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Recurrent Somatic MAP2K1 Mutations in Papillary Thyroid Cancer and Colorectal Cancer.

ABSTRACT: Mitogen-activated protein kinase kinase 1 (MAP2K1) is a dual specificity protein kinase that phosphorylates both threonine and tyrosine residues in ERK. MAP2K1 mutations have been identified in several cancers. However, their role in Middle Eastern papillary thyroid cancer (PTC) and colorectal cancer (CRC) is lacking. In this study, we evaluated the prevalence of MAP2K1 mutations in a large cohort of Middle Eastern PTC and CRC using whole-exome and Sanger sequencing technology. In the discovery cohort of 100 PTC and 100 CRC cases (comprising 50 MAPK mutant and 50 MAPK wildtype cases each), we found one MAP2K1 mutation each in PTC and CRC, both of which were MAPK wildtype. We further analyzed 286 PTC and 289 CRC MAPK wildtype cases and found three MAP2K1 mutant PTC cases and two MAP2K1 mutant CRC cases. Thus, the overall prevalence of MAP2K1 mutation in MAPK wildtype cases was 1.1% (4/336) in PTC and 0.9% (3/339) in CRC. Histopathologically, three of the four MAP2K1 mutant PTC cases were follicular variant and all four tumors were unifocal with absence of extra-thyroidal extension. All the three CRC cases harboring MAP2K1 mutation were of older age (> 50 years) and had moderately differentiated stage II/III tumors located in the left colon. In conclusion, this is the first comprehensive report of MAP2K1 somatic mutations prevalence in PTC and CRC from this ethnicity. The mutually exclusive nature of MAP2K1 and MAPK mutations suggests that each of these mutation may function as an initiating mutation driving tumorigenesis through MAPK signaling pathway.

SUBMITTER: Bu R

PROVIDER: S-EPMC8144646 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTwo recurrent TERT (telomerase reverse transcriptase) promoter mutations, C228T and C250T, have been reported in thyroid carcinomas and were correlated with high-risk clinicopathological features and a worse prognosis. Although far more frequent in the poorly differentiated and undifferentiated thyroid cancer, the TERT promoter mutations play a significant role on PTC recurrence and disease-specific mortality. However, the prevalence varies considerably through studies and it is uncertain if these differences are due to population variation or the methodology used to detect TERT mutations. In this study we aim to compare three different strategies to detect TERT promoter mutations in PTC.MethodsDNA was isolated from formalin-fixed paraffin-embedded (FFPE) specimens from 89 PTC and 40 paired lymph node metastases. The prevalence of the hot spot TERT C228T and C250T mutations was assessed in FFPE samples using TaqMan SNP genotyping assays. Random samples were tested by Sanger Sequencing and droplet digital PCR (ddPCR).ResultsIn general, 16 out of 89 (18%) PTC samples and 14 out of 40 (35%) lymph node metastases harbored TERT promoter mutations by TaqMan assay. Sanger sequencing, performed in random selected samples, failed to detect TERT mutations in four samples that were positive by TaqMan SNP genotyping assay. Remarkably, ddPCR assay allowed detection of TERT promoter mutations in six samples that harbor very low mutant allele frequency (≤ 2%) and were negative by both genotype assay and Sanger Sequencing.ConclusionThis study observed a good concordance among the methodologies used to detect TERT promoter mutations when a high percentage of mutated alleles was present. Sanger analysis demonstrated a limit of detection for mutated alleles. Therefore, the prevalence of TERT promoter mutations in PTC may be higher than previously reported, since most studies have conventionally used Sanger sequencing. The efficient characterization of genetic alterations that are used as preoperative or postoperative diagnostic, risk stratification of the patient and individualized treatment decisions, mainly in highly heterogeneous tumors, require highly sensitive and specific approaches.

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Recurrent Somatic MAP2K1 Mutations in Papillary Thyroid Cancer and Colorectal Cancer.

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