Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach.
Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach.
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DOI：
10.1016/j.bone.2011.05.008
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发表时间：
2011-09
期刊：
影响因子：
4.1
通讯作者：
Modiano, Jaime F.
中科院分区：
文献类型：
--
作者：
Scott, Milcah C.;Sarver, Aaron L.;Gavin, Katherine J.;Thayanithy, Venugopal;Getzy, David M.;Newman, Robert A.;Cutter, Gary R.;Lindblad-Toh, Kerstin;Kisseberth, William C.;Hunter, Lawrence E.;Subramanian, Subbaya;Breen, Matthew;Modiano, Jaime F.
关键词：
骨肉瘤的异质性和混乱性使其准确的分子分类、预后和预测变得混乱。自发性骨肉瘤的发生在很大程度上局限于人和狗。虽然这两个物种的临床特征非常相似，但将狗组织成定义的品种提供了更同质的遗传背景，这可能增加发现这种复杂疾病的分子亚型的可能性。因此，我们假设，当应用于人类时，从犬骨肉瘤中提取的分子图谱将有助于这种疾病的分子分类。为了验证这一假设，我们对一组患有骨肉瘤的狗进行了全基因组基因表达谱分析，这些狗主要来自高危品种。为了进一步降低样本间的异质性，我们通过使用大量骨肉瘤来源的细胞系来评估肿瘤的内在特性。我们观察到强烈的差异基因表达，将样本分成两组，具有不同的生存概率。分组的特点是与G2/M转变相关的基因表达与DNA损伤检查点和微环境相互作用类别呈负相关。这一特征被保存在来自三个独立的狗骨肉瘤队列的整个肿瘤样本的数据中，并分成两个预期的组。值得注意的是，这种限制性标记与先前定义的软组织肉瘤预测性标记部分重叠，它揭示了来自人类骨肉瘤患者的五个独立数据集中的直系分子亚型及其相应的自然历史。我们的结果表明，狗较窄的遗传多样性可用于将复杂的人类骨肉瘤分成生物学和临床相关的分子亚型。这反过来可能会增强预后和预测，并确定相关的治疗靶点。
The heterogeneous and chaotic nature of osteosarcoma has confounded accurate molecular classification, prognosis, and prediction for this tumor. The occurrence of spontaneous osteosarcoma is largely confined to humans and dogs. While the clinical features are remarkably similar in both species, the organization of dogs into defined breeds provides a more homogeneous genetic background that may increase the likelihood to uncover molecular subtypes for this complex disease. We thus hypothesized that molecular profiles derived from canine osteosarcoma would aid in molecular subclassification of this disease when applied to humans. To test the hypothesis, we performed genome wide gene expression profiling in a cohort of dogs with osteosarcoma, primarily from high-risk breeds. To further reduce inter-sample heterogeneity, we assessed tumor-intrinsic properties through use of an extensive panel of osteosarcoma-derived cell lines. We observed strong differential gene expression that segregated samples into two groups with differential survival probabilities. Groupings were characterized by the inversely correlated expression of genes associated with G2/M transition and DNA damage checkpoint and microenvironment-interaction categories. This signature was preserved in data from whole tumor samples of three independent dog osteosarcoma cohorts, with stratification into the two expected groups. Significantly, this restricted signature partially overlapped a previously defined, predictive signature for soft tissue sarcomas, and it unmasked orthologous molecular subtypes and their corresponding natural histories in five independent data sets from human patients with osteosarcoma. Our results indicate that the narrower genetic diversity of dogs can be utilized to group complex human osteosarcoma into biologically and clinically relevant molecular subtypes. This in turn may enhance prognosis and prediction, and identify relevant therapeutic targets.
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影响因子：
4.4
作者：
Paoloni M;Davis S;Lana S;Withrow S;Sangiorgi L;Picci P;Hewitt S;Triche T;Meltzer P;Khanna C
通讯作者：
Khanna C
影响因子：
11.2
作者：
Man, TK;Chintagumpala, M;Lau, CC
通讯作者：
Lau, CC
影响因子：
78.5
作者：
Sotiriou, Christos;Piccart, Martine J.
通讯作者：
Piccart, Martine J.
影响因子：
82.9
作者：
Chibon, Frederic;Lagarde, Pauline;Aurias, Alain
通讯作者：
Aurias, Alain
DOI：
10.1186/bcr2755
发表时间：
2010
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Keller PJ;Lin AF;Arendt LM;Klebba I;Jones AD;Rudnick JA;DiMeo TA;Gilmore H;Jefferson DM;Graham RA;Naber SP;Schnitt S;Kuperwasser C
通讯作者：
Kuperwasser C