Secondary Findings in Turkish Pituitary Neuroendocrine Patients

Year 2024, Volume: 14 Issue: 4, 1021 - 1027, 29.12.2024

Ceren Alavanda , Ayşenur Biber , Berre Altaş , Fatma Berna Çörekçi , Fatma Boz , Zeynep Su Acar , İlter Güney

https://doi.org/10.33808/clinexphealthsci.1444282

Abstract

Objective: A secondary finding (SF) is characterized as a genetic variant that could have medical significance but is not connected to the primary purpose of the testing. SFs were published in various communities with diverse ethnic backgrounds, however, there is limited data for patient groups with specific clinical conditions.
Methods: A total of 46 PitNETs patients were included in this study. The 81 genes recommended by the latest ACMG SF guideline (v3.2) were screened in 46 Turkish pituitary neuroendocrine tumor (PitNET) patients.
Results: For the NGS study, ''The TrueSight One Expanded'' sequencing kit containing 6.704 genes (including ACMG SF v3.2 genes) was used, and sequencing was performed using the Illumina Nextseq 550 platform. In the 81 genes included in ACMG v3.2, a total of 9.430 variants were detected in 46 patients. After filtration steps, in 3 (6.5%) patients, a total of 4 different pathogenic variants were detected in LMNA, APOB, RYR2, and TTN genes. Heterozygous c.5464del (p.Ile1822Serfs*8) variant in the RYR2 gene was novel. Additionally, in 11 patients (23.9%), a total of 13 heterozygous recurrent variants were detected in 5 different genes (BTD, HFE, GAA, MUTYH, and ATP7B) associated with autosomal recessive diseases.
Conclusion:The limited knowledge about the genetic etiology of PitNETs makes it inevitable that studies conducted in this field will contribute to shedding light on the etiology. This study, being the first investigation of SFs in PitNET patients, will make a valuable contribution to the literature.

Keywords

Pituitary neuroendocrine tumors, secondary finding, next-generation sequencing, american college of medical genetics and genomics

References

• Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab. 1990;71(6):1427-1433. DOI: 10.1210/jcem-71-6-1427.
• Marques P, Korbonits M. Genetic aspects of pituitary adenomas. Endocrinol Metab Clin North Am. 2017;46(2):335-374. DOI: 10.1016/j.ecl.2017.01.004.
• Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O'Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15(7):565-574. DOI: 10.1038/gim.2013.73.
• Miller DT, Lee K, Abul-Husn NS, Amendola LM, Brothers K, Chung WK, Gollob MH, Gordon AS, Harrison SM, Hershberger RE, Klein TE, Richards CS, Stewart DR, Martin CL; ACMG Secondary Findings Working Group. ACMG SF v3.2 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2023;25(8):100866. DOI: 10.1016/j.gim.2023.100866.
• Olfson E, Cottrell CE, Davidson NO, Gurnett CA, Heusel JW, Stitziel NO, Chen LS, Hartz S, Nagarajan R, Saccone NL, Bierut LJ. Identification of medically actionable secondary findings in the 1000 genomes. PLoS One 2015;10(9):e0135193. DOI: 10.1371/journal.pone.0135193.
• Tang CS, Dattani S, So MT, Cherny SS, Tam PKH, Sham PC, Garcia-Barcelo MM. Actionable secondary findings from whole-genome sequencing of 954 East Asians. Hum Genet. 2018;137(1):31-37. DOI: 10.1007/s00439-017-1852-1.
• Arslan Ateş E, Türkyilmaz A, Yıldırım Ö, Alavanda C, Polat H, Demir Ş, Çebi AH, Geçkinli BB, Güney Aİ, Ata P, Arman A. Secondary findings in 622 Turkish clinical exome sequencing data. J Hum Genet. 2021;66(11):1113-1119. DOI: 10.1038/s10038-021-00936-8.
• Aloraini T, Alsubaie L, Alasker S, Al Muitiri A, Alswaid A, Eyiad W, Al Mutairi F, Ababneh F, Alfadhel M, Alfares A. The rate of secondary genomic findings in the Saudi population. Am J Med Genet A. 2022;188(1):83-88. DOI: 10.1002/ajmg.a.62491.
• Skrahin A, Cheema HA, Hussain M, Rana NN, Rehman KU, Kumar R, Oprea G, Ameziane N, Rolfs A, Skrahina V. Secondary findings in a large Pakistani cohort tested with whole genome sequencing. Life Sci Alliance 2023;6(3):e202201673. DOI: 10.26508/lsa.202201673.
• Martone S, Buonagura AT, Marra R, Rosato BE, Del Giudice F, Bonfiglio F, Capasso M, Iolascon A, Andolfo I, Russo R. Clinical exome-based panel testing for medically actionable secondary findings in a cohort of 383 Italian participants. Front Genet. 2022;13:956723. DOI: 10.3389/fgene.2022.956723.
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
• Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, Massouras A. VarSome: the human genomic variant search engine. Bioinformatics 2019;35(11):1978-1980. DOI: 10.1093/bioinformatics/bty897.
• Kandert S, Wehnert M, Müller CR, Buendia B, Dabauvalle MC. Impaired nuclear functions lead to increased senescence and inefficient differentiation in human myoblasts with a dominant p.R545C mutation in the LMNA gene. Eur J Cell Biol. 2009;88(10):593-608. DOI: 10.1016/j.ejcb.2009.06.002.
• Kars ME, Başak AN, Onat OE, Bilguvar K, Choi J, Itan Y, Çağlar C, Palvadeau R, Casanova JL, Cooper DN, Stenson PD, Yavuz A, Buluş H, Günel M, Friedman JM, Özçelik T. The genetic structure of the Turkish population reveals high levels of variation and admixture. Proc Natl Acad Sci U S A. 2021;118(36):e2026076118. DOI: 10.1073/pnas.2026076118.
• Kandert S, Wehnert M, Müller CR, Buendia B, Dabauvalle MC. Impaired nuclear functions lead to increased senescence and inefficient differentiation in human myoblasts with a dominant p.R545C mutation in the LMNA gene. Eur J Cell Biol. 2009;88(10):593-608. DOI:10.1016/j.ejcb.2009.06.002
• Shimazu S, Nagamura Y, Yaguchi H, Ohkura N, Tsukada T. Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms. Cancer Sci. 2011;102(11):2097-2102. DOI:10.1111/j.1349-7006.2011.02055.x.
• Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, Bennett RL, Jones KL, Tokita MJ, Bennett JT, Kim JH, Rosenthal EA, Kim DS; National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project; Tabor HK, Bamshad MJ, Motulsky AG, Scott CR, Pritchard CC, Walsh T, Burke W, Raskind WH, Byers P, Hisama FM, Nickerson DA, Jarvik GP. Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am J Hum Genet. 2013;93(4):631-640. DOI: 10.1016/j.ajhg.2013.08.006.
• Chetruengchai W, Shotelersuk V. Actionable secondary findings in the 73 ACMG-recommended genes in 1559 Thai exomes. J Hum Genet. 2022;67(3):137-142. DOI: 10.1038/s10038-021-00982-2.
• Jain A, Gandhi S, Koshy R, Scaria V. Incidental and clinically actionable genetic variants in 1005 whole exomes and genomes from Qatar. Mol Genet Genomics. 2018;293(4):919-929. DOI: 10.1007/s00438-018-1431-8.
• Elfatih A, Mifsud B, Syed N, Badii R, Mbarek H, Abbaszadeh F; Qatar Genome Program Research Consortium; Estivill X. Actionable genomic variants in 6045 participants from the Qatar Genome Program. Hum Mutat. 2021. DOI: 10.1002/humu.24278.
• Kasak L, Lillepea K, Nagirnaja L, Aston KI, Schlegel PN, Gonçalves J, Carvalho F, Moreno-Mendoza D, Almstrup K, Eisenberg ML, Jarvi KA, O'Bryan MK, Lopes AM, Conrad DF; GEMINI Consortium; Punab M, Laan M. Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management. Hum Reprod. 2022;37(7):1652-1663. DOI: 10.1093/humrep/deac100.
• Oladayo A, Gowans LJJ, Awotoye W, Alade A, Busch T, Naicker T, Eshete MA, Adeyemo WL, Hetmanski JB, Zeng E, Adamson O, Adeleke C, Li M, Sule V, Kayali S, Olotu J, Mossey PA, Obiri-Yeboah S, Buxo CJ, Beaty T, Taub M, Donkor P, Marazita ML, Odukoya O, Adeyemo AA, Murray JC, Prince A, Butali A. Clinically actionable secondary findings in 130 triads from sub-Saharan African families with non-syndromic orofacial clefts. Mol Genet Genomic Med. 2023;11(10):e2237. DOI: 10.1002/mgg3.2237.
• Colas C, Bonadona V, Baert-Desurmont S, Bonnet D, Coulet F, Dhooge M, Saurin JC, Remenieras A, Bignon YJ, Caron O, De Pauw A, Buisine MP, Buecher B. MUTYH-associated polyposis: Review and update of the French recommendations established in 2012 under the auspices of the National Cancer Institute (INCa). Eur J Med Genet. 2020;63(12):104078. DOI: 10.1016/j.ejmg.2020.104078.
• Scarpa A, Chang DK, Nones K, Corbo V, Patch AM, Bailey P, Lawlor RT, Johns AL, Miller DK, Mafficini A, Rusev B, Scardoni M, Antonello D, Barbi S, Sikora KO, Cingarlini S, Vicentini C, McKay S, Quinn MC, Bruxner TJ, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543(7643):65-71. DOI: 10.1038/nature21063.
• Simbolo M, Bilotta M, Mafficini A, Luchini C, Furlan D, Inzani F, Petrone G, Bonvissuto D, La Rosa S, Schinzari G, Bianchi A, Rossi E, Menghi R, Giuliante F, Boccia S, Scarpa A, Rindi G. Gene expression profiling of pancreas neuroendocrine tumors with different ki67-based grades. Cancers (Basel). 2021;13(9):2054. DOI: 10.3390/cancers13092054.
• Bengtsson D, Joost P, Aravidis C, Askmalm Stenmark M, Backman AS, Melin B, von Salomé J, Zagoras T, Gebre-Medhin S, Burman P. Corticotroph pituitary carcinoma in a patient with lynch syndrome (ls) and pituitary tumors in a nationwide ls cohort. J Clin Endocrinol Metab. 2017;102(11):3928-3932. DOI: 10.1210/jc.2017-01401.