大家好,還是我zero叔叔!!

好的,接續前面的主題,前情提要在此:Zero叔叔的期刊導讀時間:p53到底跟癌症有沒有關係呢?
所以我們繼續把這篇長文繼續讀完!

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

在上篇文章已經證實了p53 pathway與癌症具有高度的相關性,
所以,作者接著進一步去分析p53 pathway(P53的傳遞路徑)中,
相關基因的突變是否會造成”除了癌症以外的疾病”。

   根據ICD10 (international classification of disease reversion 10)
   將疾病分成19大類與KEGG訊息傳遞路徑的資料庫做比對,
   分析呈現”比對後p53路徑中至少有一條訊息傳遞路徑會與該疾病產生連結的結果,
   總歸類成9大類,各別為:

  1. Neoplasms (腫瘤)
  2. Endocrine, nutritional and metabolic diseases (內分泌,營養和代謝疾病)
  3. Mental and behavioural disorders (精神和行為障礙)
  4. Diseases of the nervous system (神經系統疾病)
  5. Diseases of the circulatory system (循環系統疾病)
  6. Diseases of the digestive system (消化系統疾病)
  7. Diseases of the skin and subcutaneous tissue (皮膚和皮下組織的疾病)
  8. Diseases of the musculoskeletal system and connective tissue (肌肉骨骼系統和結締組織疾病)
  9. Congenital malformations, deformations and chromosomal aberrations (天性畸形,變形和染色體畸變)

p53 pathway genes are significantly enriched in cancer susceptibility genes, but not susceptibility genes for other major disease groupings.tif
※ 黃色標記為p53 pathway; (p53的傳遞路徑)
※ 縱軸>1.12以上具有統計學意義,而<1.12則無 (就是以虛線為界線)
 因為Zero我的數學不是太好,所以複雜的數學我們就偷偷跳過

 

最後的結論是!
p53 pathway(P53的傳遞路徑)與腫瘤還是具有高度的相關性,而且也具有統計學上的意義
在這裡說明一下,統計學上有意義的意思,是代表p53 pathway(p53的傳遞路徑)中的基因突變,
導致腫瘤形成的機率是相當高的(通常期刊會附上實際數值,可惜的是這篇内文沒有特別提及)
這意思是!腫瘤的形成與p53 pathway(p53的傳遞路徑)是非常的有關係,再次驗證了我們上一篇的結論。


但p53 pathway(p53的傳遞路徑)在其他疾病的部分,則是沒有顯著的相關性。

接著他們利用不同的資料庫進行類似的分析
這次他們使用了2個資料庫,各別是:
1. BioCarta
2. PANTHER

最後的結果如下:

BioCarta.tif

PANTHER.tif

 

結果還是p53 pathway(p53的傳遞路徑)與腫瘤具有高度相關性
又再再再一次認證了最初的結論(p53和癌症及腫瘤具有高度相關性)

如果我們已經確定了p53 pathway(p53的傳遞路徑)發生突變時,與癌症、腫瘤具有高度相關性
那麼究竟是哪些類型的癌症與p53 pathway(p53的傳遞路徑)比較有關連呢?
而針對這個部分的實驗結果如下:

Both p53 pathway mutations and cancer-associated single nucleotide polymorphisms (SNPs) occur in a high proportion of pathway genes in multiple cancer types..tif

簡單分成幾種不同類型的癌症

(a)圖:

  1. Epithelial cancers (上皮癌): 在p53 pathway的基因,有14.93%發生突變有可能導致上皮癌。
    p.s. 話說上皮癌的意思就是全身上下的組織器官,只要由”上皮細胞”轉變而來的癌症,就稱作上皮癌。
  2. Leukaemias/lymphomas (白血病/淋巴瘤)
  3. Mesenchymal (骨髓間質): 是指腫瘤細胞轉變成具有移動能力的腫瘤細胞的一個過渡期,
    當腫瘤細胞轉換成功,就可以透過血液及淋巴循環系統擴散導致腫瘤轉移。
  4. Others cancers (其他癌症)
    在這4個類型中,各別有不同的相關度,但這代表的是p53 pathway(p53的傳遞路徑)和這些癌症、腫瘤都有關係

 

(b)圖:
在這4個分類中,其中有13條訊息傳遞路徑與這4類型腫瘤形成有相關性,
而p53 pathway(p53的傳遞路徑)就是其中的一條訊息傳遞路徑!
因此!!!!!
p53 pathway(p53的傳遞路徑)中的基因(包括p53本身)與腫瘤及癌症之間的是密切相關的!

原文如下:

p53 pathway enrichment is consistent across pathway annotations. We have demonstrated that the autosomal genes (FIG. 3) of the p53 pathway overlap with cancer GWAS loci to a greater extent than the genes of 219 other well-annotated signaling pathways, and that this enrichment is limited to cancer GWAS (FIG. 5). Thus far, we have exclusively used KEGG pathway annotations for our analyses. In order to explore further the significance of our observations, we extended our analyses to pathway annotations from two different well used, curated pathway databases, namely BioCarta and PANTHER. Similar to the findings using KEGG pathway annotation, the enrichment of CSGs in the p53 pathway ranks highest for the level of significance relative to all other pathways annotated by either BioCarta (FIG. 6a; Supplementary information S9 (table)) or PANTHER (FIG. 6b; Supplementary information S10 (table)). Also similar to the analyses conducted with KEGG annotation, when we explored the potential enrichment of p53 pathway genes among the susceptibility loci of the other 18 disease groupings defined above, we found no significant enrichment for the p53 signaling pathway annotated by either database (FIG. 6a,b, additional panels).p53 pathway variants among cancers Causal mutations. As mentioned above, the ability of p53 to suppress tumor formation in numerous tissues has been demonstrated in several mouse models. Indeed, some of the genes of the p53 pathway have been found to be causally mutated in cancer genomes from all four major annotated tissue type groupings: epithelial, mesenchymal, leukemia or lymphoma and other (COSMIC). In FIG. 1, we demonstrate that p53 pathway genes are enriched in genes known to harbor causal, somatic mutations in at least one of these four tissue types, whereby the enrichment noted places the p53 pathway among the top 5% of all annotated pathways of the genome (KEGG). Interestingly, we find similar significant enrichments when we restrict our analyses to causal, somatic mutations found in the various cancer types. We find that, in all four major cancer types, p53 pathway genes were enriched in causally mutated genes (FIG. 7a). In epithelial cancers, 14.93% of p53 pathway genes can be causally mutated, which represents an 18.99-fold enrichment over the 0.79% causally mutated genes found in all 24,553 annotated autosomal genes (P = 1.20e–10, adjusted P = 2.64e–08; FIG. 7a). Of the 220 cellular signaling pathways 61 (27.7%), including the p53 pathway, demonstrated significant enrichment of causally mutated genes after correction for multiple hypothesis testing (FIG. 7a; Supplementary information S11 (table)), thereby placing the enrichment noted in the p53 pathway among the top 6.82% of all pathways. Similar significant enrichments were found in leukaemias/lymphomas (fold- enrichment 14.09; P = 2.18e–09, adjusted P = 4.79e–07), mesenchymal cancers (fold-enrichment 20.36; P = 4.77e–06, adjusted P = 1.05e–03) and cancers in the Other category (fold-e enrichment 45.81; P = 1.70e–10, adjusted P = 3.75e–8). As seen in FIG. 7b, there are only 13 signaling pathways (5.9%), including p53, that are significantly enriched in causally mutated genes shared by all four major cancer types. These pan-cancer signaling pathways include many other well-studied oncogenic and tumor suppressor pathways, such as the PI3K-AKT, RAS and MAPK signaling pathways (Supplementary information S11 (table)).

 

參考文章來源: NATURE REVIEWS | CANCER/VOLUME 16 | APRIL 2016 | 251

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