大家好,現在是Zero叔叔的P53期刊導讀時間!


今天的期刊是關於P53基因突變與疾病的關係~~

題目: The importance of p53 pathway genetics in inherited and somatic cancer genomes

期刊/卷數: NATURE REVIEWS | CANCER/VOLUME 16 | APRIL 2016 | 251

這篇期刊應用生物資訊的資料庫進行分析及整理,
藉此來歸納TP53突變與疾病的相關性(字真的超多,暈)
但內容還是非常受用的,我在下面挑了幾個段落整理給各位參考

最後附上((看起來很厲害的圖~跟原文供大家參考~


導讀內容:

目前最熟知的癌症訊息傳遞路徑就是p53 tumor suppressor pathway (p53腫瘤抑制路徑),有許多研究也已證明p53 stress response pathway (p53壓力反應途徑; 意思是當細胞內產生不利生存的壓力時所產生的反應機制)在癌症的發生率及存活率扮演著關鍵的角色。例如,在非常罕見的Li–Fraumeni syndrome (LFS) 的遺傳性疾病 (TP53基因突變),於患者之年齡大於或等於70歲之後 ,癌症的發生率為100%,且癌症可能會發生在全身上下的組織器官中,包括骨頭,結締組織、乳腺及腦等等,而某些與p53相關且具有功能性的SNPs也已證實容易增加某些類型的癌症的易感性 (Susceptibility)。此外,TP53基因體突變的發生率佔所有癌症基因組 (Cancer genomes)的50%,因此,在各種癌症中,最常發現TP53的突變。更重要的是,迄今p53 pathway (p53訊息傳遞路徑)在癌症基因中是最經常鑑別的訊息傳導網絡。實際上,p53訊息傳遞路徑中,有許多基因也會產生體突變,而且可以直接影響癌症的易感性,所以,p53 pathway的基因突變也可以開發做為臨床上治療的關鍵生物標記,將患者依照突變的基因分類來進行治療,以提高治療的效果。

 

在p53 pathway中共有67個基因,其中有15基因左右都容易發生突變,大約是22.38% (15/67)會發生基因突變的情形,而人體已知基因有24,553個,只有約2.01%會發生突變,與p53 pathway會發生突變的機率差了將近11.15倍 (22.38/2.01),為了評估p53 pathway的基因突變與癌症的重要相關性,所以檢測p53 pathway在體內中的220條訊息傳遞路徑中的關聯性,分析結果發現p53 pathway會影響66條訊息傳遞路徑,大約佔了30% (66/200),因此,p53 pathway為人體前5%的重要訊息傳遞路徑之一,也與癌症發生率及生存率有著高度的相關性。

Somatic, causal mutations occur in a high proportion of p53 pathway genes.tif

 

 

原文:

Identifying which cancer- associated pathways frequently carry SNPs associated with differential cancer susceptibility could accelerate our biological understanding of the influence of the variants on cancer and the potential clinical utility of SNP biomarkers. One of the best studied and important cancer signaling pathways is the p53 tumor suppressor pathway. Decades of intensive research in mice and humans have shown that human genetic variants in the p53 stress response pathway can have key roles in the incidence and survival of many cancers. For example, among individuals with the very rare Li–Fraumeni syndrome (LFS) — who carry inherited, heterozygous mutations in TP53 (which encodes p53) — the penetrance for cancer onset is 100% by the age of 70 years, with the cancers occurring in numerous tissues, including bone, connective tissues, breast and brain1. Indeed, candidate SNP studies have clearly demonstrated that p53 signaling can be affected by functional SNPs that in some cases result in differential cancer susceptibility. Moreover, very similar somatic mutations in the TP53 gene are found in more than 50% of all cancer genomes, making it the most frequently mutated gene that is causally implicated in cancer and the gene mutated in the broadest range of cancer types, including epithelial, mesenchymal and hematological cancers. Importantly, recent network analyses that have taken advantage of advances in high-throughput exome sequencing of cancer genomes have shown that the p53 pathway represents the largest, most frequently identified network of genes carrying mutations in the broadest spectrum of cancers identified thus far. In fact, common somatic mutations in many genes of the pathway are known to directly affect susceptibility to a broad range of cancer types and are being developed as crucial biomarkers to inform therapy in some patient-stratification strategies in the clinic. Cancer variants in p53 pathway genes.

 

Somatic, causal mutations.

Cancer driver genes, such as TP53, when mutated, can promote tumorigenesis and have been identified through studies of inherited cancer predisposition syndromes, cancer genome sequencing and experimental models of cancer. Although estimates regarding the exact number of these genes vary, one well used curated list is the COSMIC Cancer Gene Census, which uses sequencing data to identify genes for which the number and pattern of mutations are highly unlikely to be attributable to chance. The current list consists of 493 RefSeq autosomal genes that harbor somatic cancer-promoting mutations. Of the 67 autosomal genes attributed to the p53 pathway (according to the Kyoto Encyclopedia of Genes and Genomes (KEGG)), 15 have been denoted as harboring somatic, causal mutations in at least one cancer type. This group includes the well-studied oncogenes and tumor suppressor genes ataxia telangiectasia mutated (ATM), MDM2, cyclin- dependent kinase inhibitor 2A (CDKN2A; which encodes INK4A and ARF), FAS and MDM4 (FIG. 1a). Thus, 22.38% of genes of the p53 pathway contain known causal mutations; a significant 11.15-fold enrichment over the 2.01% found in all 24,553 annotated autosomal genes (FIG. 1b; RefSeq, P = 3.74e–12, adjusted for multiple hypothesis testing P = 8.22e–10). In order to assess further the importance of the 11.15-fold enrichment of cancer-associated causal mutations in genes of the p53 pathway, we compared it with potential fold enrichments of causally mutated genes in all well-annotated pathways in the genome. To do this, we determined potential enrichments in all 220 signaling pathways annotated by KEGG in the categories of metabolism, genetic information processing, environ mental information processing, cellular processes and organismal systems. We found that 66 of the 220 cellular signaling pathways (30%), including the p53 pathway, demonstrated significant enrichment of causally mutated genes after correction for multiple hypothesis testing (FIG. 1c; see Supplementary information S1 (methods) and Supplementary information S2 (table) for details). Thus, the enrichment noted in the p53 pathway places it among the top 5% of all well-annotated pathways of the genome.

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