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.
Lai et al. (Thu,) studied this question.