食道扁平上皮癌：ゲノム解析p53はやはり最強

Nature(2014)

Received 20 May 2013 
Accepted 25 February 2014 
Published online 16 March 2014 

Identification of genomic alterations in oesophageal squamous cell cancer 

Yongmei Song,Lin Li, et al. 

Oesophageal cancer is one of the most aggressive cancers and is the sixth leading cause of cancer death worldwide1. Approximately 70% of global oesophageal cancer cases occur in China, with oesophageal
squamous cell carcinoma (ESCC) being the histopathological form in the vast majority of cases (>90%). Currently, there are limited clinical approaches for the early diagnosis and treatment of ESCC, resulting in a 10% five-year survival rate for patients. However, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. 

Here we describe a comprehensive genomic analysis of 158 ESCC cases, as part of the International Cancer Genome Consortium research project. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases, plus an additional 70 ESCC cases not used in the whole-genome and whole-exome sequencing, were subjected to array comparative genomic hybridization analysis.

We identified eight significantly mutated genes, of which six are well known tumour associated genes (TP53, RB1,CDKN2A, PIK3CA,NOTCH1, NFE2L2), and two have not previously been described in ESCC (ADAM29 and FAM135B). Notably,FAM135B is identified as a novel cancer implicated gene as assayed for its ability to promote malignancy of ESCC cells. 

Additionally, MIR548K, a microRNA encoded in the amplified 11q13.3-13.4 region, is characterized as a novel oncogene, and functional assays demonstrate that MIR548K enhances malignant phenotypes of ESCC cells.

Moreover, we have found that several important histone regulator genes (MLL2 (also called KMT2D), ASH1L, MLL3 (KMT2C),SETD1B,CREBBP andEP300) are frequently altered in ESCC. 

Pathway assessment reveals that somatic aberrations are mainly involved in the Wnt, cell cycle and Notch pathways. Genomic analyses suggest that ESCCand head and neck squamous cell carcinoma share some common pathogenic mechanisms, and ESCC development is associated with alcohol drinking. This study has explored novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for ESCC.

 p53の変異率83%にはただただ驚くばかりである。その他はすでに知られている遺伝子変異が多い。

ここまで解析してあると、予後予測が知りたくなる。そんな遺伝子はないのか？

この論文ではFAM135Bが予後関連遺伝子としてあげられている。

カプランマイヤーを見せられたら、当然次は多変量解析がみたい。 

確かにまあまあである。多変量でこのp値なら
「なにかに」引っ張られているということなのかね。
この6例の変異症例に

臨床的特徴があるのかないのか？

さてさて・・・・

最後はパスウェイ解析である。p53が第一ヒットとして、次の変異は結構多彩（？）になるのか、少なくとも各種遺伝子の変異頻度はそこまで高くない。

食道扁平上皮癌のゲノム構造も近年、次第に共通のlandscapeが見えてきたというところである。

さて胃癌はどうなっているのだろう？