Horm Metab Res 2017; 49(06): 452-456
DOI: 10.1055/s-0043-107244
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

T372R Mutation Status in Yin Yang 1 Gene in Insulinoma Patients

Khushboo Irshad
1   Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
,
Viveka P. Jyotsna
2   Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India
,
Shipra Agarwal
3   Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
,
Kunzang Chosdol
1   Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
,
Sujoy Pal
4   Department of Gastro-intestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
,
Rakesh Kumar Deepak
3   Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
› Author Affiliations
Further Information

Publication History

received 21 September 2016

accepted 21 March 2017

Publication Date:
04 May 2017 (online)

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.

Supporting Information

 
  • References

  • 1 Jyotsna VP, Malik E, Birla S, Sharma A. Novel MEN 1 gene findings in rare sporadic insulinoma-a case control study. BMC Endocr Disord 2015; 15: 44
  • 2 Creutzfeldt W, Creutzfeldt C, Frerichs H, Track NS, Arnold R. Histochemistry, ultrastructure and hormone content of human insulinomas. Horm Metab Res 1976; Suppl 6: 7-18
  • 3 Arya VB, Mohammed Z, Blankenstein O, De Lonlay P, Hussain K. Hyperinsulinaemic hypoglycaemia. Horm Metab Res 2014; 46: 157-170
  • 4 Jyotsna VP, Rangel N, Pal S, Seith A, Sahni P, Ammini AC. Insulinoma: Diagnosis and surgical treatment. Retrospective analysis of 31 cases. Indian J Gastroenterol 2006; 25: 244-247
  • 5 Cao Y, Gao Z, Li L, Jiang X, Shan A, Cai J, Peng Y, Li Y, Huang X, Wang J, Wei Q, Qin G, Zhao J, Jin X, Liu L, Wang W, Ning G. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nat Commun 2013; 4: 2810
  • 6 Capurso G, Archibugi L, Delle Fave G. Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci 2015; 22: 594-601
  • 7 Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz Jr. LA, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 2011; 331: 1199-1203
  • 8 Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, della Peruta M, Piemonti L, Capurso G, Di Florio A, delle Fave G, Pederzoli P, Croce CM, Scarpa A. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 2010; 28: 245-255
  • 9 Yuan F, Shi M, Ji J, Shi H, Zhou C, Yu Y, Liu B, Zhu Z, Zhang J. KRAS and DAXX/ATRX gene mutations are correlated with the clinicopathological features, advanced diseases, and poor prognosis in Chinese patients with pancreatic neuroendocrine tumors. Int J Biol Sci 2014; 10: 957-965
  • 10 Gordon S, Akopyan G, Garban H, Bonavida B. Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene 2006; 25: 1125-1142
  • 11 Shi Y, Lee JS, Galvin KM. Everything you have ever wanted to know about Yin Yang 1. Biochim Biophys Acta 1997; 1332: F49-F66
  • 12 Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 2007; 450: 736-740
  • 13 Cromer MK, Choi M, Nelson-Williams C, Fonseca AL, Kunstman JW, Korah RM, Overton JD, Mane S, Kenney B, Malchoff CD, Stalberg P, Akerstrom G, Westin G, Hellman P, Carling T, Bjorklund P, Lifton RP. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas. Proc Natl Acad Sci USA 2015; 112: 4062-4067
  • 14 Nicholson S, Whitehouse H, Naidoo K, Byers RJ. Yin Yang 1 in human cancer. Crit Rev Oncog 2011; 16: 245-260
  • 15 Huerta-Yepez S, Liu H, Baritaki S, Del Lourdes Cebrera-Munoz M, Rivera-Pazos C, Maldonado-Valenzuela A, Valencia-Hipolito A, Vega MI, Chen H, Berenson JR, Bonavida B. Overexpression of Yin Yang 1 in bone marrow-derived human multiple myeloma and its clinical significance. Int J Oncol 2014; 45: 1184-1192
  • 16 Zhang S, Jiang T, Feng L, Sun J, Lu H, Wang Q, Pan M, Huang D, Wang X, Wang L, Jin H. Yin Yang-1 suppresses differentiation of hepatocellular carcinoma cells through the downregulation of CCAAT/enhancer-binding protein alpha. J Mol Med (Berl) 2012; 90: 1069-1077
  • 17 Yang Y, Zhou L, Lu L, Wang L, Li X, Jiang P, Chan LK, Zhang T, Yu J, Kwong J, Cheung TH, Chung T, Mak K, Sun H, Wang H. A novel miR-193a-5p-YY1-APC regulatory axis in human endometrioid endometrial adenocarcinoma. Oncogene 2013; 32: 3432-3442
  • 18 Blattler SM, Cunningham JT, Verdeguer F, Chim H, Haas W, Liu H, Romanino K, Ruegg MA, Gygi SP, Shi Y, Puigserver P. Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling. Cell Metab 2012; 15: 505-517
  • 19 Verdeguer F, Blattler SM, Cunningham JT, Hall JA, Chim H, Puigserver P. Decreased genetic dosage of hepatic Yin Yang 1 causes diabetic-like symptoms. Mol Endocrinol 2014; 28: 308-316
  • 20 Lichtenauer UD, Di Dalmazi G, Slater EP, Wieland T, Kuebart A, Schmittfull A, Schwarzmayr T, Diener S, Wiese D, Thasler WE, Reincke M, Meitinger T, Schott M, Fassnacht M, Bartsch DK, Strom TM, Beuschlein F. Frequency and clinical correlates of somatic Ying Yang 1 mutations in sporadic insulinomas. J Clin Endocrinol Metab 2015; 100: E776-E782
  • 21 Babouee Flury B, Weisser M, Prince SS, Bubendorf L, Battegay M, Frei R, Goldenberger D. Performances of two different panfungal PCRs to detect mould DNA in formalin-fixed paraffin-embedded tissue: What are the limiting factors?. BMC Infect Dis 2014; 14: 692
  • 22 Potluri K, Mahas A, Kent MN, Naik S, Markey M. Genomic DNA extraction methods using formalin-fixed paraffin-embedded tissue. Anal Biochem 2015; 486: 17-23
  • 23 Nikfarjam M, Warshaw AL, Axelrod L, Deshpande V, Thayer SP, Ferrone CR, Fernandez-del Castillo C. Improved contemporary surgical management of insulinomas: A 25-year experience at the Massachusetts General Hospital. Ann Surg 2008; 247: 165-172
  • 24 Jing L, Su L, Ring BZ. Ethnic background and genetic variation in the evaluation of cancer risk: a systematic review. PLoS One 2014; 9: e97522
  • 25 Tan DS, Mok TS, Rebbeck TR. Cancer genomics: Diversity and disparity across ethnicity and geography. J Clin Oncol 2016; 34: 91-101
  • 26 Mravcova M, Chovanova L, Paulikova L, Vlcek M, Rovensky J, Killinger Z, Wendl J, Imrich R. Genetics of neuroendocrine factors in rheumatoid arthritis. Horm Metab Res 2015; 47: 411-417
  • 27 Nikolakopoulou P, Poser SW, Masjkur J, Fernandez Rubin de Celis M, Toutouna L, Andoniadou CL, McKay RD, Chrousos G, Ehrhart-Bornstein M, Bornstein SR, Androutsellis-Theotokis A. STAT3-Ser/Hes3 signaling: A new molecular component of the neuroendocrine system?. Horm Metab Res 2016; 48: 77-82
  • 28 Delgado Verdugo A, Crona J, Maharjan R, Hellman P, Westin G, Bjorklund P. Exome sequencing and CNV Analysis on chromosome 18 in small intestinal neuroendocrine tumors: Ruling out a suspect?. Horm Metab Res 2015; 47: 452-455