Abstract：
BACKGROUND: Parathyroid cancer has been linked to germline mutations of the CDC73 gene. However, carriers harboring cancer-associated germline CDC73 mutations may develop only parathyroid adenoma or no parathyroid disease. This incomplete penetrance indicates that additional genomic events are required for parathyroid tumorigenesis.
OBJECTIVE: (1) Determine the status of the second CDC73 allele in parathyroid tumors harboring germline CDC73 mutations, and (2) compare the genomic landscapes between parathyroid carcinomas and adenomas.
METHODS: Whole-exome and RNA sequencing of 12 parathyroid tumors harboring germline CDC73 mutations (6 adenomas and 6 carcinomas) and their matched normal tissues.
RESULTS: All 12 parathyroid tumors had gained one somatic event predicted to cause a complete inactivation of the second CDC73 allele. Several distinctive genomic features were identified in parathyroid carcinomas compared to adenomas, including more single nucleotide variants bearing the C>G transversion and APOBEC deamination signatures, frequent mutations of the genes involved in the PI-3K/mTOR signaling, a greater number of copy number variations, and substantially more genes with altered expression. Parathyroid carcinomas also share some genomic features with adenomas. For instance, both have recurrent somatic mutations and copy number loss that impact the genes involved in T-cell receptor signaling and tumor antigen presentation, suggesting a shared strategy to evade immune surveillance.
CONCLUSIONS: Biallelic inactivation of CDC73 is essential for parathyroid tumorigenesis in carriers harboring germline mutations of this gene. Despite sharing some genomic features with adenomas, parathyroid carcinomas have more distinctive alterations in the genome, some of which may be critical for cancer formation.
OBJECTIVE: (1) Determine the status of the second CDC73 allele in parathyroid tumors harboring germline CDC73 mutations, and (2) compare the genomic landscapes between parathyroid carcinomas and adenomas.
METHODS: Whole-exome and RNA sequencing of 12 parathyroid tumors harboring germline CDC73 mutations (6 adenomas and 6 carcinomas) and their matched normal tissues.
RESULTS: All 12 parathyroid tumors had gained one somatic event predicted to cause a complete inactivation of the second CDC73 allele. Several distinctive genomic features were identified in parathyroid carcinomas compared to adenomas, including more single nucleotide variants bearing the C>G transversion and APOBEC deamination signatures, frequent mutations of the genes involved in the PI-3K/mTOR signaling, a greater number of copy number variations, and substantially more genes with altered expression. Parathyroid carcinomas also share some genomic features with adenomas. For instance, both have recurrent somatic mutations and copy number loss that impact the genes involved in T-cell receptor signaling and tumor antigen presentation, suggesting a shared strategy to evade immune surveillance.
CONCLUSIONS: Biallelic inactivation of CDC73 is essential for parathyroid tumorigenesis in carriers harboring germline mutations of this gene. Despite sharing some genomic features with adenomas, parathyroid carcinomas have more distinctive alterations in the genome, some of which may be critical for cancer formation.
摘要：
背景：甲状旁腺癌与CDC73基因的种系突变有关。然而,携带癌症相关种系CDC73突变的携带者可能仅发生甲状旁腺腺瘤或无甲状旁腺疾病.这种不完全的外显率表明甲状旁腺肿瘤发生需要额外的基因组事件。
目的：（1）确定第二个CDC73等位基因在具有种系CDC73突变的甲状旁腺肿瘤中的状态，（2）比较甲状旁腺癌和腺瘤的基因组景观。
方法：对12个携带种系CDC73突变的甲状旁腺肿瘤（6个腺瘤和6个癌）及其匹配的正常组织进行全外显子组和RNA测序。
结果：所有12个甲状旁腺肿瘤都获得了一个预测导致第二个CDC73等位基因完全失活的体细胞事件。与腺瘤相比，在甲状旁腺癌中发现了几种独特的基因组特征，包括更多带有C>G颠换和APOBEC脱氨基特征的单核苷酸变体，参与PI-3K/mTOR信号传导的基因的频繁突变，更多的拷贝数变化，和更多的基因表达改变。甲状旁腺癌也与腺瘤具有一些基因组特征。例如,两者都有反复的体细胞突变和拷贝数丢失，影响参与T细胞受体信号传导和肿瘤抗原呈递的基因，建议采取共同的策略来逃避免疫监视。
结论：在携带该基因种系突变的携带者中，CDC73的双等位基因失活对于甲状旁腺肿瘤发生至关重要。尽管与腺瘤有一些基因组特征，甲状旁腺癌在基因组中有更独特的改变，其中一些可能对癌症形成至关重要。
目的：（1）确定第二个CDC73等位基因在具有种系CDC73突变的甲状旁腺肿瘤中的状态，（2）比较甲状旁腺癌和腺瘤的基因组景观。
方法：对12个携带种系CDC73突变的甲状旁腺肿瘤（6个腺瘤和6个癌）及其匹配的正常组织进行全外显子组和RNA测序。
结果：所有12个甲状旁腺肿瘤都获得了一个预测导致第二个CDC73等位基因完全失活的体细胞事件。与腺瘤相比，在甲状旁腺癌中发现了几种独特的基因组特征，包括更多带有C>G颠换和APOBEC脱氨基特征的单核苷酸变体，参与PI-3K/mTOR信号传导的基因的频繁突变，更多的拷贝数变化，和更多的基因表达改变。甲状旁腺癌也与腺瘤具有一些基因组特征。例如,两者都有反复的体细胞突变和拷贝数丢失，影响参与T细胞受体信号传导和肿瘤抗原呈递的基因，建议采取共同的策略来逃避免疫监视。
结论：在携带该基因种系突变的携带者中，CDC73的双等位基因失活对于甲状旁腺肿瘤发生至关重要。尽管与腺瘤有一些基因组特征，甲状旁腺癌在基因组中有更独特的改变，其中一些可能对癌症形成至关重要。
