Maxwell Lee

National Cancer Institute

Center for Cancer Research

High-dimension Data Analysis Group

March 19, 2014

Integrated Studies Of Breast, Esophageal, And Gastric Cancers Using High

Throughput Technologies And Computational Analyses

Collaborators

• Breast cancer

1. Delineating genetic alterations for tumor progression in the MCF10A series of cell lines.

2. Identifying novel oncogenes and functional studies

3. Predicting clinical outcome using DNA methylation and gene expression signatures

• Esophageal and gastric cancers

1. Microarray data analyses

2. Whole genome sequencing data analyses

Outline Of The Talk

1. Delineating genetic alterations for tumor progression in the MCF10A series of cell lines.

2. Identifying novel oncogenes and functional studies

3. Predicting clinical outcome using DNA methylation and gene expression signatures

Part 1 Breast Cancer

Modified Wellings-Jensen Model of Breast Cancer Evolution

Breast Cancer Progression Models of the MCG10A Series of Cell Lines

DNA Copy Number

Alterations in MCF10A

Series of Cells Detected,

Using Affymetrix 500K SNP

Arrays

MCY Amplification in MCF10A Series of Cells Detected by DNA Copy Number Analysis Using SNP Arrays

CDKN2A/CDKN2B Deletions in MFC10A Series of Cells Detected by DNA Copy Number Analysis Using SNP Arrays

PIK3CA Mutation in MCF10CA1h and MCF10CA1a Cells

DNA Copy

Number Alteratio

ns in Primary Breast

Tumors Detected with SNP

Arrays

Focal Amplification Detected in Primary Breast Tumors

Focal Amplification of TBL1XR1 in Breast Tumors

Frequent Over-expression of TBL1KR1 in Primary Breast Tumors Using Tissue Microarray (TMA)

TBL1CR1-shRNA Knockdown in MCF10CA1h (M3) Suppresses in Vivo Tumor Growth

• The PBCS included 2386 cases and 2502 controls • They resided in Warsaw, Poland from 2000-2003• Median follow-up: 8 years• 208 PBCS tumors with Illumina HumanRef-8 v2

Expression data• 226 PBCS tumors with Illumina Human

Methylation27 dataIn collaboration with Mark Sherman, Jonine Figueroa, Paul Meltzer, Sean

Davis, and Melissa Troester

The Polish Breast Cancer Study (PBCS)

An Algorithm for Methylation and Expression Index (MEI)

Polish dataset: K-M survival based on MEI

Polish dataset: K-M survival using MEI for ER+ and ER- samples

Validation: K-M survival using MEI for ER+ samples

1. Microarray data analyses

2. Whole genome sequencing data analyses

In collaboration with Phil Taylor, Nan Hu, Alisa Goldstein

Part 2 Esophageal And Gastric Cancers

Clustering of ESCC

and Gastric Cancers

Using the Affymetrix U133 Gene Expression

Data

Anatomy of Esophageal Cancer and Gastric Cancer

A shared susceptibility locus in PLCE1 at 10q23 for gastric

adenocarcinoma and esophageal squamous

cell carcinoma

A shared susceptibility

locus in PLCE1 at 10q23 for

gastic adenocarcinom

a and esophageal

squamous cell carcinoma

• 4 pairs of ESCC and blood • 4 pairs of gastric non-cardia cancer and

blood • 7 pairs of gastric cardia cancer and blood

Analyses of Whole Genome Sequencing (WGS) Data Generated By The

Complete Genomics Inc.

Circos Plot of WGS data from a Gastric

Cardia Cancer: Somatic SVs, CNAs,

and SNVs

Somatic Structural Variations (SVs)

in ESCC and

Gastric Cancer

MACROD2 Exon 6 was Frequently Deleted in

Gastric Cancer

Mutation Substitution Patterns 1

Mutation Substitution Patterns 2

Collaborators

Dr. Robert WiltroutDr. Glenn Merlino