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01-12-2021 | Parathyroid Cancer | Original Article

Spectrum of mitochondrial genomic variation in parathyroid neoplasms

Authors: Ya Hu, Xiang Zhang, Ou Wang, Xiaoping Xing, Ming Cui, Mengyi Wang, Chengli Song, Quan Liao

Published in: Endocrine | Issue 3/2021

Abstract

Purpose

Mitochondrial DNA (mtDNA) variations have been implicated in various cancer types. Several attempts have been made in benign parathyroid adenoma (PA); however, mtDNA variants and copy number alterations have not been investigated in parathyroid carcinoma (PC). The present study aimed to explore the variations in the mitochondrial genome in parathyroid neoplasms.

Methods

In this study, ultradeep targeted sequencing of mtDNA was performed in 12 cases with PC and 25 cases with PA. Germline and somatic variants in the mitochondrial genome were analysed according to clinical features. The mtDNA copy number relative to nuclear DNA was measured.

Results

A total of 821 germline variants and 23 somatic mutations were identified. All 160 germline nonsynonymous variants in the coding sequence (CDS) were predicted to be likely benign, and germline variants frequently occurred (26.3%) in the displacement loop region. Tumour somatic mutation in a CDS with heteroplasmic factor (HF) >0.8 showed a higher mtDNA copy number (p = 0.039). Using Spearman’s rank test, tumour mtDNA copy number revealed a positive correlation with serum levels of intact parathyroid hormone and calcium.

Conclusion

Our results demonstrate that null recurrent mtDNA mutational hotspots were PC specific. An increased mtDNA copy number in parathyroid neoplasms was associated with somatic CDS mutations with a high HF and major clinical features. Larger cohort investigations should be performed in future analyses.

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P.K. Lee, S.L. Jarosek, B.A. Virnig, M. Evasovich, T.M. Tuttle, Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer 109, 1736–1741 (2007). https://doi.org/10.1002/cncr.22599CrossRefPubMed

O. Wang, C. Wang, M. Nie, Q. Cui, H. Guan, Y. Jiang, M. Li, W. Xia, X. Meng, X. Xing, Novel HRPT2/CDC73 gene mutations and loss of expression of parafibromin in Chinese patients with clinically sporadic parathyroid carcinomas. PLoS ONE 7, e45567 (2012). https://doi.org/10.1371/journal.pone.0045567CrossRefPubMedPubMedCentral

E.A. Asare, C. Sturgeon, D.J. Winchester, L. Liu, B. Palis, N.D. Perrier, D.B. Evans, D.P. Winchester, T.S. Wang, Parathyroid carcinoma: an update on treatment outcomes and prognostic factors from the National Cancer Data Base (NCDB). Ann. Surg. Oncol. 22, 3990–3995 (2015). https://doi.org/10.1245/s10434-015-4672-3CrossRefPubMed

K.T. Hsu, R.S. Sippel, H. Chen, D.F. Schneider, Is central lymph node dissection necessary for parathyroid carcinoma? Surgery 156, 1336–1341 (2014). https://doi.org/10.1016/j.surg.2014.08.005CrossRefPubMed

E.A. Schon, S. DiMauro, M. Hirano, Human mitochondrial DNA: roles of inherited and somatic mutations. Nat. Rev. Genet. 13, 878–890 (2012). https://doi.org/10.1038/nrg3275CrossRefPubMedPubMedCentral

W.X. Zong, J.D. Rabinowitz, E. White, Mitochondria and cancer. Mol. Cell 61, 667–676 (2016). https://doi.org/10.1016/j.molcel.2016.02.011CrossRefPubMedPubMedCentral

J.F. Hopkins, R.E. Denroche, J.A. Aguiar, F. Notta, A.A. Connor, J.M. Wilson, L.D. Stein, S. Gallinger, P.C. Boutros, Mutations in mitochondrial DNA from pancreatic ductal adenocarcinomas associate with survival times of patients and accumulate as tumors progress. Gastroenterology 154, 1620–1624.e5 (2018). https://doi.org/10.1053/j.gastro.2018.01.029CrossRefPubMed

A. Jain, S. Bakhshi, H. Thakkar, M. Gerards, A. Singh, Elevated mitochondrial DNA copy numbers in pediatric acute lymphoblastic leukemia: a potential biomarker for predicting inferior survival. Pediatr. Blood Cancer 65, (2018). https://doi.org/10.1002/pbc.26874

A.M.F. Kalsbeek, E.K.F. Chan, J. Grogan, D.C. Petersen, W. Jaratlerdsiri, R. Gupta, R.J. Lyons, A.M. Haynes, L.G. Horvath, J.G. Kench, P.D. Stricker, V.M. Hayes, Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer. Prostate 78, 25–31 (2018). https://doi.org/10.1002/pros.23440CrossRefPubMed

10.

H. Li, Z. Tian, Y. Zhang, Q. Yang, B. Shi, P. Hou, M. Ji, Increased copy number of mitochondrial DNA predicts poor prognosis of esophageal squamous cell carcinoma. Oncol. Lett. 15, 1014–1020 (2018). https://doi.org/10.3892/ol.2017.7416CrossRefPubMed

11.

A. Viale, P. Pettazzoni, C.A. Lyssiotis, H. Ying, N. Sánchez, M. Marchesini, A. Carugo, T. Green, S. Seth, V. Giuliani, M. Kost-Alimova, F. Muller, S. Colla, L. Nezi, G. Genovese, A.K. Deem, A. Kapoor, W. Yao, E. Brunetto, Y. Kang, M. Yuan, J.M. Asara, Y.A. Wang, T.P. Heffernan, A.C. Kimmelman, H. Wang, J.B. Fleming, L.C. Cantley, R.A. DePinho, G.F. Draetta, Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628–632 (2014). https://doi.org/10.1038/nature13611CrossRefPubMedPubMedCentral

12.

W.W. Wheaton, S.E. Weinberg, R.B. Hamanaka, S. Soberanes, L.B. Sullivan, E. Anso, A. Glasauer, E. Dufour, G.M. Mutlu, G.S. Budigner, N.S. Chandel, Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 3, e02242 (2014). https://doi.org/10.7554/eLife.02242CrossRefPubMedPubMedCentral

13.

K. Birsoy, T. Wang, W.W. Chen, E. Freinkman, M. Abu-Remaileh, D.M. Sabatini, An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162, 540–551 (2015). https://doi.org/10.1016/j.cell.2015.07.016CrossRefPubMedPubMedCentral

14.

M.S. Fliss, H. Usadel, O.L. Caballero, L. Wu, M.R. Buta, S.M. Eleff, J. Jen, D. Sidransky, Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 287, 2017–2019 (2000). https://doi.org/10.1126/science.287.5460.2017CrossRefPubMed

15.

Y.S. Ju, L.B. Alexandrov, M. Gerstung, I. Martincorena, S. Nik-Zainal, M. Ramakrishna, H.R. Davies, E. Papaemmanuil, G. Gundem, A. Shlien, N. Bolli, S. Behjati, P.S. Tarpey, J. Nangalia, C.E. Massie, A.P. Butler, J.W. Teague, G.S. Vassiliou, A.R. Green, M.Q. Du, A. Unnikrishnan, J.E. Pimanda, B.T. Teh, N. Munshi, M. Greaves, P. Vyas, A.K. El-Naggar, T. Santarius, V.P. Collins, R. Grundy, J.A. Taylor, D.N. Hayes, D. Malkin, C.S. Foster, A.Y. Warren, H.C. Whitaker, D. Brewer, R. Eeles, C. Cooper, D. Neal, T. Visakorpi, W.B. Isaacs, G.S. Bova, A.M. Flanagan, P.A. Futreal, A.G. Lynch, P.F. Chinnery, U. McDermott, M.R. Stratton, P.J. Campbell, Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. Elife 3, e02935 (2014). https://doi.org/10.7554/eLife.02935CrossRefPubMedCentral

16.

J. Costa-Guda, T. Tokura, S.I. Roth, A. Arnold, Mitochondrial DNA mutations in oxyphilic and chief cell parathyroid adenomas. BMC Endocr. Disord. 7, 8 (2007). https://doi.org/10.1186/1472-6823-7-8CrossRefPubMedPubMedCentral

17.

J. Müller-Höcker, S. Schäfer, S. Krebs, H. Blum, G. Zsurka, W.S. Kunz, H. Prokisch, P. Seibel, A. Jung, Oxyphil cell metaplasia in the parathyroids is characterized by somatic mitochondrial DNA mutations in NADH dehydrogenase genes and cytochrome c oxidase activity-impairing genes. Am. J. Pathol. 184, 2922–2935 (2014). https://doi.org/10.1016/j.ajpath.2014.07.015CrossRefPubMed

18.

R.V. Lloyd, R.Y. Osamura, G. Klöppel, J. Rosai. WHO/IARC Classification of Tumours: WHO Classification of Tumours of Endocrine Organs. (IARC, Lyon), 2017)

19.

Y. Hu, X. Zhang, O. Wang, Y. Bi, X. Xing, M. Cui, M. Wang, W. Tao, Q. Liao, Y. Zhao, The genomic profile of parathyroid carcinoma based on whole-genome sequencing. Int. J. Cancer 147, 2446–2457 (2020). https://doi.org/10.1002/ijc.33166CrossRefPubMed

20.

C. Calabrese, D. Simone, M.A. Diroma, M. Santorsola, C. Guttà, G. Gasparre, E. Picardi, G. Pesole, M. Attimonelli, MToolBox: a highly automated pipeline for heteroplasmy annotation and prioritization analysis of human mitochondrial variants in high-throughput sequencing. Bioinformatics 30, 3115–3117 (2014). https://doi.org/10.1093/bioinformatics/btu483CrossRefPubMedPubMedCentral

21.

D.C. Koboldt, Q. Zhang, D.E. Larson, D. Shen, M.D. McLellan, L. Lin, C.A. Miller, E.R. Mardis, L. Ding, R.K. Wilson, VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 22, 568–576 (2012). https://doi.org/10.1101/gr.129684.111CrossRefPubMedPubMedCentral

22.

N.J. Fredriksson, L. Ny, J.A. Nilsson, E. Larsson, Systematic analysis of noncoding somatic mutations and gene expression alterations across 14 tumor types. Nat. Genet. 46, 1258–1263 (2014). https://doi.org/10.1038/ng.3141CrossRefPubMed

23.

J.F. Hopkins, V.Y. Sabelnykova, J. Weischenfeldt, R. Simon, J.A. Aguiar, R. Alkallas, L.E. Heisler, J. Zhang, J.D. Watson, M.L.K. Chua, M. Fraser, F. Favero, C. Lawerenz, C. Plass, G. Sauter, J.D. McPherson, T. Van Der Kwast, J. Korbel, T. Schlomm, R.G. Bristow, P.C. Boutros, Mitochondrial mutations drive prostate cancer aggression. Nat. Commun. 8, 656 (2017). https://doi.org/10.1038/s41467-017-00377-yCrossRefPubMedPubMedCentral

24.

F.S. Hosnijeh, Q. Lan, N. Rothman, C. San Liu, W.L. Cheng, A. Nieters, P. Guldberg, A. Tjønneland, D. Campa, A. Martino, H. Boeing, A. Trichopoulou, P. Lagiou, D. Trichopoulos, V. Krogh, R. Tumino, S. Panico, G. Masala, E. Weiderpass, J.M. Huerta Castaño, E. Ardanaz, N. Sala, M. Dorronsoro, J.R. Quirós, M.J. Sánchez, B. Melin, A.S. Johansson, J. Malm, S. Borgquist, P.H. Peeters, H.B. Bueno-de-Mesquita, N. Wareham, K.T. Khaw, R.C. Travis, P. Brennan, A. Siddiq, E. Riboli, P. Vineis, R. Vermeulen, Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort. Blood 124, 530–535 (2014). https://doi.org/10.1182/blood-2013-10-532085CrossRefPubMedPubMedCentral

25.

L. Wang, H. Lv, P. Ji, X. Zhu, H. Yuan, G. Jin, J. Dai, Z. Hu, Y. Su, H. Ma, Mitochondrial DNA copy number is associated with risk of head and neck squamous cell carcinoma in Chinese population. Cancer Med 7, 2776–2782 (2018). https://doi.org/10.1002/cam4.1452CrossRefPubMedPubMedCentral

26.

E.D. Robin, R. Wong, Mitochondrial DNA molecules and virtual number of mitochondria per cell in mammalian cells. J. Cell. Physiol. 136, 507–513 (1988). https://doi.org/10.1002/jcp.1041360316CrossRefPubMed

27.

Q. Lan, U. Lim, C.S. Liu, S.J. Weinstein, S. Chanock, M.R. Bonner, J. Virtamo, D. Albanes, N. Rothman, A prospective study of mitochondrial DNA copy number and risk of non-Hodgkin lymphoma. Blood 112, 4247–4249 (2008). https://doi.org/10.1182/blood-2008-05-157974CrossRefPubMedPubMedCentral

28.

Y. He, J. Wu, D.C. Dressman, C. Iacobuzio-Donahue, S.D. Markowitz, V.E. Velculescu, L.A. Diaz, K.W. Kinzler, B. Vogelstein, N. Papadopoulos, Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature 464, 610–614 (2010). https://doi.org/10.1038/nature08802CrossRefPubMedPubMedCentral

29.

J. Müller-Höckey, Random cytochrome-C-oxidase deficiency of oxyphil cell nodules in the parathyroid gland. A mitochondrial cytopathy related to cell ageing? Pathol. Res. Pract. 188, 701–706 (1992). https://doi.org/10.1016/S0344-0338(11)80165-2CrossRef

30.

J. Müller-Höcker, D. Aust, J. Napiwotzky, C. Münscher, T.A. Link, P. Seibel, S.G. Schneeweiss, B. Kadenbach, Defects of the respiratory chain in oxyphil and chief cells of the normal parathyroid and in hyperfunction. Hum. Pathol. 27, 532–541 (1996). https://doi.org/10.1016/s0046-8177(96)90158-6CrossRefPubMed

31.

J. Müller-Höcker, S. Schäfer, W.C. Copeland, R. Wiesner, P. Seibel, Immunohistochemical detection of human mtDNA polymerase gamma and of human mitochondrial transcription factor A in cytochrome-c-oxidase-deficient oxyphil cells of hyperfunctional parathyroids. Virchows Arch 433, 529–536 (1998). https://doi.org/10.1007/s004280050285CrossRefPubMed

32.

A. Palodhi, S. Ghosh, N.K. Biswas, A. Basu, P.P. Majumder, A. Maitra, Profiling of genomic alterations of mitochondrial DNA in gingivobuccal oral squamous cell carcinoma: implications for disease progress. Mitochondrion 46, 361–369 (2019). https://doi.org/10.1016/j.mito.2018.09.006CrossRefPubMed

33.

L. Pereira, P. Soares, V. Máximo, D.C. Samuels, Somatic mitochondrial DNA mutations in cancer escape purifying selection and high pathogenicity mutations lead to the oncocytic phenotype: pathogenicity analysis of reported somatic mtDNA mutations in tumors. BMC Cancer 12, 53 (2012). https://doi.org/10.1186/1471-2407-12-53CrossRefPubMedPubMedCentral

34.

K. Popadin, K.V. Gunbin, K. Khrapko, Mitochondrial DNA mutations and cancer. Am. J. Pathol. 184, 2852–2854 (2014). https://doi.org/10.1016/j.ajpath.2014.09.001CrossRefPubMed

35.

M. Sanchez-Cespedes, P. Parrella, S. Nomoto, D. Cohen, Y. Xiao, M. Esteller, C. Jeronimo, R.C. Jordan, T. Nicol, W.M. Koch, M. Schoenberg, P. Mazzarelli, V.M. Fazio, D. Sidransky, Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors. Cancer Res. 61, 7015–7019 (2001)PubMed

36.

K. Ishikawa, K. Takenaga, M. Akimoto, N. Koshikawa, A. Yamaguchi, H. Imanishi, K. Nakada, Y. Honma, J. Hayashi, ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320, 661–664 (2008). https://doi.org/10.1126/science.1156906CrossRefPubMed

37.

S. Melov, J.M. Shoffner, A. Kaufman, D.C. Wallace, Marked increase in the number and variety of mitochondrial DNA rearrangements in aging human skeletal muscle. Nucleic Acids Res. 23, 4122–4126 (1995). https://doi.org/10.1093/nar/23.20.4122CrossRefPubMedPubMedCentral

38.

D.R. Marchington, G.M. Hartshorne, D. Barlow, J. Poulton, Homopolymeric tract heteroplasmy in mtDNA from tissues and single oocytes: support for a genetic bottleneck. Am. J. Hum. Genet. 60, 408–416 (1997)PubMedPubMedCentral

39.

R.M. Andrews, I. Kubacka, P.F. Chinnery, R.N. Lightowlers, D.M. Turnbull, N. Howell, Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat. Genet. 23, 147 (1999). https://doi.org/10.1038/13779CrossRefPubMed

40.

A. Lièvre, H. Blons, A.M. Houllier, O. Laccourreye, D. Brasnu, P. Beaune, P. Laurent-Puig, Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma. Br. J. Cancer 94, 692–697 (2006). https://doi.org/10.1038/sj.bjc.6602993CrossRefPubMedPubMedCentral

41.

V.W. Liu, Y. Wang, H.J. Yang, P.C. Tsang, T.Y. Ng, L.C. Wong, P. Nagley, H.Y. Ngan, Mitochondrial DNA variant 16189T>C is associated with susceptibility to endometrial cancer. Hum. Mutat. 22, 173–174 (2003). https://doi.org/10.1002/humu.10244CrossRefPubMed

42.

N. Shakhssalim, M. Houshmand, B. Kamalidehghan, A. Faraji, R. Sarhangnejad, S. Dadgar, M. Mobaraki, R. Rosli, M.H. Sanati, The mitochondrial C16069T polymorphism, not mitochondrial D310 (D-loop) mononucleotide sequence variations, is associated with bladder cancer. Cancer Cell Int. 13, 120 (2013). https://doi.org/10.1186/1475-2867-13-120CrossRefPubMedPubMedCentral

43.

A. Lemnrau, M.N. Brook, O. Fletcher, P. Coulson, K. Tomczyk, M. Jones, A. Ashworth, A. Swerdlow, N. Orr, M. Garcia-Closas, Mitochondrial DNA copy number in peripheral blood cells and risk of developing breast cancer. Cancer Res. 75, 2844–2850 (2015). https://doi.org/10.1158/0008-5472.can-14-1692CrossRefPubMed

44.

B. Thyagarajan, W. Guan, V. Fedirko, H. Barcelo, H. Tu, M. Gross, M. Goodman, R.M. Bostick, No association between mitochondrial DNA copy number and colorectal adenomas. Mol. Carcinog. 55, 1290–1296 (2016). https://doi.org/10.1002/mc.22370CrossRefPubMed

Title: Spectrum of mitochondrial genomic variation in parathyroid neoplasms
Authors: Ya Hu
Xiang Zhang
Ou Wang
Xiaoping Xing
Ming Cui
Mengyi Wang
Chengli Song
Quan Liao
Publication date: 01-12-2021
Publisher: Springer US
Keyword: Parathyroid Cancer
Published in: Endocrine / Issue 3/2021
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-021-02825-8

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