Pan-cancer functional evaluation of non-coding DNA mutations

Informazioni relative al progetto

PCFENCM

ID dell’accordo di sovvenzione: 703543

DOI

10.3030/703543

Progetto concluso il 31 Maggio 2019

Data della firma CE 31 Marzo 2016

Data di avvio 1 Gennaio 2017

Data di completamento 31 Dicembre 2019

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 251 857,80

Contributo UE

€ 251 857,80

Coordinato da

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)

Periodo di rendicontazione: 2019-01-01 al 2019-12-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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)