Alternative splicing expands the prognostic impact of KRAS in microsatellite stable primary colorectal cancer.
Alternative splicing expands the prognostic impact of KRAS in microsatellite stable primary colorectal cancer.
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选择性剪接扩大了KRAS在微卫星稳定型原发性结直肠癌中的预后影响。
DOI：
10.1002/ijc.31809
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发表时间：
2019-02-15
影响因子：
6.4
通讯作者：
Lothe RA
中科院分区：
文献类型：
--
作者：
Eilertsen IA;Sveen A;Strømme JM;Skotheim RI;Nesbakken A;Lothe RA
KRAS突变是微卫星稳定（MSS）结直肠癌（CRC）靶向治疗反应不良和患者预后不良的众所周知的标志物。然而，KRAS野生型患者的临床结局差异强调这不是一个同质人群。在这里，我们评估了KRAS选择性剪接与单个医院系列原发性MSS CRC（N = 258）中突变状态相关的预后影响。使用剪接敏感微阵列和RNA测序，证实与正常结肠粘膜相比，CRC中KRAS-4A与KRAS-4B转录变体的相对表达下调（N = 41; p ≤ 0.001）。这与突变状态无关，然而，基因集富集分析显示剪接对KRAS信号传导的影响对KRAS野生型亚组具有特异性，其中相对较低的KRAS-4A表达与较高水平的KRAS信号传导相关（p = 0.005）。与此一致，KRAS剪接的预后价值也取决于突变状态，对于I-III期KRAS野生型MSS CRC患者，相对较低的KRAS-4A表达与较差的总生存期相关（HR：2.36，95% CI：1.07 - 5.18，p = 0.033），在突变病例中未发现该结果（p相互作用= 0.026）。在多变量分析中，野生型亚组的预后相关性与临床病理因素无关，包括癌症分期（HR：2.68，95% CI：1.18 - 6.09，p = 0.018）。这表明KRAS在MSS CRC中具有超出突变状态的预后价值，并强调了临床相关KRAS野生型亚组中分子异质性的重要性。 有什么新消息吗？ 缺乏KRAS突变的微卫星稳定（MSS）结直肠癌（CRC）患者可从靶向治疗中获益。尽管如此，临床结果的变化表明KRAS野生型CRC是一种异质性疾病。在这里，研究了通过选择性剪接产生的两种KRAS转录变体KRAS-4A和KRAS-4B与KRAS突变状态和MSS CRC预后的关系。相对于KRAS-4B转录本，导致KRAS-4A转录本变体低表达的异常剪接与KRAS信号传导增加和患者预后不良相关，特别是在KRAS野生型MSS CRC中。研究结果表明，KRAS剪接与KRAS野生型CRC的预后相关。
KRAS mutation is a well‐known marker for poor response to targeted treatment and patient prognosis in microsatellite stable (MSS) colorectal cancer (CRC). However, variation in clinical outcomes among patients wild‐type for KRAS underlines that this is not a homogeneous population. Here, we evaluated the prognostic impact of KRAS alternative splicing in relation to mutation status in a single‐hospital series of primary MSS CRCs (N = 258). Using splicing‐sensitive microarrays and RNA sequencing, the relative expression of KRAS‐4A versus KRAS‐4B transcript variants was confirmed to be down‐regulated in CRC compared to normal colonic mucosa (N = 41; p ≤ 0.001). This was independent of mutation status, however, gene set enrichment analysis revealed that the effect of splicing on KRAS signaling was specific to the KRAS wild‐type subgroup, in which low relative KRAS‐4A expression was associated with a higher level of KRAS signaling (p = 0.005). In concordance, the prognostic value of KRAS splicing was also dependent on mutation status, and for patients with Stage I–III KRAS wild‐type MSS CRC, low relative KRAS‐4A expression was associated with inferior overall survival (HR: 2.36, 95% CI: 1.07–5.18, p = 0.033), a result not found in mutant cases (p interaction = 0.026). The prognostic association in the wild‐type subgroup was independent of clinicopathological factors, including cancer stage in multivariable analysis (HR: 2.68, 95% CI: 1.18–6.09, p = 0.018). This suggests that KRAS has prognostic value beyond mutation status in MSS CRC, and highlights the importance of molecular heterogeneity in the clinically relevant KRAS wild‐type subgroup. What's new? Patients with microsatellite stable (MSS) colorectal cancer (CRC) that lacks KRAS mutation benefit from targeted therapy. Nonetheless, variations in clinical outcome suggest that KRAS wild‐type CRC is a heterogeneous disease. Here, two KRAS transcript variants, KRAS‐4A and KRAS‐4B, generated through alternative splicing, were investigated in relation to KRAS mutation status and MSS CRC prognosis. Aberrant splicing resulting in low expression of the KRAS‐4A transcript variant, relative to the KRAS‐4B transcript, was associated with increased KRAS signaling and poor patient prognosis specifically in KRAS wild‐type MSS CRC. The findings suggest that KRAS splicing is of prognostic relevance in KRAS wild‐type CRC.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1093/bioinformatics/bts452
发表时间：
2012-09-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Ryan MC;Cleland J;Kim R;Wong WC;Weinstein JN
通讯作者：
Weinstein JN
影响因子：
14.9
作者：
Ryan M;Wong WC;Brown R;Akbani R;Su X;Broom B;Melott J;Weinstein J
通讯作者：
Weinstein J
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
11.5
作者：
Sveen, Anita;Bruun, Jarle;Lothe, Ragnhild A.
通讯作者：
Lothe, Ragnhild A.