# Presentation: 831366

## The NCI-NHGRI Cancer Genome Atlas (TCGA) Pilot Project

- Genomic Aberrations in GBM from the TCGA pilot projectSubclasses and Targets

_**Copy Number Platforms**_
**Broad – Affymetrix SNP 6.0 **
**Harvard – Agilent Whole Genome**
**MSKCC – Agilent Whole Genome, Custom High-density**
**Stanford – Illumina Infinium SNP**

## Example tumor profile, Agilent, MSKCC

- Example tumor profile, Agilent, MSKCC

- Example profile, focal CNA events marked by circles

## EGFR amplicon

**EGFR**

## High concordance between centers

**Harvard**

**MSKCC**

## Copy number profiling

- 165 tumors profiled to date

## Subclass Discovery byNon-negative Matrix Factorization (NMF)

- Subclass Discovery byNon-negative Matrix Factorization (NMF)

- 3 kinds of genomic profile found
- (NMF cluster medians)

**2-way**

**3-way**

**4-way**

**5-way**

## Subclass Discovery by NMF3-way grouping

- 3-way grouping

**+19,+20**

**-13, -14**

**+7         -9p   -10**

- Subclass Discovery by NMF3-way grouping

## Clustering by transcriptome

**+19,+20**

**-13, -14**

- Copy number profiles clustered by matching transcriptome data (Neil Hayes & Katherine Hoadley, UNC)
- Possible overlap of -13/14 and +19/20 subclasses

## 3-way NMF groupsshow no survival difference

- 3-way grouping

- 3-way NMF groupsshow no survival difference

- Survival (weeks)

**1**
**        ****2**
**                     ****3**

## Survival as a function of regional gain and loss

- Survival as a function of regional gain and loss

**Gain**

**Loss**

**better survival****  / ****poorer survival**

## Survival-associated gain/loss:correlation with reported regions

**Overexpressed Skp2 within 5p amplification detected by array-based comparative genomic hybridization is associated with poor prognosis of glioblastomas.**
**Saigusa et al.;  Cancer Sci., 2005 **

**+5p**

- Survival-associated gain/loss:correlation with reported regions

## Regions of Interest for CNA

**Derive ROI from copy number profiles **
**by 3 essential features:**
**       ****1. Amplitude**
**       ****2. Recurrence**
**       ****3. Focality**

## Focal amplifications

- _226 genes_,
- enriched for “oncogene” CANDID score, p<0.05
- Top 20 include: EGFR, PDGFRA, KIT, MET, AKT1, AKT3,
- 	PIK3C2B, MDM2, MDM4, CDK4, GLI2
- Others:  GFI1B, PLAG1, RALGDS

**MDM4**

**PDGFRA,**
**KIT**

**EGFR**

**MET**

**CDK4**

**MDM2**

**GLI2**

**+**

**+**

**+**

**+**

**+**

**+**

**+**

**AKT1**

**+**

**+**

**Notes:**
GROWTH FACTOR-INDEPENDENT 1B; GFI1B: proto-oncogene; STAT5 signaling; inhibits p21
PLEOMORPHIC ADENOMA GENE 1; PLAG1 
RAL GUANINE NUCLEOTIDE DISSOCIATION STIMULATOR; RALGDS : HRas signaling

## Focal deletions

- _219 genes_,
- enriched for “tumor suppressor” CANDID score, p<0.013
- Top 20 include: PTEN, CDKN2A/B/C, NF1, NF2, RB1, PTPRD
- Others: PTPRD, WWOX, APAF1, FBXW7, BMPR2

**PTEN**

**CDKN2A**
**CDKN2B**

**CDKN2C**

**+**

**+**

**+**

**+**

**+**

**NF2**

**+**

**NF1**

**+**

**RB1**

**+**

**PTPRD**

**+**

**Notes:**
GROWTH FACTOR-INDEPENDENT 1B; GFI1B: proto-oncogene; STAT5 signaling; inhibits p21
PLEOMORPHIC ADENOMA GENE 1; PLAG1 
RAL GUANINE NUCLEOTIDE DISSOCIATION STIMULATOR; RALGDS : HRas signaling

## High-density custom array forintragenic deletions, translocations

- High-density custom array forintragenic deletions, translocations

## High-density custom array forintragenic deletions, translocations

_**Custom array:  580bp**_**  **resolution vs**  **_**whole genome 10,000bp**_

- High-density custom array forintragenic deletions, translocations

## Novel TK fusion protein in GBM:  KDR-PDGFRA

**Notes:**
Jak3=Janus Kinase 3; SPTBN4-Jak3
PTK2/FAK= focal adhesion kinase

## The KP fusion kinase is constitutively phosphorylated and transforming

_***Tatsuya Ozawa***_