Pathogenic Germline PALB2 and RAD50 Variants in Patients With Relapsed Ewing Sarcoma.

Area of Science:

• Oncology
• Genetics
• Cancer Research

Background:

• Ewing sarcoma (EwS) is a rare bone and soft tissue cancer.
• Germline pathogenic variants are found in approximately 10% of EwS patients, influencing cancer risk and behavior.
• Understanding these variants is crucial for personalized medicine and risk assessment.

Purpose of the Study:

• To report two distinct cases of Ewing sarcoma associated with rare germline pathogenic variants.
• To investigate the functional impact of a novel PALB2 variant on homologous recombination.
• To discuss the implications of these genetic findings for cancer risk, treatment response, and toxicities.

Main Methods:

• Case report analysis of two EwS patients with germline variants.
• Functional studies to assess the impact of the PALB2 variant on DNA repair pathways.
• Review of clinical data, including cancer history, treatment, and outcomes.

Main Results:

• A novel germline pathogenic variant in PALB2 was identified in a patient with late-onset EwS relapse, impacting homologous recombination.
• A pathogenic germline variant in RAD50 was found in a patient with rare prostate primary EwS, concurrent relapsed EwS, and therapy-related acute myeloid leukemia (tAML).
• The RAD50 variant case involved complex secondary malignancies with rare KMT2A translocations.

Conclusions:

• Rare germline variants, such as those in PALB2 and RAD50, can significantly influence EwS presentation, progression, and secondary cancer development.
• These findings underscore the importance of genetic screening in EwS patients to identify individuals at higher risk for specific cancer types or treatment complications.
• Further research into the functional consequences of rare germline variants is essential for improving patient management and therapeutic strategies in oncology.