Genetic analysis of primary lung interdigitating dendritic cell sarcomas

Area of Science:

• Oncology
• Genetics
• Pathology

Background:

• Interdigitating dendritic cell sarcomas (IDCSs) are rare neoplasms with poorly understood genetic underpinnings, limiting therapeutic strategies.
• IDCSs typically originate in the hematopoietic system but can rarely occur extranodally, such as in the lung.

Purpose of the Study:

• To investigate somatic gene mutations and copy-number alterations (CNAs) in lung-based IDCSs.
• To identify potential druggable genetic targets for IDCS treatment.

Main Methods:

• Whole-exome sequencing (WES) and shallow whole-genome sequencing (sWGS) were performed on nine IDCS samples.
• Immunohistochemistry and morphological analysis excluded other tumor types like follicular dendritic cell sarcomas, Langerhans cell sarcomas, and inflammatory myofibroblastic tumors.
• Tumors were stratified into low-grade (Ki-67 ≤ 20%) and high-grade (Ki-67 > 20%) based on Ki-67 proliferation index.

Main Results:

• High-grade IDCSs exhibited a significantly higher fraction of genome altered by CNA (48.42%) compared to low-grade IDCSs (18.15%).
• Chromosomal gains on chromosome 17 were observed in 89% of cases, irrespective of tumor grade.
• Druggable CNAs, including amplifications and losses in cancer-actionable genes (e.g., EGFR, MYC, TP53, CDKN2A), were identified in most IDCSs.

Conclusions:

• The genetic landscape of IDCSs is heterogeneous, suggesting diverse etiologies and genomic instability in high-grade tumors.
• Distinct, druggable genetic biomarkers were identified in nearly all investigated IDCSs.
• These findings provide a foundation for novel therapeutic strategies targeting specific genetic alterations in IDCSs.