Proximately 30-fold genome coverage of paired-end, short-read sequencing on the IlluminaProximately 30-fold genome coverage of

Proximately 30-fold genome coverage of paired-end, short-read sequencing on the Illumina
Proximately 30-fold genome coverage of paired-end, short-read sequencing on the Illumina platform. After mapping reads to the human reference genome, they found that each cancer genome possessed on average less than one somatic point mutation per megabase. is mutation rate is far lower than that previously seen in genomes of lung cancer and melanoma (Table 1), but similar to that reported for breast cancer and acute myelogenous leukemia [2,3,5]. is pattern supports the notion that the mechanisms underlying the genesis of MK-5172MedChemExpress Grazoprevir Prostate cancer do not include common environmental carcinogens, such as UV radiation in melanoma or tobacco exposure in lung cancer, which result in DNA point mutations. e tumors had an average of 20 non-synonymous (protein-changing) substitutions per genome. Despite this relatively low mutation frequency, two genes, SPTA1 and SPOP, were recurrently mutated. SPOP has been shown to interact with a cell-death-associated protein Daxx, and SPTA1 encodes a scaffold protein involved in determining cell morphology. e specific mechanism by which these genes influence tumorigenesis remains to be established. Additionally, genes encoding proteins involved in chromatin remodeling, antigen processing and heat shock were enriched for mutations, suggesting that these pathways may be relevant in prostate tumorigenesis.Kumar et al. Genome Medicine 2011, 3:23 http://genomemedicine.com/content/3/4/Page 2 ofTable 1. Genome alterations reported in published whole genome studiesTumortype Lung (non-small-cell) Melanoma Lung (small-cell) Breast Prostate AML Numberof tumors sequenced 1 1 1 2 7 1 Approximatenumber Averagenumberof Numberof ofpointmutations non-synonymous rearrangements pertumor mutationspertumor pertumor 50,000 30,000 20,000 6,000 4,000 1,000 302 187 94 30 20 8 43 74 58 40 100 ND Reference(s) Lee et al. (2010) [8] Pleasance et PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/27906190 al. (2010) [2] Pleasance et al. (2010) [3] Ding et al. (2010) [4]; Shah et al. (2009) [9] Berger et al. (2011) [1] Mardis et al. (2009) [5]AML, acute myelogenous leukemia; ND, not determined.A larger role for rearrangements Perhaps the most striking finding of the study by Berger et al. [1] concerned chromosomal alterations. Each cancer genome contained an average of 100 inter- and intrachromosomal rearrangements. Unsurprisingly, three tumors contained rearrangements involving TMPRSS2 and ERG (ETS-related gene) – an event previously reported to occur in approximately 50 of primary prostate carcinomas [6]. Of great interest, the investigators reported that a subset of rearrangements participated in a `closed chain’ pattern in which multiple inter- and intrachromosomal locations exchange breakpoint arms without any loss in total genetic material (Figure 1). This pattern is distinct from one in which all breaks occur as reciprocal pairs, and the authors hypothesized that these events may be due to the simultaneous disruption of many co-localized chromosomes through a mechanism depicted in Figure 1. Genomic insults such as genotoxic damage produced by oxidative stress or ionizing radiation can induce DNA breaks. Subsequent reshuffling of chromosomal material may help to drive the derangement of many genes in parallel, the importance of which is bolstered by the recent findings of `chromothripsis’ or chromosomal `shattering’ in other tumor types [7]. In contrast to the events seen in chromothripsis, the rearrangements seen in these prostate cancers affected multiple chromosomes at once. This pattern of rear.