Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma.
Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma.
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DOI：
10.1245/s10434-013-2910-0
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发表时间：
2013-07
影响因子：
3.7
通讯作者：
Garcia-Aguilar J
中科院分区：
文献类型：
--
作者：
Duldulao MP;Lee W;Nelson RA;Li W;Chen Z;Kim J;Garcia-Aguilar J
KRAS和TP53突变在结直肠癌发生中很常见，并与治疗耐药性有关。与野生型肿瘤相比，携带这两种突变的直肠癌对新辅助放化疗（CRT）的反应较小。密码子特异性KRAS突变与靶向治疗的可变耐药性有关，但它们与直肠癌对CRT的反应的关系尚不清楚。我们的目的是建立特异性KRAS突变与直肠癌对CRT反应之间的相关性，并研究这种相关性是否与KRAS和TP53突变之间的不同关联有关。148例II-III期直肠癌患者术前行CRT，术后行手术。从预处理肿瘤活检和配对正常手术组织中提取DNA，并进行KRAS和TP53基因分型。特异的KRAS突变与肿瘤反应相关，并伴有TP53突变。60例患者发生KRAS突变；密码子13有12个，其他地方有48个。TP53突变80例；27例并发KRAS/TP53突变。与野生型KRAS相比，任何KRAS突变的肿瘤都不太可能出现pCR （p=0.006）。具体来说，没有KRAS密码子13突变的肿瘤出现pCR （p=0.03）。KRAS密码子13突变的肿瘤与其他KRAS突变的肿瘤相比，并发TP53突变的发生率也更高（p=0.02）。不同KRAS密码子突变对直肠癌CRT耐药的影响可能不同。这种可变的耐药性可能与KRAS突变肿瘤中TP53突变的不同频率有关。
Mutations in KRAS and TP53 are common in colorectal carcinogenesis and are associated with resistance to therapy. Rectal cancers carrying both mutations are less likely to respond to neoadjuvant chemoradiation therapy (CRT) compared to wildtype tumors. Codon-specific KRAS mutations are associated with variable resistance to targeted therapies, but their association with rectal cancer response to CRT remains unclear. Our objective was to establish a correlation between specific KRAS mutations and rectal cancer response to CRT, and investigate if the correlation was related to a different association between KRAS and TP53 mutations. One hundred forty-eight stage II–III rectal cancer patients underwent pre-operative CRT followed by surgery. DNA was extracted from pretreatment tumor biopsies and paired normal surgical tissues and KRAS and TP53 genotyping was performed. Specific KRAS mutations were then correlated with tumor response, and with concurrent TP53 mutation. Sixty patients had KRAS mutation; 12 in codon 13, and 48 in other locations. Eighty patients had TP53 mutation; 27 had concurrent KRAS/TP53 mutations. Tumors with any KRAS mutation were less likely to have a pCR compared to wildtype KRAS (p=0.006). Specifically, no tumors with KRAS codon 13 mutations had a pCR (p=0.03). Tumors with KRAS codon 13 mutations also had a higher incidence of concurrent TP53 mutation compared to tumors with other KRAS mutations (p=0.02). Mutations in different KRAS codons may have different effects on rectal cancer resistance to CRT. This variable resistance may be related to a different frequency of TP53 mutations in KRAS mutant tumors.
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DOI：
10.1038/nrc3106
发表时间：
2011-10-13
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
56.9
作者：
Tournier, C;Hess, P;Davis, RJ
通讯作者：
Davis, RJ
影响因子：
9
作者：
Yen, Li-Chen;Uen, Yih-Huei;Wang, Jaw-Yuan
通讯作者：
Wang, Jaw-Yuan
影响因子：
5.7
作者：
Buhrman, Greg;Wink, Glenna;Mattos, Carla
通讯作者：
Mattos, Carla
影响因子：
5.2
作者：
Samowitz, Wade S.;Slattery, Martha L.;Albertsen, Hans
通讯作者：
Albertsen, Hans