An analysis of genetic heterogeneity in untreated cancers.,Nature Reviews Cancer

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An analysis of genetic heterogeneity in untreated cancers.
Nature Reviews Cancer ( IF 72.5 ) Pub Date : 2019-08-27 , DOI: 10.1038/s41568-019-0185-x
Johannes G Reiter ₁ , Marina Baretti ₂ , Jeffrey M Gerold ₃ , Alvin P Makohon-Moore ₄ , Adil Daud ₅ , Christine A Iacobuzio-Donahue _{4,

6} , Nilofer S Azad ₂ , Kenneth W Kinzler _{2,

7,

8} , Martin A Nowak _{3,

9,

10} , Bert Vogelstein _{2,

7,

8,

11}

Affiliation

Canary Center for Cancer Early Detection, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA.
The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Program for Evolutionary Dynamics, Harvard University, Cambridge, MA, USA.
The David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
University of California, San Francisco, San Francisco, CA, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
The Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
Department of Mathematics, Harvard University, Cambridge, MA, USA.
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations in driver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver-gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44 patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative.

中文翻译：

未经治疗的癌症的遗传异质性分析。

肿瘤内遗传异质性是不完美 DNA 复制的自然结果。因此，任何两个随机选择的细胞，无论是正常细胞还是癌性细胞，在遗传上都是不同的。在这里，我们回顾了癌症中不同形式的遗传异质性，并重新分析了七种未经治疗的上皮癌的遗传异质性程度，特别是其临床相关性。我们发现驱动基因中预测的功能突变的同质性是规则而不是例外。在具有多个样本的原发性肿瘤中，38 名患者中 97% 的驱动基因突变是同质的。此外，在同一原发肿瘤的转移中，17 名患者的驱动突变 100% 是同质的。通过对 14 名患者的原发性肿瘤进行单次活检，发现所有转移瘤中都存在的功能性驱动基因突变缺失的可能性为 2.6%。此外，在这 14 个原发性肿瘤中检测到的所有功能性驱动基因突变都存在于其所有转移瘤中。最后，我们发现 44 名患者中 91% 的个体转移病灶对靶向治疗的反应一致。这些分析表明，原发肿瘤内引起转移的细胞在功能性驱动基因突变方面具有遗传同质性，我们建议未来开发联合疗法的努力有可能获得治愈。

更新日期：2019-08-27

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