preponderance of breast tumor specimens, each obtained from different cancer patients, comprising the steps of:
(a) determining a first set of genes having euploid (or stable) copy number in a set of abnormal tumor genomes, each genome containing distinct changes in chromosomal copy number by:
(i) determining the copy numbers of each of the genome-coordinate defined sequences,(ii) grouping all adjacent genomic intervals that exhibit the same copy number in a tumor to form a larger contiguous interval,(iii) defining contiguous genomic intervals of aneuploid copy number in the set of all tumors as those which are segmentally aneuploid the tumor genomes of at least 10% of the patients,(iv) determining the set of unstable genes as the set of genes contained within contiguous genomic intervals of segmentally aneuploid copy number and the genes which partially overlap aneuploid copy number regions;(iv) determining the coordinates of the genome sequence regions between segmentally aneuploid genomic intervals as having stable copy number regions by complementing the genomic coordinates of contiguous chromosomal intervals of aneuploidy copy number, and(v) convolving the genomic coordinates of each of the known protein coding genes in the genome with the coordinates of the stable copy number regions, and (b) determining a second gene set comprising genes having stable expression levels by
(i) determining which genes in each breast tumor genome are expressed in breast tissue ductal and lobular carcinomas at statistically different levels at a significance of p≦0.05 from their corresponding expression levels in adjacent ductal and lobular tissues from normal breast of the same tumors, and(ii) selecting the genes that are not differentially expressed in >90% of tumors as a set of stably expressed genes in all of the tumor genomes,wherein steps (a) and (b) can be performed in either order and,
(c) combining the first gene set with the second gene set using a joining operation that forms a set of dually stable genes, defined as having both euploid copy number and stable expression in a set of tumors, wherein the genes that are dually stable can be independently confirmed as stable based on repeating the same copy number, expression, and nucleic acid sequence analysis in an independent set of different tumors and matched normal tissues originating from the same type of tumor, and selecting the genes as dually stable gene sets that are determined to be dually stable in both the initial set and confirming tumor gene analyses.