甲状腺乳头状癌突变等位基因肿瘤异质性的临床及其与预后相关性研究

doi:10.3877/cma.j.issn.1674-0785.2019.11.007

目的

探讨突变等位基因肿瘤异质性(MATH)在甲状腺乳头状癌（PTC）中的临床意义。

方法

从癌症基因图谱公共数据集下载并预处理PTC肿瘤测序数据及临床资料数据，分析MATH与PTC临床病理特征的相关性，使用Kaplan-Meier法进行生存分析，验证MATH对PTC患者的预后价值。

结果

PTC患者中MATH值为2.57~93.72，平均29.45±16.19；将≥29.45者纳入高MATH组，<29.45者纳入低MATH组。高MATH组与低MATH组的患者年龄、性别、临床分期、BRAF基因型差异无统计学意义（P>0.05）。MATH不是PTC患者总体生存期（OS）的显著预测因素（P=0.4595）；在BRAF突变型PTC患者中，高MATH者的OS低于低MATH者（P=0.0252），而在BRAF野生型PTC患者中，高MATH者的OS高于低MATH者（P=0.0495）。

结论

MATH可在BRAF突变型和野生型亚组中可预测PTC患者的预后及指导临床治疗。

关键词: 突变, 等位基因, 肿瘤异质性, 甲状腺肿瘤, BRAF基因型, 总体生存期

Objective

To investigate the clinical significance of mutant-allele tumor heterogeneity (MATH) levels in papillary thyroid carcinoma (PTC).

Methods

The sequencing data and clinical data of PTC were downloaded from the public data sets of The Cancer Genome Atlas (TCGA) and preprocessed. The correlation between MATH and clinicopathological features of PTC was analyzed. Kaplan-Meier survival analysis was used to verify the prognostic value of MATH in patients with PTC.

Results

MATH scores ranged from 2.57 to 93.72 in PTC patients, with an average of 29.45±16.19. The patients with an MATH score ≥ 29.45 were assigned to a high-MATH group, and those with an MATH score <29.45 were assigned to a low-MATH group. There was no significant difference in age, gender, tumor stage and BRAF genotype between the high-MATH group and low-MATH group (P>0.05). MATH was not a significant predictor of overall survival (OS) in patients with PTC (P=0.4595). Whereas in PTC patients with BRAF mutation, the OS in patients with a high MATH score was significantly worse than that in patients with a low MATH score (P=0.0252). In PTC patients with wild-type BRAF, the OS was significantly better in patients with a high MATH score than in those with a low MATH (P=0.0495).

Conclusion

MATH can predict the prognosis of PTC patients with wild type or mutant BRAF, which can be used to guide clinical treatment.

Key words: Mutation, Alleles, Tumor heterogeneity, Thyroid neoplasms, BRAF genotype, Overall survival

图1 甲状腺乳头状癌突变等位基因肿瘤异质性值的分布

表1 2组甲状腺乳头状癌患者临床病理特征比较

?	例数	年龄		性别		临床分期				BRAF基因型
?	例数	<45岁	≥45岁	男	女	Ⅰ	Ⅱ	Ⅲ	Ⅳ	野生型	突变型
高MATH组	147	63	84	36	111	83	17	37	10	55	92
低^MATH组	205	80	125	57	148	99	23	50	33	73	132
χ^2值	?	0.521		0.484		7.19				0.121
P值	?	0.47		0.487		0.066				0.728

表1 2组甲状腺乳头状癌患者临床病理特征比较

?	例数	年龄		性别		临床分期				BRAF基因型
?	例数	<45岁	≥45岁	男	女	Ⅰ	Ⅱ	Ⅲ	Ⅳ	野生型	突变型
高MATH组	147	63	84	36	111	83	17	37	10	55	92
低^MATH组	205	80	125	57	148	99	23	50	33	73	132
χ^2值	?	0.521		0.484		7.19				0.121
P值	?	0.47		0.487		0.066				0.728

图2 突变等位基因肿瘤异质性值与甲状腺乳头状癌患者预后的关系

图3 BRAF基因型与甲状腺乳头状癌患者预后的关系

图4 BRAF突变型甲状腺乳头状癌患者中突变等位基因肿瘤异质性值与预后的关系

图5 BRAF野生型甲状腺乳头状癌患者中突变等位基因肿瘤异质性值与预后的关系

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Clinical and prognostic significance of mutant-allele tumor heterogeneity in thyroid papillary carcinoma

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Clinical and prognostic significance of mutant-allele tumor heterogeneity in thyroid papillary carcinoma