Changes on chromosome 11p15.5 as specific marker for embryonal rhabdomyosarcoma?

Area of Science:

• Oncology
• Molecular Genetics
• Cancer Genomics

Background:

• Rhabdomyosarcomas (RMS) are a diverse group of tumors with varying clinical and morphological features.
• Paternal uniparental disomy (pUPD) of chromosome 11p15.5 is a known molecular alteration primarily associated with embryonal RMS (ERMS).
• The MLPA technique offers a comprehensive analysis of copy number variants and gene methylation, including H19 and KCNQ1OT1, which warrants systematic investigation in RMS.

Purpose of the Study:

• To investigate the frequency and spectrum of molecular alterations at 11p15.5 in a cohort of 127 RMS tumors across different histological subtypes.
• To determine if pUPD 11p15.5 is exclusive to ERMS or also present in other RMS subtypes, such as alveolar RMS (ARMS).
• To identify novel molecular markers for ERMS and ARMS using MLPA analysis.

Main Methods:

• MLPA (ME030 kit) analysis was performed on 127 RMS tumors.
• Tumors were classified by histology and PAX fusion status into four groups: pleomorphic, PAX-positive ARMS, ERMS, and PAX-negative ARMS with alveolar pattern.
• Analysis included detection of loss of heterozygosity (LOH), UPD, copy number variants, and methylation status of H19 and KCNQ1OT1.

Main Results:

• pUPD 11p15.5 was detected in 75 tumors and was not significantly different across all RMS subtypes.
• Novel findings included gain of paternal allele (9 tumors), loss of maternal allele (9 tumors), H19 hypermethylation (6 tumors), KCNQ1OT1 hypomethylation (6 tumors), and CDKN1C deletion (1 tumor).
• pUPD 11p15.5 was found in both ERMS and ARMS, challenging the notion of its exclusivity to ERMS.

Conclusions:

• Alterations in 11p15.5 are not confined to ERMS but are also frequently observed in ARMS.
• New potential diagnostic markers for ERMS include paternal duplication and whole chromosome 11 UPD.
• Hypomethylation of KCNQ1OT1 emerged as a potential diagnostic marker for PAX-positive ARMS.