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首页> 外文期刊>BMC Medical Genomics >Intratumoral genetic heterogeneity in metastatic melanoma is accompanied by variation in malignant behaviors
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Intratumoral genetic heterogeneity in metastatic melanoma is accompanied by variation in malignant behaviors

机译：转移性黑色素瘤的肿瘤内遗传异质性伴随着恶性行为的变化

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Background Intratumoral heterogeneity is a major obstacle for the treatment of cancer, as the presence of even minor populations that are insensitive to therapy can lead to disease relapse. Increased clonal diversity has been correlated with a poor prognosis for cancer patients, and we therefore examined genetic, transcriptional, and functional diversity in metastatic melanoma. Methods Amplicon sequencing and SNP microarrays were used to profile somatic mutations and DNA copy number changes in multiple regions from metastatic lesions. Clonal genetic and transcriptional heterogeneity was also assessed in single cell clones from early passage cell lines, which were then subjected to clonogenicity and drug sensitivity assays. Results MAPK pathway and tumor suppressor mutations were identified in all regions of the melanoma metastases analyzed. In contrast, we identified copy number abnormalities present in only some regions in addition to homogeneously present changes, suggesting ongoing genetic evolution following metastatic spread. Copy number heterogeneity from a tumor was represented in matched cell line clones, which also varied in their clonogenicity and drug sensitivity. Minor clones were identified based on dissimilarity to the parental cell line, and these clones were the most clonogenic and least sensitive to drugs. Finally, treatment of a polyclonal cell line with paclitaxel to enrich for drug-resistant cells resulted in the adoption of a gene expression profile with features of one of the minor clones, supporting the idea that these populations can mediate disease relapse. Conclusion Our results support the hypothesis that minor clones might have major consequences for patient outcomes in melanoma.
机译：背景技术肿瘤内异质性是治疗癌症的主要障碍，因为即使对治疗不敏感的少数人群的存在也会导致疾病复发。克隆多样性的增加与癌症患者预后差相关，因此我们研究了转移性黑色素瘤的遗传，转录和功能多样性。方法使用扩增子测序和SNP微阵列分析转移性病变多个区域的体细胞突变和DNA拷贝数变化。还评估了来自早期传代细胞系的单细胞克隆的克隆遗传和转录异质性，然后对其进行克隆形成性和药物敏感性测定。结果在分析的黑色素瘤转移的所有区域均鉴定出MAPK途径和抑癌基因突变。相反，我们发现除了均一的当前变化外，仅在某些区域存在拷贝数异常，表明转移扩散后正在进行的遗传进化。来自肿瘤的拷贝数异质性表现在匹配的细胞系克隆中，它们的克隆形成性和药物敏感性也不同。根据与亲本细胞系的相似性鉴定了次要克隆，这些克隆对药物的克隆性最高，敏感性最低。最后，用紫杉醇处理多克隆细胞系以富集抗药性细胞导致采用具有少数克隆之一特征的基因表达谱，支持了这些种群可以介导疾病复发的想法。结论我们的结果支持以下假设：较小的克隆可能对黑素瘤患者的预后产生重大影响。

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