Somatic Mutation Profiling in Head and Neck Paragangliomas

Abstract

Context Head and neck paragangliomas (HNPGLs) are rare neoplasms with a high degree of heritability. Nevertheless, paragangliomas present as polygenic diseases caused by combined alterations in multiple genes, however, many driver changes remain unknown. Objective The objective of the study was to analyze somatic mutation profiles in HNPGLs. Design Whole-exome sequencing of 42 tumors and matched normal tissues obtained from Russian patients with HNPGLs was carried out. Somatic mutation profiling included variant calling and utilizing of MutSig and SigProfiler packages. Results 57% of patients harbored germline and somatic variants in the PGL susceptibility genes or potentially related genes. Somatic variants in novel genes were found in 17% of patients without mutations in any known PGL-related genes. The studied cohort was characterized by six significantly mutated genes: SDHD, BCAS4, SLC25A14, RBM3, TP53, and ASCC1, as well as four COSMIC SBS-96 mutational signatures (SBS5, SBS29, SBS1, and SBS7b). Tumors with germline variants specifically displayed SBS11 and SBS19, when SBS33 specific mutational signature was identified for cases without those. B allele frequency analysis of copy number variations revealed loss of heterozygosity of the wild-type allele in one patient with germline mutation c.287-2A>G in the SDHB gene. In patients with germline mutation c.A305G in the SDHD gene, frequent potential loss of chromosome 11 was observed. Conclusion These results give an understanding of somatic changes and the mutational landscape associated with HNPGLs and are important for the identification of molecular mechanisms involved in tumor development.

Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-basedde novomutation analyses

“…To identify the operational mutational signatures in the samples, we generated trinucleotide spectra by considering the flanking bases on either side of mutated bases 31 . We used SigProfilerExtractor, 32,33 34,35 , version 1.1.14, to decompose the trinucleotide spectrum observed in our data and assign them to known COSMIC mutational signatures (version 3.3) and reconstruct the original mutation matrix. 34 We then calculated the cosine similarity between the spectra from both blood and sperm, and the COSMIC signatures.…”

Genetic changes in the FH gene cause vagal paraganglioma

“…Somatic variants were discovered using GATK Mutect2 ( 20 ). First, we created a list of variants observed in normal tissues, which were obtained from patients with HNPGLs (PoN, panel of norms) ( 6 ), with the GATK Mutect2, GenomicsDBImport and CreateSomaticPanelOfNormals tools. Then we supplied it to the final GATK Mutect2 search for tumor-paired sample which was started with the default parameters except for max-reads-per-alignment-start 0, –f1r2-tar-gz <filename>, –germline-resource <gnomad_vcf>, -A StrandBiasBySample, -A StrandOddsRatio, -A AS_StrandOddsRatio .…”

“…Recently, we presented a series of genetic analyses of HNPGLs covering VPGLs. Germline mutations have been observed in PPGL susceptibility genes, such as SDHB , SDHD , NF1 , FH , and IDH2 , as well as in candidate PPGL-associated genes, ACLY , OGDH , and PDHA2 ( 6 ). Most SDHx -mutated VPGLs were multifocal tumors that manifest simultaneously as carotid paragangliomas.…”

“…Most SDHx -mutated VPGLs were multifocal tumors that manifest simultaneously as carotid paragangliomas. Somatic variants of ACO1 , PIK3CA , and TP53 have been identified ( 6 ). Ding et al.…”

“…This study presents an analysis of the clinical phenotype and molecular genetics of VPGL with germline missense variant in the FH gene, which have been previously revealed in a comprehensive mutation profile analysis of HNPGLs ( 6 ). FH is considered a susceptibility gene for PPGLs; however, the frequency of FH -related cases is low (~ 1%) ( 14 ).…”