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Differentiated exophytic vulvar intraepithelial lesions are genetically distinct from keratinizing squamous cell carcinomas and contain mutations in PIK3CA.

分化型外生性外阴上皮内病变在基因层面与角化型鳞状细胞癌不同并且包含PIK3CA的突变

Watkins JC,Howitt BE,Horowitz NS,Ritterhouse LL,Dong F,MacConaill LE,Garcia E,Lindeman NI,Lee LJ,Berkowitz RS,Nucci MR,Crum CP
阅读:1251 Modern PathologyMar 2017; 30 (3): 316 - 469:448-458 

Abstract

Human papillomavirus-negative keratinizing vulvar cancers typically harbor TP53 mutations as do their precursors, differentiated vulvar intraepithelial neoplasia. However, atypical verruciform proliferations are also associated with these malignancies and their pathogenesis is poorly understood. This study compared 11 atypical verruciform lesions, including atypical verruciform hyperplasia, vulvar acanthosis with altered differentiation, and verruciform lichen simplex chronicus, with 14 human papillomavirus-negative keratinizing squamous cell carcinomas. Extracted tissue DNA was subjected to targeted massively parallel sequencing of the exonic regions of 300 genes. Eight (73%) and six (55%) of eleven atypical verruciform lesions contained mutations in PIK3CA and ARID2, respectively. No TP53 mutations were identified. Eleven (79%) and five (36%) of fourteen keratinizing squamous cell carcinomas tested contained TP53 and CDKN2A mutations, respectively. Keratinizing squamous cell carcinomas displayed the majority of copy number variations with some variations (7p gain and 8p loss) shared by some cases in both groups. One patient developed atypical verruciform lesions with PIK3CA mutations followed by a keratinizing carcinoma with mutations in both PIK3CA and TP53. This study, for the first time segregates atypical verruciform lesions by virtue of a unique genotype (PIK3CA mutant/TP53 wild type) illustrating an example of progression to a TP53-mutated keratinizing carcinoma. The findings indicate that although PIK3CA mutations are found in <10% of vulvar squamous cell carcinomas, they may be specific for a particular pathway involving atypical verruciform lesions, which could function as either a direct precursor or a risk factor for vulvar squamous cell carcinoma. Given the presence of a molecular signature, we propose the term 'differentiated exophytic vulvar intraepithelial lesion' for this group. Whether they function as direct precursors to a less common form of squamous cell carcinoma will require further study, but carcinomas associated with these lesions might warrant testing for PIK3CA mutations to address this question.

摘要

人乳头瘤病毒阴性的角化型外阴癌一般含有TP53突变,正如它的癌前病变——分化型外阴上皮内瘤变一样。然而,不典型疣状增生也和这些恶性肿瘤相关,其发病机制尚不清楚。这项研究比较了11例不典型疣状病变(包括不典型疣状增生、不同分化的外阴棘层增厚和疣状慢性单纯苔藓)和14例人乳头瘤病毒阴性的角化型鳞状细胞癌。对所提取组织DNA中特定的300个基因的外显子进行平行测序,11例不典型疣状病变里包含的PIK3CA和ARID2突变分别为8例(73%)和6例(55%),没有发现TP53突变。测序的14例角化型鳞状细胞癌中含有TP53和CDKN2A突变者分别为11例(79%)和5例(36%)。角化型鳞状细胞癌含有的拷贝数量占突变的大部分,其中一些突变(7p增加,8p缺失)在两组的某些病例中同时存在。一个病人先是患了含有PIK3CA突变的不典型疣状病变,随后又患上了同时含有PIK3CA和TP53突变的角化型癌。这项研究首次用特定的基因型(PIK3CA突变/TP53野生型)诊断了不典型疣状病变,提供了一个进展为含有TP53突变的角化型癌的病例。这项研究表明,尽管仅在不到10%的外阴鳞状细胞癌中发现有PIK3CA突变,但是它们可能在不典型疣状病变的某个通路中发挥重要作用,这个通路要么是外阴鳞状细胞癌的癌前病变,要么是它的一项危险因素。考虑到分子标记的存在,我们建议使用“分化型外生性外阴上皮内病变”这一术语来表示这一组病变。它们到底是癌前病变还是鳞状细胞癌的一种少见类型,仍需要进一步研究,但是与这些病变相关的癌可能仍需要检测PIK3CA突变才能确诊。

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