Clinical application of tumor evolution analysis

Translating insights into tumor evolution to clinical practice: promises and challenges

Matthew W. Fittall and Peter Van Loo

Genome Medicine (Review Article)

Abstract—Accelerating technological advances have allowed the widespread genomic profiling of tumors. As yet, however, the vast catalogues of mutations that have been identified have made only a modest impact on clinical medicine. Massively parallel sequencing has informed our understanding of the genetic evolution and heterogeneity of cancers, allowing us to place these mutational catalogues into a meaningful context. Here, we review the methods used to measure tumor evolution and heterogeneity, and the potential and challenges for translating the insights gained to achieve clinical impact for cancer therapy, monitoring, early detection, risk stratification, and prevention. We discuss how tumor evolution can guide cancer therapy by targeting clonal and subclonal mutations both individually and in combination…

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BRCA Challenge creates database for fighting cancer

BRCA Exchange aggregates data on thousands of BRCA variants to inform understanding of cancer risk

A global resource that includes data on thousands of inherited variants in the BRCA1 and BRCA2 genes is available to the public. The BRCA Exchange was created through the BRCA Challenge, a long-term demonstration project initiated by the Global Alliance for Genomics and Health (GA4GH) to enhance sharing of BRCA1 andBRCA2 data. The resource, available through a website and a new smartphone appExit Disclaimer, allows clinicians to review expert classifications of variants in these major cancer predisposition genes as part of their individual assessment of complex questions related to cancer prevention, screening, and intervention for high-risk patients. 

The five-year BRCA Challenge project was funded in part by the National Cancer Institute (NCI), part of the National Institutes of Health, and through the Cancer Moonshot℠. A paper detailing the development of the BRCA Exchange was published January 8, 2019, in PLOS Genetics. READ MORE …

Immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion

Neoantigen-directed immune escape in lung cancer evolution

Rachel Rosenthal, Elizabeth Larose Cadieux, Roberto Salgado, Maise Al Bakir, David A. Moore, Crispin T. Hiley, Tom Lund, Miljana Tanić, James L. Reading, Kroopa Joshi, Jake Y. Henry, Ehsan Ghorani, Gareth A. Wilson, Nicolai J. Birkbak, Mariam Jamal-Hanjani, Selvaraju Veeriah, Zoltan Szallasi, Sherene Loi, Matthew D. Hellmann, Andrew Feber, Benny Chain, Javier Herrero, Sergio A. Quezada, Jonas Demeulemeester, Peter Van Loo, Stephan Beck, Nicholas McGranahan, Charles Swanton & The TRACERx consortium

Nature (Research Article)

Abstract

The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival.

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Exome sequencing reveals molecular features of the pediatric variants of follicular lymphoma

Molecular Characterization of Pediatric Follicular Lymphoma

“Pediatric follicular lymphomas involve interactions in MAPK and G-protein protein receptor signaling pathways, according to results of a new study. This study, published online in Haematologica, identified a number of novel mutations and signaling pathways associated with pediatric follicular lymphomas.

Classic follicular lymphoma, an indolent B-cell lymphoma, is very rare in children, whereas pediatric-type nodal follicular lymphoma (PTNFL) and primary follicular lymphoma of the testis (PFLT) occur more frequently in this population compared with adults. While the molecular landscape of classic follicular lymphoma has been more thoroughly studied, comparatively little is known about the molecular features of the pediatric variants of follicular lymphoma.”

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Pediatric cancer mutation review

The genomic landscape of pediatric cancers: Implications for diagnosis and treatment

E. Alejandro Sweet-Cordero1 and Jaclyn A. Biegel

Science (Review Artice)

Abstract-The past decade has witnessed a major increase in our understanding of the genetic underpinnings of childhood cancer. Genomic sequencing studies have highlighted key differences between pediatric and adult cancers. Whereas many adult cancers are characterized by a high number of somatic mutations, pediatric cancers typically have few somatic mutations but a higher prevalence of germline alterations in cancer predisposition genes. Also noteworthy is the remarkable heterogeneity in the types of genetic alterations that likely drive the growth of pediatric cancers, including copy number alterations, gene fusions, enhancer hijacking events, and chromoplexy. Because most studies have genetically profiled pediatric cancers only at diagnosis, the mechanisms underlying tumor progression, therapy resistance, and metastasis remain poorly understood. We discuss evidence that points to a need for more integrative approaches aimed at identifying driver events in pediatric cancers at both diagnosis and relapse. We also provide an overview of key aspects of germline predisposition for cancer in this age group.

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Cancers are tissue-specific, truly important perspective

Tissue-specificity in cancer: The rule, not the exception

Kevin M. Haigis, Karen Cichowski, and Stephen J. Elledge

Science (article)

“Abstract—We are in the midst of a renaissance in cancer genetics. Over the past several decades, candidate-based targeted sequencing efforts provided a steady stream of information on the genetic drivers for certain cancer types. However, with recent technological advances in DNA sequencing, this stream has become a torrent of unbiased genetic information revealing the frequencies and patterns of point mutations and copy number variations (CNVs) across the entire spectrum of cancers. One of the most important observations from this work is that genetic alterations in bona fide cancer drivers (those genes that, when mutated, promote tumorigenesis) show a remarkable spectrum of tissue specificity”

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Gene expression used for leukemia diagnostics

Gene expression patterns identify high-risk chronic lymphocytic leukemia

A 290-gene expression signature and IGHV mutation status stratified patients with chronic lymphocytic leukemia to identify those with high-risk disease who might benefit from prompt initiation of therapy, according to a study published in Frontiers in Oncology.

Although CLL treatment is typically delayed until disease progression, it is uncertain whether patients would benefit from treatment immediately following diagnosis, when they have a smaller tumor mass and are in better physical condition.

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Single-cell sequencing reveals important cancer mutation signatures (original article)

Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.

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Mutation bursts associated with cancer -- a very good summary

Researchers have created a huge resource for investigating the biological mechanisms that cause cancer. The scientists from the Wellcome Sanger Institute and their collaborators identified which patterns of DNA damage—mutational fingerprints that represent the origins of cancer—were present in over a thousand human cancer cell lines. They also revealed that a major mutation pattern found in human cancer, previously linked to a virus-fighting immune response, occurred in bursts in cancer cell lines with long periods of silence in between, but the cause of these mutational bursts remains mysterious.

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Original article here …

Insights into how prostate cancers become resistant, and new potential targets (original article)

Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer

Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.

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Cancer mutation characterization with machine learning (original article -- very cool)

Integrated structural variation and point mutation signatures in cancer genomes using correlated topic models

Loss of DNA repair mechanisms can leave specific mutation signatures in the genomes of cancer cells. To identify cancers with broken DNA-repair processes, accurate methods are needed for detecting mutation signatures and, in particular, their activities or probabilities within individual cancers. In this paper, we introduce a class of statistical modeling methods used for natural language processing, known as “topic models”, that outperform standard methods for signature analysis. We show that topic models that incorporate signature probability correlations across cancers perform best, while jointly analyzing multiple mutation types improves robustness to low mutation counts.

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More to consider with Cancer Genetics, Inc.

What’s at Stake for Cancer Genetics, Inc. (NasdaqCM:CGIX)? Cash Flow Change of -1.00000 Tells a Story

Cancer Genetics, Inc. (NasdaqCM:CGIX) has seen year over year cash flow change of -1.00000.  This is calculated as the one year percentage growth of the firm’s cash flow from operations from their publicly filed statement of cash flows.  Cash reserves are an important element for an investor to consider when analyzing a stock.  A continued reduction in cash flow could spell trouble for a firm while on the other hand solid continued cash flow growth should translate into stock growth.

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