Pan-cancer functional evaluation of non-coding DNA mutations

Projektinformationen

PCFENCM

ID Finanzhilfevereinbarung: 703543

DOI

10.3030/703543

Das Projekt endete am 31 Mai 2019

EK-Unterschriftsdatum 31 März 2016

Startdatum 1 Januar 2017

Enddatum 31 Dezember 2019

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 251 857,80

EU-Beitrag

€ 251 857,80

Koordiniert durch

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom

Periodic Reporting for period 2 - PCFENCM (Pan-cancer functional evaluation of non-coding DNA mutations)

Berichtszeitraum: 2019-01-01 bis 2019-12-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Cancer is a genetic disease that arises from the accumulation of somatic alterations (mutations) in the DNA of the cells. Somatic mutations in human cancers come in many ways, from base substitutions to the loss or duplication of entire chromosomes. The advent of Next Generation Sequencing (NGS) over the last decade has permitted the analysis of human cancers at an unprecedented resolution.
Traditionally, studies of cancer mutations have focused on the analysis of protein-coding mutations using Sanger, targeted or exome sequencing (that is, the analysis of mutations in genes).
Although the study of mutations in genes using these sequencing modalities, especially those in cancer-related and tumor suppressors, provide a great amount of information to guide therapeutic intervention and to characterize the mutational processes operative in cancer cells, such approaches do not permit to study the non-coding genome (~98% of the genome), whose relevance for disease (not only cancer) is becoming more and more apparent.
Moreover, these technologies do not permit the study of the large structural alterations of the genome, which are a hallmark of cancer, at base resolution. This is due to the fact that structural alterations often map to the non-coding genome. The analysis of the entire genome of cancer cells using whole-genome sequencing (WGS) has been hampered by technical limitations, data analysis limitations and sequencing cost.
Today, given the decrease in sequencing costs and the increase in computational power and data storage capabilities cloud-computing capabilities, whole-genome sequencing of large collections of tumors has become feasible.
The overall goal of this project is to study genomic rearrangements in human cancers on a genome-wide basis using whole-genome sequencing.
Whole-genome analysis of tumors will enable the characterization of the large-scale mutational processes operative in human tumors and establish their role in cancer progression.
Finally, interrogating the entire genome of human tumors will also permit to assess the relevance and practical usefulness of whole-genome sequencing for biomarker discovery and cancer subtype diagnosis in clinical settings.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

In the outgoing phase of this project, we aimed to characterize the landscape of complex rearrangements in human cancers using whole-genome sequencing data from >2,600 patients
collected under the auspices of the International Cancer Genome Consortium (ICGC) and the Pan-Cancer Analysis of Whole Genomes project (PCAWG).
Complex rearrangements consist of massive alterations of chromosomes that often lead to the rearrangement of large DNA segments, which can lead to e.g. gene fusions, amplification of oncogenes or loss of tumor suppressors.
This work has been performed at the laboratory of Prof. Peter Park at Harvard Medical School and as part of the Structural Variation Working Group of PCAWG.

Among the diverse types of complex rearrangements, we focused in particular on the analysis of chromothripsis patterns.
Chromothripsis is a recently discovered mutational process characterized by massive genomic rearrangements, which are often generated in a single catastrophic event and can affect from one to multiple chromosomes.
In contrast to the traditional view of tumorigenesis as a gradual process of mutation accumulation, chromothripsis represents a mechanism for the rapid acquisition of hundreds of rearrangements in few cell divisions.
Although initial studies of human tumors using low-resolution array data estimated a frequency of chromothripsis of 3-5%, our analysis has revealed that chromothripsis is pervasive in human cancers,
with a frequency of >50% in several cancer types. We have found that about 50% of the events we detect show the canonical pattern of chromothripsis, characterized by random rejoining of DNA fragments, copy number oscillations between two states and interspersed loss of heterozygosity. However, the remaining cases show more complex rearrangement patterns, usually colocalized with other complex alterations, such as secondary massive amplification of oncogenes, indicating that multiple types of complex rearrangements often coexist in cancer cells. Analysis of cancer-related genes in tumors harboring chromothripsis events revealed that chromothripsis contributes to oncogene amplification, as well as to inactivation of tumor suppressor genes, such as mismatch-repair related genes. Overall, our findings show that chromothripsis is a major process driving genome evolution in human cancer.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Our analysis has characterized the rates and features of complex rearrangements in human cancers at base resolution, revealing that chromothripsis plays a major role in shaping the architecture of cancer genomes across diverse human cancers, with prevalence and heterogeneity much higher than previously appreciated and marked variability across cancer types.
To facilitate the access and reproducibility or our results to the entire society, and to the scientific community in particular, we have created a dedicated website for the exploration of cancer genomes. This resource permits the exploration and analysis of DNA alterations across >2,600 tumors spanning >30 cancer types using interactive plots. This resource uses the largest collection of cancer whole genomes assembled to date.
The analysis of human cancers performed by PCAWG using whole-genome sequencing will permit to evaluate the usefulness of this type of sequencing platform in clinical settings, and evaluate the most effective sequencing-based approach for patient screening and diagnosis.

Chromothripsis Explorer (see https://docs.icgc.org/pcawg/ for further details)