Eskander Ramez N, Elvin Julia, Gay Laurie, Ross Jeffrey S, Miller Vincent A, Kurzrock Razelle
Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of California San Diego, La Jolla, CA.
Center for Personalized Cancer Therapy, University of California San Diego, La Jolla, CA.
JCO Precis Oncol. 2020 Sep 3;4. doi: 10.1200/PO.19.00248. eCollection 2020.
High-grade neuroendocrine cervical cancer (HGNECC) is an uncommon malignancy with limited therapeutic options; treatment is patterned after the histologically similar small-cell lung cancer (SCLC). To better understand HGNECC biology, we report its genomic landscape.
Ninety-seven patients with HGNECC underwent comprehensive genomic profiling (182-315 genes). These results were subsequently compared with a cohort of 1,800 SCLCs.
The median age of patients with HGNECC was 40.5 years; 83 patients (85.6%) harbored high-risk human papillomavirus (HPV). Overall, 294 genomic alterations (GAs) were identified (median, 2 GAs/sample; average, 3.0 GAs/sample, range, 0-25 GAs/sample) in 109 distinct genes. The most frequently altered genes were (19.6% of cohort), (15.5%), (15.5%), and (14.4%). GAs occurred in 4% versus 32% of HPV-positive versus HPV-negative tumors ( < .0001). GAs in HGNECC involved the following pathways: PI3K/AKT/mTOR (41.2%); RAS/MEK (11.3%); homologous recombination (9.3%); and ERBB (7.2%). Two tumors (2.1%) had high tumor mutational burden (TMB; both with alterations); 16 (16.5%) had intermediate TMB. Seventy-one patients (73%) had ≥ 1 alteration that was theoretically druggable. Comparing HGNECC with SCLC, significant differences in TMB, microsatellite instability, HPV-positive status, and in , , , , and alteration rates were found.
This large cohort of patients with HGNECC demonstrated a genomic landscape distinct from SCLC, calling into question the biologic and therapeutic relevance of the histologic similarities between the entities. Furthermore, 73% of HGNECC tumors had potentially actionable alterations, suggesting novel treatment strategies for this aggressive malignancy.
高级别神经内分泌宫颈癌（HGNECC）是一种罕见的恶性肿瘤，治疗选择有限；其治疗模式仿照组织学上相似的小细胞肺癌（SCLC）。为了更好地了解HGNECC的生物学特性，我们报告了其基因组图谱。
97例HGNECC患者接受了全面的基因组分析（182 - 315个基因）。随后将这些结果与1800例SCLC患者的队列进行比较。
HGNECC患者的中位年龄为40.5岁；83例患者（85.6%）携带高危人乳头瘤病毒（HPV）。总体而言，在109个不同基因中鉴定出294个基因组改变（GAs）（中位值，每个样本2个GAs；平均值，每个样本3.0个GAs，范围，0 - 25个GAs/样本）。最常发生改变的基因是 （占队列的19.6%）、 （15.5%）、 （15.5%）和 （14.4%）。HPV阳性肿瘤与HPV阴性肿瘤中GAs的发生率分别为4%和32%（P <.0001）。HGNECC中的GAs涉及以下通路：PI3K/AKT/mTOR（41.2%）；RAS/MEK（11.3%）；同源重组（9.3%）；以及ERBB（7.2%）。2例肿瘤（2.1%）具有高肿瘤突变负荷（TMB；均有 改变）；16例（16.5%）具有中等TMB。71例患者（73%）有≥1种理论上可靶向治疗的改变。将HGNECC与SCLC进行比较，发现TMB、微卫星不稳定性、HPV阳性状态以及 、 、 、 和 的改变率存在显著差异。
这一大型HGNECC患者队列显示出与SCLC不同的基因组图谱，这使得实体之间组织学相似性的生物学和治疗相关性受到质疑。此外，73%的HGNECC肿瘤具有潜在可采取行动的改变，这为这种侵袭性恶性肿瘤提示了新的治疗策略。
