A Novel Targeted Sequence for Chromosome 11p15.5 Maternal Loss in SDHD-Related Paragangliomas.
Journal
Genes, chromosomes & cancer
Journal Volume
65
Journal Issue
1
Start Page
Article number e70107
ISSN
1098-2264
Date Issued
2026-01
Author(s)
Abstract
Hereditary paragangliomas (PGLs) caused by germline SDHD pathogenic variants (PVs) exhibit a parent-of-origin effect, with tumors arising almost exclusively when the PV is inherited from the paternal allele. The Hensen model proposes that a cluster of maternally expressed tumor suppressor genes (TSGs) on chromosome 11p15.5 may play a crucial role in SDHD-related PGL tumorigenesis, wherein somatic loss of maternal 11p and wild-type SDHD allele, in conjunction with a paternally inherited SDHD PV, triggers tumor development. To systematically localize and identify the most crucial maternal-expressed TSGs within 11p15.5, we developed a novel single nucleotide variant (SNV)-oriented, capture-based targeted enrichment approach followed by next-generation sequencing (NGS) to enable high-resolution loss-of-heterozygosity (LOH) analysis. Among 13 SDHD-related PGLs and 23 non-SDHD-related PGLs, a somatic loss of 11p15.5-15.4 was detected in 92% and 47%, respectively, a significant difference (p = 0.0035). Parental genotype analysis confirmed that the lost chromosome was of maternal origin. In our studies, 12/13 SDHD-related tumors demonstrated complete loss of the maternal 11p15.5-15.4 region, preventing localization of a specific driver TSG. Only one exceptional SDHD-related tumor retained this region, warranting further investigation into the mechanism underlying parent-of-origin tumorigenesis.
Subjects
SDHD‐related paraganglioma
parent‐of‐origin tumorigenesis
single nucleotide variant
targeted NGS
Type
journal article