SWITCHdna

SWITCHdna identifies subtype-associated copy number aberrations (CNA) in breast cancer by analyzing intensity data from copy number platforms to detect and significance-test transition points within defined genomic segments.

Key Features:

• Subtype-Specific CNA Identification: Classifies tumors by gene expression subtypes and identifies subtype-associated CNAs using a training set of 180 tumors with validation on 359 tumors.
• Transition-Point Detection: Detects transition points within defined genomic segments from intensity data generated by copy number platforms.
• Significance Testing: Performs statistical significance testing of detected CNAs and transition points.
• Statistical Analysis Methods: Implements Fisher's exact tests, Chi-square approximations, and Wilcoxon rank-sum tests to evaluate differences in CNAs across subtypes.
• Functional Significance Assessment: Integrates RNA interference (RNAi) knockdown experiments with drug sensitivity assays and DNA repair foci formation studies to assess functional consequences of CNAs.

Scientific Applications:

• Breast Cancer Subtype Characterization: Identifies subtype-specific CNAs that define distinct genomic profiles, including losses in Basal-like tumors affecting genes such as RB1 and BRCA1.
• Genomic Instability Insights: Highlights CNAs associated with increased genomic instability, for example loss of 5q11-35 encompassing RAD17, RAD50, and RAP80, which correlates with genomic instability and poorer survival.
• Therapeutic Implications: Supports therapeutic hypotheses targeting DNA repair pathways, noting increased sensitivity to PARP inhibitors and carboplatin in cell lines with knockdown of RAD17 or RAD17/RAD50.

Methodology:

Analyzes intensity data from copy number platforms, detects transition points within defined genomic segments, conducts significance testing, classifies tumors by gene expression subtype with a 180-sample training set and 359-sample validation set, and applies Fisher's exact tests, Chi-square approximations, and Wilcoxon rank-sum tests.