Complex rearrangement detection in cancer genomes using long reads

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Structural variation is a key mutational process that contributes to cancer initiation and progression. In contrast to SNVs and small indels, SVs vary greatly in size and complexity and are known to be difficult to profile using the current state-of-the-art short-read sequencing. Here we will apply the methods developed in sub-project 1 to study SV prevalence, evolution and effects in several different tumor types. In Aim 2.1, in collaboration with Dr. Michael Dean (DCEG), we will study the prevalence and mechanisms of Breakage-Fusion-Bridge and chromothripsis events in cervical cancer. Our preliminary data suggests that in some cancers genomic instability is caused by HPV integrations, which may also form ecDNA amplicons. In Aim 2.2, we study the revolve of structural variants in tumor evolution. In collaboration with Drs. Cenk Sahinalp and Chi-Ping Day (CCR) study mouse melanoma models, in which multiple sublines propagate from the original tumor (multi-omics data for each sublime is available). Further, in collaboration with Dr. Paul Meltzer (CCR) will apply multi-site nanopore sequencing of dog osteosarcoma to gain insights into complex karyotype changes associated with this type of cancer. In Aim 2.3, we collaborate with Dr. Midhat Farooqi (U Missouri) to explore clinical applications of long-read structural variant analysis. In particular, we perform PacBio HiFi sequencing of various pediatric tumors, with the goal to develop a long-read based genomic diagnostics workflow.