Top

01-04-2024 | Astrocytoma | Case Study

Loss of methylthioadenosine phosphorylase immunoreactivity correlates with poor prognosis and elevated uptake of ¹¹C-methionine in IDH-mutant astrocytoma

Authors: Toshihiro Yamamura, Kaoru Tamura, Daisuke Kobayashi, Motoki Inaji, Yuka Toyama, Hiroaki Wakimoto, Juri Kiyokawa, Shoko Hara, Yoji Tanaka, Tadashi Nariai, Kazuhide Shimizu, Kenji Ishii, Taketoshi Maehara

Published in: Journal of Neuro-Oncology

Abstract

Purpose

The proximate localization of MTAP, which encodes methylthioadenosine phosphorylase, and CDKN2A/B on Chromosome 9q21 has allowed the loss of MTAP expression as a surrogate for homozygous deletion of CDKN2A/B. This study aimed to determine whether MTAP status correlates with clinical outcomes and ¹¹C-methionine uptake in astrocytomas with IDH mutations.

Methods

We conducted immunohistochemistry for MTAP in 30 patients with astrocytoma, IDH-mutant who underwent ¹¹C-methionine positron emission tomography scans prior to surgical resection. The tumor-to-normal (T/N) ratio of ¹¹C-methionine uptake was calculated using the mean standardized uptake value (SUV) for tumor and normal brain tissues. Cox regression analysis was used for multivariate survival analysis.

Results

Among IDH-mutant astrocytomas, 26.7% (8/30) exhibited the loss of cytoplasmic MTAP expression, whereas 73.3% (22/30) tumors retained MTAP expression. The median progression-free survival (PFS) was significantly shorter in patients with MTAP loss than those with MTAP retention (1.88 years vs. 6.80 years, p = 0.003). The median overall survival (OS) was also shorter in patients with MTAP loss than in MTAP-retaining counterparts (5.23 years vs. 10.69 years, p = 0.019). Multivariate analysis identified MTAP status (hazard ratio (HR), 0.081) and extent of resection (HR, 0.104) as independent prognostic factors for PFS. Astrocytomas lacking cytoplasmic MTAP expression showed a significantly higher median T/N ratio for ¹¹C-methionine uptake than tumors retaining MTAP (2.12 vs. 1.65, p = 0.012).

Conclusion

Our study revealed that the loss of MTAP expression correlates with poor prognosis and an elevated T/N ratio of ¹¹C-methionine uptake in astrocytoma, IDH-mutant.

Available only for authorised users

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-1CrossRefPubMed

Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 23:1231–1251. https://doi.org/10.1093/neuonc/noab106CrossRefPubMedPubMedCentral

Appay R, Dehais C, Maurage CA, Alentorn A, Carpentier C, Colin C, Ducray F, Escande F, Idbaih A, Kamoun A, Marie Y, Mokhtari K, Tabouret E, Trabelsi N, Uro-Coste E, Delattre JY, Figarella-Branger D, Network P (2019) CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas. Neuro Oncol 21:1519–1528. https://doi.org/10.1093/neuonc/noz124CrossRefPubMedPubMedCentral

Shirahata M, Ono T, Stichel D, Schrimpf D, Reuss DE, Sahm F, Koelsche C, Wefers A, Reinhardt A, Huang K, Sievers P, Shimizu H, Nanjo H, Kobayashi Y, Miyake Y, Suzuki T, Adachi JI, Mishima K, Sasaki A, Nishikawa R, Bewerunge-Hudler M, Ryzhova M, Absalyamova O, Golanov A, Sinn P, Platten M, Jungk C, Winkler F, Wick A, Hanggi D, Unterberg A, Pfister SM, Jones DTW, van den Bent M, Hegi M, French P, Baumert BG, Stupp R, Gorlia T, Weller M, Capper D, Korshunov A, Herold-Mende C, Wick W, Louis DN, von Deimling A (2018) Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol 136:153–166. https://doi.org/10.1007/s00401-018-1849-4CrossRefPubMed

Jeuken J, Cornelissen S, Boots-Sprenger S, Gijsen S, Wesseling P (2006) Multiplex ligation-dependent probe amplification: a diagnostic tool for simultaneous identification of different genetic markers in glial tumors. J Mol Diagn 8:433–443. https://doi.org/10.2353/jmoldx.2006.060012CrossRefPubMedPubMedCentral

Chapel DB, Schulte JJ, Berg K, Churg A, Dacic S, Fitzpatrick C, Galateau-Salle F, Hiroshima K, Krausz T, Le Stang N, McGregor S, Nabeshima K, Husain AN (2020) MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma. Mod Pathol 33:245–254. https://doi.org/10.1038/s41379-019-0310-0CrossRefPubMed

Hida T, Hamasaki M, Matsumoto S, Sato A, Tsujimura T, Kawahara K, Iwasaki A, Okamoto T, Oda Y, Honda H, Nabeshima K (2017) Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: comparison with 9p21 FISH and BAP1 immunohistochemistry. Lung Cancer 104:98–105. https://doi.org/10.1016/j.lungcan.2016.12.017CrossRefPubMed

Kinoshita Y, Hamasaki M, Yoshimura M, Matsumoto S, Sato A, Tsujimura T, Ueda H, Makihata S, Kato F, Iwasaki A, Nabeshima K (2018) A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleuritis. Lung Cancer 125:198–204. https://doi.org/10.1016/j.lungcan.2018.09.019CrossRefPubMed

Hustinx SR, Leoni LM, Yeo CJ, Brown PN, Goggins M, Kern SE, Hruban RH, Maitra A (2005) Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion. Mod Pathol 18:959–963. https://doi.org/10.1038/modpathol.3800377CrossRefPubMed

10.

Hustinx SR, Hruban RH, Leoni LM, Iacobuzio-Donahue C, Cameron JL, Yeo CJ, Brown PN, Argani P, Ashfaq R, Fukushima N, Goggins M, Kern SE, Maitra A (2005) Homozygous deletion of the MTAP gene in invasive adenocarcinoma of the pancreas and in periampullary cancer: a potential new target for therapy. Cancer Biol Ther 4:83–86. https://doi.org/10.4161/cbt.4.1.1380CrossRefPubMed

11.

Powell EL, Leoni LM, Canto MI, Forastiere AA, Iocobuzio-Donahue CA, Wang JS, Maitra A, Montgomery E (2005) Concordant loss of MTAP and p16/CDKN2A expression in gastroesophageal carcinogenesis: evidence of homozygous deletion in esophageal noninvasive precursor lesions and therapeutic implications. Am J Surg Pathol 29:1497–1504. https://doi.org/10.1097/01.pas.0000170349.47680.e8CrossRefPubMed

12.

Su CY, Chang YC, Chan YC, Lin TC, Huang MS, Yang CJ, Hsiao M (2014) MTAP is an independent prognosis marker and the concordant loss of MTAP and p16 expression predicts short survival in non-small cell lung cancer patients. Eur J Surg Oncol 40:1143–1150. https://doi.org/10.1016/j.ejso.2014.04.017CrossRefPubMed

13.

de Oliveira SF, Ganzinelli M, Chila R, Serino L, Maciel ME, Urban Cde A, de Lima RS, Cavalli IJ, Generali D, Broggini M, Damia G, Ribeiro EM (2016) Characterization of MTAP gene expression in breast cancer patients and cell lines. PLoS One 11:e0145647. https://doi.org/10.1371/journal.pone.0145647CrossRefPubMedPubMedCentral

14.

Bataille F, Rogler G, Modes K, Poser I, Schuierer M, Dietmaier W, Ruemmele P, Muhlbauer M, Wallner S, Hellerbrand C, Bosserhoff AK (2005) Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin. Lab Invest 85:124–136. https://doi.org/10.1038/labinvest.3700192CrossRefPubMed

15.

Olopade OI, Pomykala HM, Hagos F, Sveen LW, Espinosa R, 3rd, Dreyling MH, Gursky S, Stadler WM, Le Beau MM, Bohlander SK (1995) Construction of a 2.8-megabase yeast artificial chromosome contig and cloning of the human methylthioadenosine phosphorylase gene from the tumor suppressor region on 9p21. Proc Natl Acad Sci U S A 92: 6489-6493.https://doi.org/10.1073/pnas.92.14.6489

16.

Satomi K, Ohno M, Matsushita Y, Takahashi M, Miyakita Y, Narita Y, Ichimura K, Yoshida A (2021) Utility of methylthioadenosine phosphorylase immunohistochemical deficiency as a surrogate for CDKN2A homozygous deletion in the assessment of adult-type infiltrating astrocytoma. Mod Pathol 34:688–700. https://doi.org/10.1038/s41379-020-00701-wCrossRefPubMed

17.

Nariai T, Tanaka Y, Wakimoto H, Aoyagi M, Tamaki M, Ishiwata K, Senda M, Ishii K, Hirakawa K, Ohno K (2005) Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma. J Neurosurg 103:498–507. https://doi.org/10.3171/jns.2005.103.3.0498CrossRefPubMed

18.

Nojiri T, Nariai T, Aoyagi M, Senda M, Ishii K, Ishiwata K, Ohno K (2009) Contributions of biological tumor parameters to the incorporation rate of L: -[methyl-(11)C] methionine into astrocytomas and oligodendrogliomas. J Neurooncol 93:233–241. https://doi.org/10.1007/s11060-008-9767-2CrossRefPubMed

19.

Ogishima T, Tamura K, Kobayashi D, Inaji M, Hayashi S, Tamura R, Nariai T, Ishii K, Maehara T (2017) ATRX status correlates with 11 C-methionine uptake in WHO grade II and III gliomas with IDH1 mutations. Brain Tumor Pathol 34:20–27. https://doi.org/10.1007/s10014-017-0280-1CrossRefPubMed

20.

Nakano T, Tamura K, Tanaka Y, Inaji M, Hayashi S, Kobayashi D, Nariai T, Toyohara J, Ishii K, Maehara T (2018) Usefulness of (11)C-methionine positron emission tomography for monitoring of treatment response and recurrence in a glioblastoma patient on bevacizumab therapy: A case report. Case Rep Oncol 11:442–449. https://doi.org/10.1159/000490457CrossRefPubMedPubMedCentral

21.

Shimizu Y, Suzuki M, Akiyama O, Ogino I, Matsushita Y, Satomi K, Yanagisawa S, Ohno M, Takahashi M, Miyakita Y, Narita Y, Ichimura K, Kondo A (2023) Utility of real-time polymerase chain reaction for the assessment of CDKN2A homozygous deletion in adult-type IDH-mutant astrocytoma. Brain Tumor Pathol 40:93–100. https://doi.org/10.1007/s10014-023-00450-zCrossRefPubMed

22.

Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S, Inamura K, Takada S, Ueno T, Yamashita Y, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y, Mano H (2009) KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 15:3143–3149. https://doi.org/10.1158/1078-0432.Ccr-08-3248CrossRefPubMed

23.

Kanda Y (2013) Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 48:452–458. https://doi.org/10.1038/bmt.2012.244CrossRefPubMed

24.

Menezes WP, Silva VAO, Gomes INF, Rosa MN, Spina MLC, Carloni AC, Alves ALV, Melendez M, Almeida GC, Silva LSD, Clara C, da Cunha IW, Hajj GNM, Jones C, Bidinotto LT, Reis RM (2020) Loss of 5'-methylthioadenosine phosphorylase (MTAP) is frequent in high-grade gliomas; nevertheless, it is not associated with higher tumor aggressiveness. Cells 9. https://doi.org/10.3390/cells9020492

25.

Hansen LJ, Sun R, Yang R, Singh SX, Chen LH, Pirozzi CJ, Moure CJ, Hemphill C, Carpenter AB, Healy P, Ruger RC, Chen CJ, Greer PK, Zhao F, Spasojevic I, Grenier C, Huang Z, Murphy SK, McLendon RE, Friedman HS, Friedman AH, Herndon JE 2nd, Sampson JH, Keir ST, Bigner DD, Yan H, He Y (2019) MTAP loss promotes stemness in glioblastoma and confers unique susceptibility to purine starvation. Cancer Res 79:3383–3394. https://doi.org/10.1158/0008-5472.CAN-18-1010CrossRefPubMedPubMedCentral

26.

Li Z, Jin Y, Zou Q, Shi X, Wu Q, Lin Z, He Q, Huang G, Qi S (2021) Integrated genomic and transcriptomic analysis suggests KRT18 mutation and MTAP are key genetic alterations related to the prognosis between astrocytoma and glioblastoma. Ann Transl Med 9:713. https://doi.org/10.21037/atm-21-1317CrossRefPubMedPubMedCentral

27.

Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707. https://doi.org/10.1038/366704a0CrossRefPubMed

28.

Sherr CJ (1996) Cancer cell cycles. Science 274:1672–1677. https://doi.org/10.1126/science.274.5293.1672CrossRefPubMed

29.

Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH, Peters G (1998) The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J 17:5001–5014. https://doi.org/10.1093/emboj/17.17.5001CrossRefPubMedPubMedCentral

30.

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404. https://doi.org/10.1158/2159-8290.CD-12-0095CrossRefPubMed

31.

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6:11. https://doi.org/10.1126/scisignal.2004088CrossRef

32.

Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, Morozova O, Newton Y, Radenbaugh A, Pagnotta SM, Anjum S, Wang J, Manyam G, Zoppoli P, Ling S, Rao AA, Grifford M, Cherniack AD, Zhang H, Poisson L, Carlotti CG Jr, Tirapelli DP, Rao A, Mikkelsen T, Lau CC, Yung WK, Rabadan R, Huse J, Brat DJ, Lehman NL, Barnholtz-Sloan JS, Zheng S, Hess K, Rao G, Meyerson M, Beroukhim R, Cooper L, Akbani R, Wrensch M, Haussler D, Aldape KD, Laird PW, Gutmann DH, Network TR, Noushmehr H, Iavarone A, Verhaak RG (2016) Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164:550–563. https://doi.org/10.1016/j.cell.2015.12.028CrossRefPubMedPubMedCentral

33.

Varn FS, Johnson KC, Martinek J, Huse JT, Nasrallah MP, Wesseling P, Cooper LAD, Malta TM, Wade TE, Sabedot TS, Brat D, Gould PV, Woehrer A, Aldape K, Ismail A, Sivajothi SK, Barthel FP, Kim H, Kocakavuk E, Ahmed N, White K, Datta I, Moon HE, Pollock S, Goldfarb C, Lee GH, Garofano L, Anderson KJ, Nehar-Belaid D, Barnholtz-Sloan JS, Bakas S, Byrne AT, D’Angelo F, Gan HK, Khasraw M, Migliozzi S, Ormond DR, Paek SH, Van Meir EG, Walenkamp AME, Watts C, Weiss T, Weller M, Palucka K, Stead LF, Poisson LM, Noushmehr H, Iavarone A, Verhaak RGW, Consortium G (2022) Glioma progression is shaped by genetic evolution and microenvironment interactions. Cell 185:2184-2199 e2116. https://doi.org/10.1016/j.cell.2022.04.038CrossRefPubMedPubMedCentral

34.

Zaragoza R (2020) Transport of amino acids across the blood-brain barrier. Front Physiol 11:973. https://doi.org/10.3389/fphys.2020.00973CrossRefPubMedPubMedCentral

35.

Nawashiro H, Otani N, Uozumi Y, Ooigawa H, Toyooka T, Suzuki T, Katoh H, Tsuzuki N, Ohnuki A, Shima K, Shinomiya N, Matsuo H, Kanai Y (2005) High expression of L-type amino acid transporter 1 in infiltrating glioma cells. Brain Tumor Pathol 22:89–91. https://doi.org/10.1007/s10014-005-0188-zCrossRefPubMed

36.

Singhal T, Narayanan TK, Jacobs MP, Bal C, Mantil JC (2012) 11C-methionine PET for grading and prognostication in gliomas: a comparison study with 18F-FDG PET and contrast enhancement on MRI. J Nucl Med 53:1709–1715. https://doi.org/10.2967/jnumed.111.102533CrossRefPubMed

37.

Grosu AL, Weber WA, Riedel E, Jeremic B, Nieder C, Franz M, Gumprecht H, Jaeger R, Schwaiger M, Molls M (2005) L-(methyl-11C) methionine positron emission tomography for target delineation in resected high-grade gliomas before radiotherapy. Int J Radiat Oncol Biol Phys 63:64–74. https://doi.org/10.1016/j.ijrobp.2005.01.045CrossRefPubMed

38.

Herholz K, Holzer T, Bauer B, Schroder R, Voges J, Ernestus RI, Mendoza G, Weber-Luxenburger G, Lottgen J, Thiel A, Wienhard K, Heiss WD (1998) 11C-methionine PET for differential diagnosis of low-grade gliomas. Neurology 50:1316–1322. https://doi.org/10.1212/wnl.50.5.1316CrossRefPubMed

39.

Matsuo M, Miwa K, Tanaka O, Shinoda J, Nishibori H, Tsuge Y, Yano H, Iwama T, Hayashi S, Hoshi H, Yamada J, Kanematsu M, Aoyama H (2012) Impact of [11C]methionine positron emission tomography for target definition of glioblastoma multiforme in radiation therapy planning. Int J Radiat Oncol Biol Phys 82:83–89. https://doi.org/10.1016/j.ijrobp.2010.09.020CrossRefPubMed

40.

Palanichamy K, Thirumoorthy K, Kanji S, Gordon N, Singh R, Jacob JR, Sebastian N, Litzenberg KT, Patel D, Bassett E, Ramasubramanian B, Lautenschlaeger T, Fischer SM, Ray-Chaudhury A, Chakravarti A (2016) Methionine and kynurenine activate oncogenic kinases in glioblastoma, and methionine deprivation compromises proliferation. Clin Cancer Res 22:3513–3523. https://doi.org/10.1158/1078-0432.CCR-15-2308CrossRefPubMedPubMedCentral

41.

Ishiwata K, Kubota K, Murakami M, Kubota R, Sasaki T, Ishii S, Senda M (1993) Re-evaluation of amino acid PET studies: can the protein synthesis rates in brain and tumor tissues be measured in vivo? J Nucl Med 34:1936–1943PubMed

Title: Loss of methylthioadenosine phosphorylase immunoreactivity correlates with poor prognosis and elevated uptake of 11C-methionine in IDH-mutant astrocytoma
Authors: Toshihiro Yamamura
Kaoru Tamura
Daisuke Kobayashi
Motoki Inaji
Yuka Toyama
Hiroaki Wakimoto
Juri Kiyokawa
Shoko Hara
Yoji Tanaka
Tadashi Nariai
Kazuhide Shimizu
Kenji Ishii
Taketoshi Maehara
Publication date: 01-04-2024
Publisher: Springer US
Keywords: Astrocytoma
Astrocytoma
Astrocytoma
Positron Emission Tomography
Glioma
Glioma
Glioma
Published in: Journal of Neuro-Oncology
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-024-04661-y

At a glance: The STEP trials

Springer Medicine

Loss of methylthioadenosine phosphorylase immunoreactivity correlates with poor prognosis and elevated uptake of ¹¹C-methionine in IDH-mutant astrocytoma

Abstract

Purpose

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content