Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, California.
Department of Information Sciences, Beckman Research Institute of City of Hope, Duarte, California.
Clin Cancer Res. 2019 Jan 15;25(2):544-551. doi: 10.1158/1078-0432.CCR-18-0841. Epub 2018 Aug 9.
Thyroid cancer is frequently difficult to diagnose due to an overlap of cytologic features between malignant and benign nodules. This overlap leads to unnecessary removal of the thyroid in patients without cancer. While providing some improvement over cytopathologic diagnostics, molecular methods frequently fail to provide a correct diagnosis for thyroid nodules. These approaches are based on the difference between cancer and adjacent thyroid tissue and assume that adjacent tissues are the same as benign nodules. However, in contrast to adjacent tissues, benign thyroid nodules can contain genetic alterations that can be found in cancer. For the development of a new molecular diagnostic test for thyroid cancer, we evaluated DNA methylation in 109 thyroid tissues by using genome-wide single-base resolution DNA methylation analysis. The test was validated in a retrospective cohort containing 65 thyroid nodules.
By conducting reduced representation bisulfite sequencing in 109 thyroid specimens, we found significant differences between adjacent tissue, benign nodules, and cancer. These tissue-specific signatures are strongly linked to active enhancers and cancer-associated genes. Based on these signatures, we developed a new epigenetic approach for thyroid diagnostics. According to the validation cohort, our test has an estimated specificity of 97% [95% confidence interval (CI), 81-100], sensitivity of 100% (95% CI, 87-100), positive predictive value of 97% (95% CI, 83-100), and negative predictive value of 100% (95% CI, 86-100).
These data show that epigenetic testing can provide outstanding diagnostic accuracy for thyroid nodules..
由于恶性和良性结节之间的细胞学特征重叠，甲状腺癌常常难以诊断。这种重叠导致了无癌症患者的甲状腺不必要的切除。虽然分子方法比细胞病理诊断学提供了一些改善，但它们经常无法为甲状腺结节提供正确的诊断。这些方法基于癌症与相邻甲状腺组织之间的差异，并假设相邻组织与良性结节相同。然而，与相邻组织不同，良性甲状腺结节可能包含可以在癌症中发现的遗传改变。为了开发新的甲状腺癌分子诊断测试，我们使用全基因组单碱基分辨率 DNA 甲基化分析对 109 个甲状腺组织进行了 DNA 甲基化评估。该测试在包含 65 个甲状腺结节的回顾性队列中进行了验证。
通过对 109 个甲状腺标本进行简化代表性双硫代测序，我们发现相邻组织、良性结节和癌症之间存在显著差异。这些组织特异性特征与活性增强子和癌症相关基因密切相关。基于这些特征，我们开发了一种新的甲状腺诊断表观遗传方法。根据验证队列，我们的测试估计具有 97%的特异性[95%置信区间 (CI)，81-100]，100%的敏感性[95%CI，87-100]，97%的阳性预测值[95%CI，83-100]和 100%的阴性预测值[95%CI，86-100]。
这些数据表明，表观遗传测试可为甲状腺结节提供出色的诊断准确性。
