Rapid progressive lung cancers harbouring multiple clonal driver mutations with big bang evolution model.,Cancer Genetics

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Rapid progressive lung cancers harbouring multiple clonal driver mutations with big bang evolution model.
Cancer Genetics ( IF 1.9 ) Pub Date : 2019-12-25 , DOI: 10.1016/j.cancergen.2019.12.006
Kei Kunimasa ₁ , Yosuke Hirotsu ₂ , Harumi Nakamura ₃ , Motohiro Tamiya ₄ , Yuki Iijima ₅ , Hiroto Ishida ₆ , Yuichiro Hamamoto ₃ , Tomohiro Maniwa ₇ , Toru Kimura ₇ , Kazumi Nishino ₄ , Taichiro Goto ₈ , Kenji Amemiya ₂ , Hitoshi Mochizuki ₂ , Toshio Oyama ₉ , Shin-Ichi Nakatsuka ₃ , Toru Kumagai ₄ , Jiro Okami ₇ , Masahiko Higashiyama ₇ , Fumio Imamura ₁₀ , Masao Omata ₁₁

Affiliation

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan; Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan.
Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan.
Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka, Japan.
Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.
Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Thoracic Surgery, Osaka University Hospital, Osaka, Japan.
Department of General Thoracic Surgery, Osaka International Cancer Institute, Osaka, Japan.
Department of Surgery, School of Medicine, Keio University, Tokyo, Japan; Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi, Japan.
Department of Pathology, Yamanashi Central Hospital, Yamanashi, Japan.
Department of Clinical Oncology, Osaka International Cancer Institute, Osaka, Japan.
Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan; The University of Tokyo, Tokyo, Japan.

Introduction

Next-generation sequencing (NGS) of multiple metastases in an advanced cancer patient reveals the evolutional history of the tumor. The evolutionary model is clinically valuable because it reflects the future course of the tumorigenic process and prognosis of the patient.

Materials and Methods

We experienced two lung cancer patients whose clinical courses were abruptly deteriorating resulting in very poor prognosis. To investigate the evolutionary model of these patients, we performed targeted sequencing covering whole exons of 53 significantly mutated genes associated with lung cancer of multiple metastases by autopsy. We conducted PyClone analysis to infer subclonal archtecture of multi-lesional samples.

Results

The NGS analysis revealed both patients harboring multiple clonal driver mutations. In Case.1, KRAS Q61H, KEAP1 G333C, STK11 K312*, RBM10 Q320* and MGA I1429V and in Case.2, TP53 R337L, TP53 Q192*, PTEN W274C, RB1 P29fs and CREBBP P696L with high allele fraction were detected in all lesions. These mutations were clustered and occupied major population across multi-lesional tumor samples. Our data suggested their lung cancers progressed with punctuated and big bang evolutional model.

Conclusion

We should pay attention to clinical course of lung cancer patients harboring multiple clonal driver mutations in their primary lesions. Their punctuated and big bang evolutionary process could develop systemic clinically undetectable metastases with an unexpected speed.

中文翻译：

具有大爆炸进化模型的具有多个克隆驱动程序突变的快速进展性肺癌。

介绍

晚期癌症患者中多个转移的下一代测序（NGS）揭示了肿瘤的进化史。进化模型具有临床价值，因为它反映了致瘤过程和患者预后的未来过程。

材料和方法

我们经历了两名肺癌患者，他们的临床病程突然恶化，导致预后很差。为了研究这些患者的进化模型，我们进行了靶向测序，通过尸检覆盖了与多发性肺癌肺癌相关的53个显着突变基因的整个外显子。我们进行了PyClone分析，以推断多病灶样品的亚克隆架构。

结果

NGS分析显示，两名患者都有多个克隆驱动程序突变。在案例1中，在所有等位基因分数中均检测到KRAS Q61H，KEAP1 G333C，STK11 K312 *，RBM10 Q320 *和MGA I1429V，以及案例2中的TP53 R337L，TP53 Q192 *，PTEN W274C，RB1 P29fs和CREBBP P696L病变。这些突变被聚类并占据了多病灶肿瘤样本中的主要人群。我们的数据表明，他们的肺癌以标点和大爆炸进化模型发展。