Hao Chuncheng, Wang Li, Peng Shaohua, Cao Mengru, Li Hongyu, Hu Jing, Huang Xiao, Liu Wei, Zhang Hui, Wu Shuhong, Pataer Apar, Heymach John V, Eterovic Agda Karina, Zhang Qingxiu, Shaw Kenna R, Chen Ken, Futreal Andrew, Wang Michael, Hofstetter Wayne, Mehran Reza, Rice David, Roth Jack A, Sepesi Boris, Swisher Stephen G, Vaporciyan Ara, Walsh Garrett L, Johnson Faye M, Fang Bingliang
Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Department of Thoracic and Head/Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Lett. 2015 Feb 1;357(1):179-185. doi: 10.1016/j.canlet.2014.11.024. Epub 2014 Nov 18.
Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies.
分子注释的患者来源异种移植（PDX）模型对于抗癌药物的临床前研究和个体化抗癌治疗很有用。我们从88例肺癌患者的手术标本中建立了23个PDX，并通过对202个癌症相关基因进行超深度外显子组测序，确定了这些PDX及其配对的原发性肿瘤中的基因突变。TP53、KRAS、PI3KCA、ALK、STK11和EGFR中存在有害突变的原发性肿瘤数量分别为43.5%、21.7%、17.4%、17.4%、13.0%和8.7%。在≥3（13.0%）例原发性肿瘤中存在有害突变的其他基因有MLL3、SETD2、ATM、ARID1A、CRIPAK、HGF、BAI3、EP300、KDR、PDGRRA和RUNX1。在原发性肿瘤中检测到的315个突变中，有293个（93%）在其相应的PDX中也被检测到，这表明PDX有能力重现原发性肿瘤中的突变。然而，相当数量的突变在PDX中的等位基因频率高于原发性肿瘤，或者在原发性肿瘤中无法检测到，这表明PDX中可能存在肿瘤细胞富集或原发性肿瘤存在异质性。本研究产生的分子注释PDX可能对未来的转化研究有用。
