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Intratumoral molecular heterogeneity in a BRAF-mutant, BRAF inhibitor-resistant melanoma : a case illustrating the challenges for personalized medicine

机译:BRAF突变,BRAF抑制剂耐药的黑色素瘤中的肿瘤内分子异质性:案例说明个性化医学的挑战

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摘要

Targeted therapies are increasingly being used to treat a variety of cancers. Their efficacy depends upon the accurate detection and targeting of a specific mutation or aberration in the tumor. All cancers, such as melanoma, are molecularly heterogeneous, with drug-resistant subclones present before the treatment or emerging as a result of targeted therapies. Here, we show intralesional molecular heterogeneity in a progressing V600E BRAF-mutant melanoma metastasis from a patient treated for 7 months with the BRAF inhibitor vemurafenib. In the single metastasis, two distinct subclones were observed, both V600E BRAFmutant and only one with an additional G13R NRAS mutation. Molecular heterogeneity even at the intralesional level shows that personalizing or adjusting therapies based on genotyping of a portion of a single lesion may not accurately depict the molecular profile or drivers of oncogenesis across the entire patient's melanoma.
机译:靶向疗法正越来越多地用于治疗多种癌症。它们的功效取决于肿瘤中特定突变或畸变的准确检测和靶向。所有癌症(例如黑素瘤)在分子上都是异质的,在治疗前或针对性疗法的结果出现耐药性亚克隆。在这里,我们显示了由BRAF抑制剂维罗非尼治疗7个月的患者,正在进展的V600E BRAF突变型黑色素瘤转移中的病灶内分子异质性。在单个转移中,观察到两个不同的亚克隆,均为V600E BRAF突变体,只有一个具有其他G13R NRAS突变。甚至在病灶内水平的分子异质性也表明,基于单个病灶的一部分的基因分型进行个性化或调整疗法可能无法准确描述整个患者黑色素瘤的分子谱或致癌因素。

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