Resolving genetic heterogeneity in cancer

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

<p class="first" id="d11607024e131">To a large extent, cancer conforms to evolutionary rules defined by the rates at which clones mutate, adapt and grow. Next-generation sequencing has provided a snapshot of the genetic landscape of most cancer types, and cancer genomics approaches are driving new insights into cancer evolutionary patterns in time and space. In contrast to species evolution, cancer is a particular case owing to the vast size of tumour cell populations, chromosomal instability and its potential for phenotypic plasticity. Nevertheless, an evolutionary framework is a powerful aid to understand cancer progression and therapy failure. Indeed, such a framework could be applied to predict individual tumour behaviour and support treatment strategies. </p>

Related collections

Most cited references 155

Record: found
Abstract: found
Article: not found

Fundamental Mechanisms of Immune Checkpoint Blockade Therapy

Spencer Wei, James P Allison, Colm Duffy (2018)

Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge.Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069-86. ©2018 AACR.

0 comments Cited 1086 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Immune checkpoint blockade: a common denominator approach to cancer therapy.

Suzanne Topalian, Charles Drake, Drew M Pardoll (2015)

The immune system recognizes and is poised to eliminate cancer but is held in check by inhibitory receptors and ligands. These immune checkpoint pathways, which normally maintain self-tolerance and limit collateral tissue damage during anti-microbial immune responses, can be co-opted by cancer to evade immune destruction. Drugs interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, anti-PD-L1, and others in early development, can unleash anti-tumor immunity and mediate durable cancer regressions. The complex biology of immune checkpoint pathways still contains many mysteries, and the full activity spectrum of checkpoint-blocking drugs, used alone or in combination, is currently the subject of intense study. Copyright © 2015 Elsevier Inc. All rights reserved.

0 comments Cited 1064 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Mutational heterogeneity in cancer and the search for new cancer genes

Michael S Lawrence, Petar Stojanov, Paz Polak … (2013)

Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention.