Whole genome sequencing of HER2-positive metastatic extramammary Paget’s disease: a case report

• Published in: Orphanet journal of rare diseases Vol. 19; no. 1; pp. 223 - 14
• Main Authors: Lim, Boon Yee, Guo, Zexi, Lim, Jing Quan, Ko, Tun Kiat, Lee, Elizabeth Chun Yong, Kannan, Bavani, Lee, Jing Yi, Lim, Abner Herbert, Li, Zhimei, Ng, Cedric Chuan-Young, Busmanis, Inny, Chan, Jason Yongsheng
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.06.2024; BioMed Central; BMC
• Subjects: Aged; Analysis; Care and treatment; Diagnosis; DNA Copy Number Variations - genetics; DNA sequencing; ERBB2; Fibroblast growth factors; Humans; Male; Metastasis; Next generation sequencing; Nucleotide sequencing; Paget Disease, Extramammary - genetics; Paget Disease, Extramammary - metabolism; Paget Disease, Extramammary - pathology; Precision oncology; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Targeted therapy; Trastuzumab; Whole Genome Sequencing; Singapore; Precision oncology; Targeted therapy; Next generation sequencing; Trastuzumab; ERBB2
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/s13023-024-03169-y

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. 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. Notable copy number gains (log FC > 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 (log FC = 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. 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.