PTEN 错构瘤肿瘤综合征 (PHTS) 患者是一种针对携带种系 PTEN 致病性变异的患者的分子诊断，其良性和恶性甲状腺疾病的患病率很高。表征 PHTS 甲状腺肿瘤的基因组景观可以深入了解恶性潜力和肿瘤进展，从而帮助优化该人群的诊断、监测和治疗。为了揭示 PHTS 相关甲状腺肿瘤的体细胞改变，我们对 19 名 PHTS 患者的 58 个甲状腺肿瘤（28 个癌症，30 个良性结节）进行了外显子组测序。使用癌症基因组图谱中 447 例散发性乳头状甲状腺癌 (PTC) 的对照队列进行比较。与一般人群相比，PHTS 相关甲状腺肿瘤在致病性种系 PTEN 突变的背景下具有独特的基因组景观。 PHTS 相关甲状腺肿瘤表现出高频率的二次打击体细胞 PTEN 改变，包括变异和杂合性丢失事件。二次打击体细胞 PTEN 改变在 PHTS 相关 PTC 中比散发性 PTC 更常见（65.2% vs. 0.067%），在 PHTS 相关滤泡性甲状腺癌（100%）和良性滤泡结节（90%）中频繁发生。 PHTS 相关的 PTC 还存在 BRAF、RAS 家族成员和与 DNA 双链断裂修复相关的基因的体细胞改变，以及体细胞臂水平拷贝数变异。总之，这些发现表明，双等位基因 PTEN 改变可能作为 PHTS 甲状腺组织的基础突变发挥作用，通过受损的 DNA 双链断裂修复和增加的基因组不稳定性促进良性生长并增加恶性转化的可能性。 PHTS 相关甲状腺肿瘤独特的基因组景观对患者的分子靶向治疗具有重要意义。外显子组测序揭示了 PTEN 错构瘤肿瘤综合征相关甲状腺癌与散发性甲状腺癌的独特突变景观，提供了对肿瘤进展和行为的见解，可能有助于改善诊断、监测和治疗。©2023 美国癌症研究协会。

Patients with PTEN hamartoma tumor syndrome (PHTS), a molecular diagnosis for those carrying germline PTEN pathogenic variants, have a high prevalence of benign and malignant thyroid disease. Characterizing the genomic landscape in PHTS thyroid tumors could provide insights into malignant potential and tumor progression to help optimize diagnosis, surveillance, and treatment in this population. To reveal the somatic alterations in PHTS-associated thyroid tumors, we conducted exome sequencing on 58 thyroid tumors (28 cancers, 30 benign nodules) from 19 patients with PHTS. A control cohort of 447 sporadic papillary thyroid cancers (PTC) from The Cancer Genome Atlas was used for comparison. PHTS-associated thyroid tumors had a unique genomic landscape in the setting of a pathogenic germline PTEN mutation, when compared with the general population. PHTS-associated thyroid tumors demonstrated a high frequency of second-hit somatic PTEN alterations, including variants and loss-of-heterozygosity events. Second-hit somatic PTEN alterations were more prevalent in PHTS-associated PTC than sporadic PTC (65.2% vs. 0.067%), occurring frequently in PHTS-associated follicular thyroid cancer (100%) and benign follicular nodules (90%). PHTS-associated PTC additionally harbored somatic alterations in BRAF, RAS family members, and genes associated with DNA double-stranded break repair, as well as somatic arm-level copy-number variations. Together, these findings suggest that biallelic PTEN alterations may function as foundational mutations in PHTS thyroid tissue, promoting benign growth and increasing potential for malignant transformation through impaired DNA double-stranded break repair and increased genomic instability. The unique genomic landscape of PHTS-associated thyroid tumors carries implications for molecular-targeted therapies for patients.Exome sequencing reveals the distinct mutational landscape of PTEN hamartoma tumor syndrome-associated thyroid cancers from sporadic counterparts, providing insights into tumor progression and behavior that could help improve diagnosis, surveillance, and treatment.©2023 American Association for Cancer Research.