bims-tumhet 2022-06-26 papers

Issue of 2022–06–26
four papers selected by
Sergio Marchini, Humanitas Research

Methods Mol Biol. 2022 ;2493 89-105

FACETS: Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing.

Arshi Arora, Ronglai Shen, Venkatraman E Seshan.

Clinical sequencing studies routinely involve molecular profiling of patients for mutations and copy number alterations. However, detection of "actionable" aberrations to guide treatment decisions require accurate, tumor purity-, ploidy-, and clonal heterogeneity-adjusted integer copy number calls. In this chapter, we describe the FACETS algorithm, an Allele-Specific Copy Number (ASCN) analysis tool with a broad application to whole-genome, whole-exome, as well as targeted panel sequencing platforms to annotate the genome for the detection of copy number alterations including homozygous/heterozygous deletions, copy-neutral loss-of-heterozygosity (LOH) events, allele-specific gains/amplifications, and cellular fraction profiles.We will describe some methodological details on joint segmentation of total and allele-specific copy number, on the estimation of integer copy number calls adjusting for tumor purity, ploidy, and intratumor heterogeneity, along with comprehensive output and integrated visualization. We also provide a tutorial on the installation, application, and tips to run and interpret FACETS.

Keywords: Allele-specific copy number analysis; High-throughput DNA sequencing; Integer copy number; Ploidy; Purity

DOI: https://doi.org/10.1007/978-1-0716-2293-3_7

Sci Rep. 2022 Jun 21. 12(1): 10447

Integrating chromatin accessibility states in the design of targeted sequencing panels for liquid biopsy.

Pegah Taklifi, Fahimeh Palizban, Mahya Mehrmohamadi.

Dying tumor cells shed DNA fragments into the circulation that are known as circulating tumor DNA (ctDNA). Liquid biopsy tests aim to detect cancer using known markers, including genetic alterations and epigenetic profiles of ctDNA. Despite various advantages, the major limitation remains the low fraction of tumor-originating DNA fragments in a high background of normal blood-cell originating fragments in the cell-free DNA (cfDNA) pool in plasma. Deep targeted sequencing of cfDNA allows for enrichment of fragments in known cancer marker-associated regions of the genome, thus increasing the chances of detecting the low fraction variant harboring fragments. Most targeted sequencing panels are designed to include known recurrent mutations or methylation markers of cancer. Here, we propose the integration of cancer-specific chromatin accessibility states into panel designs for liquid biopsy. Using machine learning approaches, we first identify accessible and inaccessible chromatin regions specific to each major human cancer type. We then introduce a score that quantifies local chromatin accessibility in tumor relative to blood cells and show that this metric can be useful for prioritizing marker regions with higher chances of being detected in cfDNA for inclusion in future panel designs.

DOI: https://doi.org/10.1038/s41598-022-14675-z

Cells. 2022 Jun 17. pii: 1958. [Epub ahead of print]11(12):

Telomere Maintenance and the cGAS-STING Pathway in Cancer.

Hiroshi Ebata, Tze Mun Loo, Akiko Takahashi.

Cancer cells exhibit the unique characteristics of high proliferation and aberrant DNA damage response, which prevents cancer therapy from effectively eliminating them. The machinery required for telomere maintenance, such as telomerase and the alternative lengthening of telomeres (ALT), enables cancer cells to proliferate indefinitely. In addition, the molecules in this system are involved in noncanonical pro-tumorigenic functions. Of these, the function of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which contains telomere-related molecules, is a well-known contributor to the tumor microenvironment (TME). This review summarizes the current knowledge of the role of telomerase and ALT in cancer regulation, with emphasis on their noncanonical roles beyond telomere maintenance. The components of the cGAS-STING pathway are summarized with respect to intercell communication in the TME. Elucidating the underlying functional connection between telomere-related molecules and TME regulation is important for the development of cancer therapeutics that target cancer-specific pathways in different contexts. Finally, strategies for designing new cancer therapies that target cancer cells and the TME are discussed.

Keywords: ALT; DNA damage; cGAS-STING; cancer; cellular senescence; telomere

DOI: https://doi.org/10.3390/cells11121958

Cancer Res. 2022 Jun 22. pii: canres.CAN-22-0562-E.2022. [Epub ahead of print]

Treatment represents a key driver of metastatic cancer evolution.

Ditte Sigaard Christensen, Johanne Ahrenfeldt, Mateo Sokač, Judit Kisistók, Martin K Thomsen, Lasse Maretty, Nicholas McGranahan, Nicolai J Birkbak.

Metastasis is the main cause of cancer death, yet the evolutionary processes behind it remain largely unknown. Here, through analysis of large panel-based genomic datasets from the AACR GENIE project, including 40,979 primary and metastatic tumors across 25 distinct cancer types, we explore how the evolutionary pressure of cancer metastasis shapes the selection of genomic drivers of cancer. The most commonly affected genes were TP53, MYC, and CDKN2A, with no specific pattern associated with metastatic disease. This suggests that, on a driver mutation level, the selective pressure operating in primary and metastatic tumors is similar. The most highly enriched individual driver mutations in metastatic tumors were mutations known to drive resistance to hormone therapies in breast and prostate cancer (ESR1 and AR), anti-EGFR therapy in non-small cell lung cancer (EGFR T790M), and imatinib in gastrointestinal cancer (KIT V654A). Specific mutational signatures were also associated with treatment in three cancer types, supporting clonal selection following anti-cancer therapy. Overall, this implies that initial acquisition of driver mutations is predominantly shaped by the tissue of origin, where specific mutations define the developing primary tumor and drive growth, immune escape, and tolerance to chromosomal instability. However, acquisition of driver mutations that contribute to metastatic disease is less specific, with the main genomic drivers of metastatic cancer evolution associating with resistance to therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0562