Newfield Ron S, Jiang Wen, Sugganth Daniel X, Hantash Feras M, Lee Euyhyun, Newbury Robert O
Division of Pediatric Endocrinology, University of California San Diego, And Rady Children's Hospital San Diego, California, 3020 Children's Way, MC 5103, San Diego, CA, 92123, United States.
Department of Otolaryngology, University of California San Diego, And Rady Children's Hospital of San Diego, 3030 Children's Way, Suite 402, San Diego, CA, 92123-4295, United States.
Int J Pediatr Otorhinolaryngol. 2022 Jun;157:111121. doi: 10.1016/j.ijporl.2022.111121. Epub 2022 Mar 28.
We previously described mutation rates of BRAF, RAS, RET-PTC and PAX8-PPARγ in pediatric subjects with well-differentiated thyroid cancer (WDTC). We expanded the cohort adding next-generation sequencing (NGS) and assessed genotype-phenotype correlations.
Single-center retrospective cohort examining thyroidectomy tissue blocks from consecutive pediatric WDTC patients between 2001 and 2015. Tissues were analyzed at Quest Diagnostics for BRAF, RAS mutations, RET-PTC and PAX8-PPARγ, and additional fusions, using standalone and NGS tests. WDTC included papillary (PTC), follicular (FTC) and follicular-variant PTC (FVPTC).
We genotyped 46 samples (36 females). Mean age at diagnosis was 14.7 years and the cohort comprised of mostly Hispanic (60.9%) and Caucasian (26.1%) patients. Mean follow-up was 3.5 years. Genetic alterations (GA) were noted in 69.6%, with BRAF (n = 11), and RET-PTC (n = 8) detected only in PTC. GA were detected in 2/7 FTC (1 PAX8-PPARγ, 1 NRAS) and 6/10 FVPTC (3 PAX8-PPARγ, 1 STRN-ALK, 1 BRAF, 1 NRAS). Patients with BRAF were predominantly Hispanic (81.8%) and >15 years (81.8%), whereas 87.5% RET-PTC and 50% other-fusions occurred in patients ≤15 years (p = 0.044). Of the 29 PTC patients, 82.8% had GA: BRAF (37.9%), RET-PTC (27.6%), 17.2% other fusion-oncogenes (2 -ALK, 3 -NTRK). Non-RET fusions had the highest vascular invasion (100%, p = 0.042 vs RET-PTC) and frequent lymphatic invasion (80%). GA were most common in PTC with cervical metastasis.
BRAF was the most common single mutation, especially in older and Hispanic adolescents. All fusions combined are more common than BRAF. NGS reveals a genetic basis in most pediatric WDTC, which may have implications for the role of molecular testing and systemic therapy.
我们之前描述了分化型甲状腺癌（WDTC）儿科患者中BRAF、RAS、RET-PTC和PAX8-PPARγ的突变率。我们扩大了队列，增加了下一代测序（NGS）并评估了基因型与表型的相关性。
单中心回顾性队列研究，检查2001年至2015年间连续的儿科WDTC患者的甲状腺切除组织块。在奎斯特诊断公司使用独立检测和NGS检测对组织进行BRAF、RAS突变、RET-PTC和PAX8-PPARγ以及其他融合基因的分析。WDTC包括乳头状癌（PTC）、滤泡状癌（FTC）和滤泡状变异型PTC（FVPTC）。
我们对46个样本（36名女性）进行了基因分型。诊断时的平均年龄为14.7岁，队列主要由西班牙裔（60.9%）和白种人（26.1%）患者组成。平均随访时间为3.5年。69.6%的患者存在基因改变（GA），BRAF（n = 11）和RET-PTC（n = 8）仅在PTC中检测到。在2/7的FTC（1例PAX8-PPARγ，1例NRAS）和6/10的FVPTC（3例PAX8-PPARγ，1例STRN-ALK，1例BRAF，1例NRAS）中检测到GA。BRAF患者主要是西班牙裔（81.8%）且年龄>15岁（81.8%），而87.5%的RET-PTC和50%的其他融合基因改变发生在年龄≤15岁的患者中（p = 0.044）。在29例PTC患者中，82.8%存在GA：BRAF（37.9%），RET-PTC（27.6%），17.2%为其他融合致癌基因（2例-ALK，3例-NTRK）。非RET融合基因改变具有最高的血管侵犯率（100%，与RET-PTC相比p = 0.042）和频繁的淋巴侵犯（80%）。GA在伴有颈部转移的PTC中最为常见。
BRAF是最常见的单一突变，尤其是在年龄较大的西班牙裔青少年中。所有融合基因改变加起来比BRAF更常见。NGS揭示了大多数儿科WDTC的遗传基础，这可能对分子检测和全身治疗的作用有影响。
