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Abstract：
BACKGROUND: Extramammary Paget\'s disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, penis and perianal regions. Here, we aim to integrate clinicopathological data with genomic analysis of aggressive, rapidly-progressing de novo metastatic EMPD responding to HER2-directed treatment in combination with other agents, to attain a more comprehensive understanding of the disease landscape.
METHODS: Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression. Whole genome sequencing of the tumor and matched blood was performed.
RESULTS: Notable copy number gains (log2FC > 0.9) on chromosomes 7 and 8 were detected (n = 81), with 92.6% of these unique genes specifically located on chromosome 8. Prominent cancer-associated genes include ZNF703, HOOK3, DDHD2, LSM1, NSD3, ADAM9, BRF2, KAT6A and FGFR1. Interestingly, ERBB2 gene did not exhibit high copy number gain (log2FC = 0.4) although 90% of tumor cells stained HER2-positive. Enrichment in pathways associated with transforming growth factor-beta (TGFβ) (FDR = 0.0376, Enrichment Ratio = 8.12) and fibroblast growth factor receptor (FGFR1) signaling (FDR = 0.0082, Enrichment Ratio = 2.3) was detected. Amplicon structure analysis revealed that this was a simple-linear amplification event.
CONCLUSIONS: Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen.
METHODS: Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression. Whole genome sequencing of the tumor and matched blood was performed.
RESULTS: Notable copy number gains (log2FC > 0.9) on chromosomes 7 and 8 were detected (n = 81), with 92.6% of these unique genes specifically located on chromosome 8. Prominent cancer-associated genes include ZNF703, HOOK3, DDHD2, LSM1, NSD3, ADAM9, BRF2, KAT6A and FGFR1. Interestingly, ERBB2 gene did not exhibit high copy number gain (log2FC = 0.4) although 90% of tumor cells stained HER2-positive. Enrichment in pathways associated with transforming growth factor-beta (TGFβ) (FDR = 0.0376, Enrichment Ratio = 8.12) and fibroblast growth factor receptor (FGFR1) signaling (FDR = 0.0082, Enrichment Ratio = 2.3) was detected. Amplicon structure analysis revealed that this was a simple-linear amplification event.
CONCLUSIONS: Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen.
摘要：
背景：乳腺外Paget病（EMPD）是一种罕见的癌症，发生在皮肤上皮内，主要出现在高顶分泌腺浓度的区域，如外阴，阴囊,阴茎和肛周区域。这里,我们的目标是将临床病理数据与侵袭性基因组分析相结合，快速进展的从头转移性EMPD响应HER2定向治疗与其他药物联合治疗，以更全面地了解疾病景观。
方法：阴囊壁肿瘤和骨髓转移的免疫组织化学染色显示HER2过表达。对肿瘤和匹配的血液进行全基因组测序。
结果：在染色体7和8上检测到显著的拷贝数增加（log2FC>0.9）（n=81），这些独特的基因中有92.6％专门位于8号染色体上。突出的癌症相关基因包括ZNF703、HOOK3、DDHD2、LSM1、NSD3、ADAM9、BRF2、KAT6A和FGFR1。有趣的是,ERBB2基因没有表现出高拷贝数增加(log2FC=0.4),尽管90%的肿瘤细胞染色HER2阳性。检测到与转化生长因子β（TGFβ）（FDR=0.0376，富集比=8.12）和成纤维细胞生长因子受体（FGFR1）信号传导（FDR=0.0082，富集比=2.3）相关的途径的富集。扩增子结构分析揭示这是简单线性扩增事件。
结论：全基因组测序揭示了HER2阳性转移性EMPD中潜在的拷贝数变异。替代信号通路和遗传变异的存在表明与HER2信号的潜在相互作用，这可能是HER2过表达的原因,并且在综合治疗方案中观察到HER2定向治疗联合其他药物的反应.
方法：阴囊壁肿瘤和骨髓转移的免疫组织化学染色显示HER2过表达。对肿瘤和匹配的血液进行全基因组测序。
结果：在染色体7和8上检测到显著的拷贝数增加（log2FC>0.9）（n=81），这些独特的基因中有92.6％专门位于8号染色体上。突出的癌症相关基因包括ZNF703、HOOK3、DDHD2、LSM1、NSD3、ADAM9、BRF2、KAT6A和FGFR1。有趣的是,ERBB2基因没有表现出高拷贝数增加(log2FC=0.4),尽管90%的肿瘤细胞染色HER2阳性。检测到与转化生长因子β（TGFβ）（FDR=0.0376，富集比=8.12）和成纤维细胞生长因子受体（FGFR1）信号传导（FDR=0.0082，富集比=2.3）相关的途径的富集。扩增子结构分析揭示这是简单线性扩增事件。
结论：全基因组测序揭示了HER2阳性转移性EMPD中潜在的拷贝数变异。替代信号通路和遗传变异的存在表明与HER2信号的潜在相互作用，这可能是HER2过表达的原因,并且在综合治疗方案中观察到HER2定向治疗联合其他药物的反应.
