T372R Mutation Status in Yin Yang 1 Gene in Insulinoma Patients

Abstract

Insulinomas are rare pancreatic neuroendocrine tumors. The genetic causes underlying insulinoma are still being investigated. Recently, 3 independent studies reported a recurrent somatic mutation in YY1 gene (C>G; Thr372Arg) among insulinoma patients belonging to Chinese and Western Caucasian populations, which was found to increase insulin secretion by β-cells. However, the status of this key gene variation remains unknown in patients of other ethnicities. We, therefore, screened Indian sporadic insulinoma patients for YY1 T372R mutation in the present study. Seventeen patients diagnosed with insulinoma were recruited retrospectively and their records of family history and clinical parameters were collected. Formalin-fixed paraffin-embedded tumor tissues were used to extract genomic DNA, which was subjected to PCR amplification of YY1 exon 5, followed by Sanger sequencing. Nucleotide sequences thus obtained were aligned against the documented sequence of YY1 exon 5. We found absence of C to G mutation at YY1 codon 372 in all 17 (100%) insulinoma tissues analyzed. On comparison with the mutation frequency observed in the Chinese patients, our results point to genetic heterogeneity in the pathogenesis of insulinoma. This is the first report on the status of YY1 T372R in insulinoma cases of Indian origin. This also warrants analysis of other documented as well as novel mutations in genes in insulinoma tumorigenesis.

Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms

“…Mutation prevalence ranged from 10% to 30% of cases, with the higher proportion found in Asian patients (191–194). A Sanger sequencing study from India did not find this hotspot Yin Yang 1 mutation in 17 insulinomas (195), whereas a similar study on 23 US patients found two hotspot mutations in 23 (8%) insulinomas (196). This mutation was associated with a late onset of the tumor and was reported to affect YY protein transcriptional activity.…”

Frequency and consequence of the recurrent YY1 p.T372R mutation in sporadic insulinomas

“…However, four different WES studies of sporadic insulinomas found <2% with somatic MEN1 mutation, but rather they found a somatic heterozygous recurrent mutation in the Yin Yang 1 ( YY1 ) gene (c.C1115G/p.T372R) in 30%, 33% and 13% of tumor samples (Cao, et al 2013; Cromer, et al 2015; Lichtenauer, et al 2015; Wang, et al 2017). Another study from India did not find this YY1 mutation in their insulinoma samples (Irshad, et al 2017). To determine the frequency and consequence of the recurrent YY1 mutation we analyzed a cohort of 23 sporadic insulinomas.…”

Effect of the transcription factor YY1 on the development of pancreatic endocrine and exocrine tumors: a narrative review

“…Lichtenauer et al analyzed 47 samples from German insulinoma patients and found that the frequency of the YY1 T372R mutation was 13% (6/47), significantly lower than that in the Chinese and Caucasian patient cohorts [ 66 ]. In addition, Irshad et al screened patients with sporadic insulinoma in India for the YY1 T372R mutation and found none of the above mentioned missense mutations at YY1 codon 372 in any of the 17 (100%) islet tissues analyzed [ 70 ]. Therefore, differences in genetic makeup based on ethnicity may affect disease susceptibility.…”