Center for the Comprehensive Analysis of Cancer Somatic Copy-Number Alterations, Rearrangements, and Long-Read Sequencing Data

Abstract
We propose to continue our established Genomics Data Analysis Center for the analysis of
structural variants in cancer, including somatic copy-number alterations (SCNAs) and
rearrangements, addressing the Copy Number competency required by GDAN. We also add
capabilities to analyze long- and linked-read data, addressing a second competency. We led
SCNA analyses throughout The Cancer Genome Atlas (TCGA) and the first iteration of the
Genomics Data Analysis Network (GDAN). We also co-led the Structural Variations Working
Group of the International Cancer Genome Consortium Pan-Cancer Analysis of Whole Genomes
(PCAWG). For these efforts, we have developed a large suite of tools and deep expertise
covering all aspects of analysis of SVs in cancer. Specifically, we will accomplish five Aims: In
Aims 1 and 2, we will determine SCNA and rearrangement profiles from either short-read (whole
exome or whole genome) or long-/linked-read sequencing data, and determine germline
genotypes, parental haplotypes, and ancestry groups. The haplotype information will be used to
improve our copy-number resolution. In Aim 3, we reconstruct the tumor genome and its
evolutionary history. We evaluate sample heterogeneity including tumor purity, ploidy, and
subclonal alterations, and phase rearrangements to homologous chromosomes—determining
somatic distances between all pairs of loci. Using these data, we determine mechanisms of DNA
damage and repair and infer the events that occurred over tumor evolution. In Aim 4, we integrate
data across samples to identify SVs and genomic loci that impact tumor evolution, detect
associations with other molecular and clinical features, and evaluate potential SCNA-determined
subclasses. Moreover, we perform association and admixture analyses with the germline
genotypes detected in Aim 1. In Aim 5, we indicate ways in which we will immerse ourselves
within the GDAN and disseminate our analysis results both within the GDAN and to the wider
community. Within this, we offer secondary competencies in single-cell and circulating DNA
analysis. Our GDAC will provide a comprehensive analysis of the roles of structural variations in
cancer development and progression through treatment among GDAN samples. We will also
optimize interactions with the wider GDAN and scientific community to make maximal use of these
data.

Grant Number: 5U24CA264029-05
NIH Institute/Center: NIH
Principal Investigator: RAMEEN BEROUKHIM