Absence of EIF1AX, PPM1D, and CHEK2 mutations reported in Thyroid Cancer Genome Atlas (TCGA) in a large series of thyroid cancer

Endocrine. 2019 Jan;63(1):94-100. doi: 10.1007/s12020-018-1762-6. Epub 2018 Sep 29.

Abstract

Introduction: The Thyroid Cancer Genome Atlas (TCGA) was a major project that significantly clarified the key underlying genetic aberrations in papillary thyroid cancer. It confirmed the previously known somatic mutations and gene fusions and disclosed additional genetic alterations that were previously unknown. Among the most significant novel genetic mutations were those in EIF1AX, PPM1D, and CHEK2.

Objectives: We sought to determine the rates of these novel genetic alterations in a large sample of our patients to test the prevalence, reproducibility, and significance of these findings.

Patients and methods: We studied thyroid cancer (TC) tumor tissues from 301 unselected patients using polymerase chain reaction (PCR) and direct Sanger sequencing. DNA was isolated from paraffin-embedded formalin-fixed tumor tissue. Exons and exon-intron boundaries harboring the previously reported mutations in TCGA were amplified using PCR and directly sequenced.

Results: We found only one of the 301 tumors (0.3%) harboring A113_splice site mutation at the intron 5/exon 6 splice site of EIF1AX gene. Apart from this single mutation, none of the 301 tumors harbored any of the previously reported mutations in any of the three genes, EIF1AX, PPM1D, and CHEK2. A number of previously reported single nucleotide polymorphisms (SNP) were found in CHEK2, PPM1D but not in EIF1AX. These include CHEK2 SNPs, rs375130261, rs200928781, rs540635787, rs142763740, and rs202104749. The PPM1D SNPs rs771831676 and rs61757742 were present in 1.49% and 0.74%, respectively. Each of these SNPs was present in a heterozygous form in 100% of the tumors. An additional analysis of these samples for the most frequently reported mutations in DTC such as BRAFV600E, TERT promoter, and RAS showed a prevalence of 38.87% (117/301), 11.96% (36/301), and 7.64% (23/301), respectively.

Conclusions: Except for a rare A113_splice site mutation in EIF1AX, other recently described somatic mutations in EIF1AX, PPM1D, and CHEK2 were absent in this large series of patients with TC from a different racial group (Saudi Arabia). This might be related to the different techniques used (PCR and direct sequencing) or low density of the mutants. It might also reflect racial differences in the rate of these mutations.

Keywords: Mutations; TCGA; Thyroid Cancer Genome Atlas; Thyroid cancer.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Carcinoma, Papillary / epidemiology
  • Carcinoma, Papillary / genetics*
  • Checkpoint Kinase 2 / genetics*
  • Child
  • DNA, Neoplasm / genetics
  • Databases, Genetic*
  • Eukaryotic Initiation Factor-1 / genetics*
  • Exons / genetics
  • Female
  • Gene Frequency
  • Genome, Human*
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide
  • Prevalence
  • Protein Phosphatase 2C / genetics*
  • Saudi Arabia / epidemiology
  • Thyroid Neoplasms / epidemiology
  • Thyroid Neoplasms / genetics*
  • Young Adult

Substances

  • DNA, Neoplasm
  • Eukaryotic Initiation Factor-1
  • eukaryotic peptide initiation factor-1A
  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • PPM1D protein, human
  • Protein Phosphatase 2C