Division of Hematology Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Cancer. 2012 Jun 1;118(11):2905-14. doi: 10.1002/cncr.26617. Epub 2011 Oct 17.
The identification of new genes that are mutated in osteosarcomas is critical to developing a better understanding of the molecular pathogenesis of this disease and discovering new targets for therapeutic development.
The authors identified somatic nonsynonymous coding mutations in oncogenes associated with human cancers and hotspot mutations from tumor suppressor genes that were either well described in the literature or observed multiple times in human cancer sequencing efforts. Then, 961 mutations in 89 genes were systematically characterized across 98 osteosarcoma tumor samples and cell lines. All identified mutations were replicated on an independent platform using homogeneous mass extend matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
In total, 14 mutations were identified in at least 1 osteosarcoma tumor sample or cell line. Some of the genetic changes identified were in tumor suppressor genes previously identified as altered in osteosarcoma: p53 (arginine→histidine at codon 273 [R273H], R→cysteine at codon 723 [R273C], and tyrosine→C at codon 163 [Y163C]) and retinoblastoma 1 (RB1) (glutamic acid→* at codon 137 [E137*]). Notably, multiple mutations were identified in phosphoinositide-3-kinase (PI3K), catalytic, alpha polypeptide (PIK3CA) (H1047R, E→lysine at codon 545 [E545K], and H→proline at codon 701 [H701P]) that were not observed previously in osteosarcoma. In addition, mutations in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) (glycine→serine at codon 12 [G12S]); cubilin (CUBN) (isolucine→valine at codon 3189 [I3189V]; observed in 2 separate tumor samples); cadherin 1, type 1, epithelial (CDH1) (alanine→threonine at codon 617 [A617T]; observed in 2 separate tumor samples); catenin (cadherin-associated protein), beta 1, 88 kDa (CTNNB1) (asparagine→S at codon 287 [N287S]); and fibrous sheath CABYR binding protein (FSCB) (S→leucine at codon 775 [S775L]) were observed.
In this largest mutational profiling of osteosarcoma to date, the authors identified for the first time several mutations involving the PI3K pathway, adding osteosarcoma to the growing list of malignancies with PI3K mutations. In addition, they initiated a mutational map detailing DNA sequence changes across a variety of osteosarcoma subtypes and offered new candidates for therapeutic targeting.
鉴定骨肉瘤中突变的新基因对于更好地了解这种疾病的分子发病机制以及发现新的治疗靶点至关重要。
作者鉴定了与人类癌症相关的致癌基因中的体细胞非同义编码突变以及肿瘤抑制基因中的热点突变，这些突变要么在文献中有很好的描述，要么在人类癌症测序工作中多次观察到。然后，在 98 个骨肉瘤肿瘤样本和细胞系中系统地分析了 89 个基因中的 961 个突变。所有鉴定的突变都使用均质质量延伸基质辅助激光解吸/电离飞行时间质谱在独立平台上进行了复制。
总共在至少 1 个骨肉瘤肿瘤样本或细胞系中鉴定到 14 个突变。一些鉴定出的遗传变化涉及先前在骨肉瘤中发现改变的肿瘤抑制基因：p53（精氨酸→密码子 273 处的组氨酸[R273H]，精氨酸→密码子 723 处的半胱氨酸[R273C]和酪氨酸→密码子 163 处的 C [Y163C]）和视网膜母细胞瘤 1（RB1）（谷氨酸→密码子 137 处[E137]）。值得注意的是，在磷酸肌醇-3-激酶（PI3K），催化，α多肽（PIK3CA）（H1047R，E→赖氨酸密码子 545 [E545K]和 H→脯氨酸密码子 701 [H701P]）中鉴定到多个突变，这些突变以前在骨肉瘤中没有观察到。此外，在 v-Ki-ras2 Kirsten 大鼠肉瘤病毒癌基因同源物（KRAS）（甘氨酸→密码子 12 处的丝氨酸[G12S]）；钙网蛋白（CUBN）（亮氨酸→密码子 3189 处的缬氨酸[I3189V]；在 2 个单独的肿瘤样本中观察到）；钙粘蛋白 1，类型 1，上皮（CDH1）（丙氨酸→密码子 617 处的苏氨酸[A617T]；在 2 个单独的肿瘤样本中观察到）；连环蛋白（钙粘蛋白相关蛋白），β 1，88kDa（CTNNB1）（天冬酰胺→密码子 287 处的 S [N287S]）和纤维鞘 CABYR 结合蛋白（FSCB）（丝氨酸→密码子 775 处的亮氨酸[S775L]）也被观察到。
在迄今为止对骨肉瘤进行的最大突变分析中，作者首次鉴定了涉及 PI3K 途径的几个突变，将骨肉瘤添加到具有 PI3K 突变的不断增长的恶性肿瘤列表中。此外，他们启动了一个突变图谱，详细描述了各种骨肉瘤亚型中的 DNA 序列变化，并为治疗靶点提供了新的候选基因。
