Molecular Characterization of Seminoma Utilizing the AACR Project GENIE: A Retrospective Observational Study

TL;DR

This study uses genomic data to explore the molecular features of seminoma, a type of testicular cancer, and identifies key mutations and pathways that could lead to new treatment strategies.

Contribution

The study provides a comprehensive molecular profiling of seminoma and identifies novel mutations and pathways specific to different patient populations and tumor stages.

Findings

KIT, KRAS, and MTOR were the most frequently mutated genes in seminoma.

Copy number alterations were significant in CDKN1B, KRAS, CCND2, and H3F3C.

BRD4 mutations were found only in metastatic samples, while KMT2C, STAG2, ALK, AXL, and EGFR were found only in primary samples.

Abstract

Around 50–60% of testicular cancer cases consist of seminoma: a malignant germ cell tumor primarily diagnosed in middle-aged adults. This study explores the genomic landscape of seminoma by utilizing a de-identified publicly available dataset through the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE). The goal of this study was to further the understanding behind the biological implications of seminoma through analysis of somatic alterations, copy number alterations, therapeutic strategies, and signal cascade pathways. The findings in this study propose alternative therapeutic strategies and additional biomarkers through the investigation of various pathways.

Background: Seminoma is a malignant germ cell tumor that most commonly involves the testicles but may involve the mediastinum, the retroperitoneum, and other extra-gonadal sites as well. This study aims to investigate the somatic genomic landscape of seminoma. Methods: Data for a retrospective observational analysis of seminoma was acquired from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) with clinical and genomic data from 2017 and beyond. Using the R and R Studio software (R 4.5.0), analyses for common somatic mutations and copy number alterations were run with a statistical significance of p < 0.05. Results: The most mutated genes included KIT (22.6%), KRAS (17.1%), and MTOR (5.1%), with significant copy number alterations in CDKN1B (17.2%), KRAS (14.7%), CCND2 (10.3%), and H3F3C (9.8%). These suggest involvement within the KIT/RAS/MAPK and PI3K/AKT/mTOR (PAM) pathways for seminoma development. A novel finding within comparative evaluation of PMS1 and AMER1 mutations were found in Black individuals. Additionally, our findings were consistent with a lower testicular cancer rate among individuals with African ancestry than European ancestry. BRD4 mutations were found only in metastatic samples while KMT2C, STAG2, ALK, AXL, and EGFR were only found in primary samples, suggesting a possible association. Conclusions: This study provided a comprehensive molecular and genetic profiling of seminoma including key genetic alterations, affected pathways, and potential therapeutic strategies. Moreover, overlap between pathways and gene mutations provides the potential for alternative treatment options for seminoma via multiple pathways.

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