Kashofer Karl, Regauer Sigrid, Reich Olaf, Petru Edgar, Winter Elke
Diagnostic- and Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria.
Diagnostic- and Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria.
Gynecol Oncol. 2022 Apr;165(1):121-128. doi: 10.1016/j.ygyno.2022.01.020. Epub 2022 Jan 31.
To evaluate the prevalence of somatic gene mutations in different stages of cervical carcinogenesis placing special emphasis on micro-invasive pT1a cervical squamous cell cancers (SCC).
Micro-dissected samples of 32 micro-invasive pT1a and 55 ≥ pT1b SCC were evaluated by next generation sequencing of 50 cancer genes (cancer hot spot panel).
At primary diagnosis, 8/32 (25%) pT1a SCC, 10/28 (36%) pT1b SCC and 15/27 (56%) pT2/3 SCC carried somatic gene mutations. The most commonly affected gene was the PIK3CA gene in hot spot regions E545K and E453K in 5/8 (62%) pT1a SCC, 7/15 (70%) pT1b SCC and 10/15 (66%) pT2/3 SCC followed by FBXW7 (n = 4), KRAS and RB1 (n = 2 each). ERBB2, APC, ATM, MLP gene mutations occurred only once. Solitary activating oncogenic somatic mutations dominated over tumor suppressor mutation in 88% pT1a, 80% pT1b and 60% pT2/3 SCC. Concomitant mutations involved typically an activating oncogenic mutation and an inactivating tumor-suppressor gene mutation. All patients with pT1a SCC are alive without evidence of disease after surgical treatment, independent of mutational status or lympho-vascular space invasion.
Activating oncogenic gene mutations, in particular in the PIK3CA gene, occur early in cervical carcinogenesis. Although driver gene mutations bestow tumor cells with a growth advantage, early detection and complete removal of all cancer cells - with or without somatic gene mutations - are essential for cure. In contrast to advanced inoperable SCC, where PIK3CA driver gene mutations carry an adverse prognosis, the mutational status in surgically treated micro-invasive SCC is prognostically irrelevant.
评估宫颈癌发生不同阶段体细胞基因突变的发生率，特别关注微浸润性pT1a期宫颈鳞状细胞癌（SCC）。
通过对50个癌症基因（癌症热点基因 panel）进行二代测序，对32例微浸润性pT1a期和55例≥pT1b期SCC的显微切割样本进行评估。
在初次诊断时，8/32（25%）的pT1a期SCC、10/28（36%）的pT1b期SCC和15/27（56%）的pT2/3期SCC携带体细胞基因突变。最常受影响的基因是PIK3CA基因，在热点区域E545K和E453K，5/8（62%）的pT1a期SCC、7/15（70%）的pT1b期SCC和10/15（66%）的pT2/3期SCC出现该突变，其次是FBXW7（n = 4）、KRAS和RB1（各n = 2）。ERBB2、APC、ATM、MLP基因突变仅出现一次。在88%的pT1a期、80%的pT1b期和60%的pT2/3期SCC中，单独的激活致癌性体细胞突变多于肿瘤抑制基因突变。伴随突变通常涉及一个激活致癌性突变和一个失活性肿瘤抑制基因突变。所有pT1a期SCC患者术后均存活且无疾病证据，与突变状态或淋巴血管间隙浸润无关。
激活致癌基因突变，特别是PIK3CA基因的突变，在宫颈癌发生早期出现。尽管驱动基因突变赋予肿瘤细胞生长优势，但早期检测并彻底清除所有癌细胞（无论有无体细胞基因突变）对于治愈至关重要。与晚期不可手术切除的SCC不同，PIK3CA驱动基因突变在晚期不可手术切除的SCC中预后不良，而在手术治疗的微浸润性SCC中，突变状态在预后方面无关紧要。
