Corresponding author: Sean M. Grimmond
Director, University of Melbourne Centre for Cancer Research at University of Melbourne
Samples and Methods
樣本來源：
Australian Pancreatic Cancer Genome Initiative (APGI; http://www.pancreaticcancer.net.au) as part of the International Cancer Genome Consortium (ICGC; http://www.icgc.org)
方法：
Array-based CNV分析：GAP
Tumour cellularity 分析： qPure
Mutations檢測：qSNP和GATK
indels檢測：Pindel and GATK.
測序：
100 primary PDACs with an epithelial cellularity of ≥ 40% (n = 75)
cell lines derived from APGI participants (n = 25) to an average depth of 65×
compared to the germline (average depth 38×)
Point mutations and structural variation in PDAC
突變數(shù)概覽：A total of 857,971 somatic point mutations and small insertions and deletions were detected in the cohort: 7,888 were non-silent mutations in 5,424 genes
突變負荷：the average mutational burden across the cohort was 2.64 per Mb (range 0.65–28.2 per Mb)
結(jié)構(gòu)變異：In total, 11,868 somatic structural variants were detected at an average of 119 per individual (range 15–558) 膨处，主要分類intra-chromosomal rearrangements (5,860), deletions (1,393), duplications (128), tandem duplications (179), inversions (1,629), fold-back inversions (579) and amplified inversions (346)见秤。A total of 6,908 rearrangements directly disrupted gene sequences （大概有一半了） and 1,220 genes contained a breakpoint in 2 or more patients
基因融合：1,236 structural variants led to the joining of two gene loci, however, only 183 of these events were fused in an orientation and frame that was capable of expressing a product 只有183個融合可能導致基因產(chǎn)物改變，而且都只發(fā)生一次
Genes affected by mutation and structural variation
用Mutsig方法分析SMG真椿，除了TP53鹃答、SMAD4、CDKN2A 等胰腺癌常見高突變基因外突硝，還有KDM6A和PREX2等等测摔。
Subtyping using structural rearrangements
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Stable subtype
20% of all samples
These tumour genomes contained ≤ 50 structural variation events and often exhibited widespread aneuploidy非整倍體 suggesting defects in cell cycle/mitosis 細胞周期/有絲分裂存在缺陷
KRAS和SMAD4的點突變率與其他人群相似，TP53突變的患病率僅略低(61%解恰，而所有樣本的平均值為70%)锋八。此外，與其他亞組相比护盈，端粒長度無明顯差異挟纱。 -
Locally rearranged subtype
30% of all samples
This subtype exhibited a significant focal event on one or two chromosomes.
大約有1/3的樣本有copy number gain that harboured known oncogenes，包括常見的KRAS, SOX9 and GATA6腐宋，其余的有breakage–fusion–bridge (BFB, n = 9) or chromothripsis (n = 15)紊服。 -
Scattered subtype
36% of all samples
Tumours in this class exhibited a moderate range of non-random chromosomal damage and less than 200 structural variation events. -
Unstable subtype
14% of all samples
The tumours exhibited a large number of structural variation events (>200; maximum of 558)
Genomic markers of defective DNA maintenance
The majority of unstable tumours (10 of 14) fell within the top quintile of the BRCA signature when ranked by prevalence per Mb。方法見Signatures of mutational processes in human cancer.
Defective DNA repair without BRCA pathway mutations
BRCA通路基因突變約占具有高BRCA突變特征和/或不穩(wěn)定基因組的一半脏款。在某些乳腺癌和卵巢癌中围苫，超甲基化在沉默BRCA1、BRCA2和PALB2中發(fā)揮作用撤师，然而剂府，該基因組的高密度甲基化組陣列分析使我們排除了這一作用機制。
一例雙等位基因失活的體細胞突變被觀察到剃盾，已知的兩個基因在失活時誘導基因組不穩(wěn)定性和化學敏感性腺占；我們還在基因組不穩(wěn)定或具有BRCA突變特征的腫瘤中檢測到ATM淤袜、FANCM、XRCC4和XRCC6等參與DNA維持的其他基因突變衰伯；然而因果關系還不清楚铡羡。
Putative genotypes of platinum responsiveness 鉑類化療反應
on-genotype tumours (with unstable genomes and/or a high BRCA mutational signature burden) were associated with response to platinum-based therapy.
Conclusion
本研究提供了迄今為止最全面的關于胰腺癌基因組事件的描述，并證明結(jié)構(gòu)變異是胰腺癌基因組損傷的重要機制意鲸。它強調(diào)了KRAS烦周、TP53、SMAD4怎顾、CDKN2A和ARID1A基因突變的重要性读慎，此外還有許多低發(fā)生率的基因突變。KDM6A中發(fā)現(xiàn)的反復突變進一步強調(diào)了染色質(zhì)修飾的作用槐雾，而抑癌基因(如ROBO1夭委、ROBO2、SLIT2和RNF43)相對頻繁的失活與WNT信號異常的更廣泛作用有關募强。
結(jié)構(gòu)變異分析將PDAC分為四種亞型株灸，具有潛在的臨床意義。
