Familial Cancer DOI 10.1007/s10689-014-9725-4

SHORT COMMUNICATION

Exploring the association of succinate dehydrogenase complex mutations with lymphoid malignancies R. Renella • J. Carnevale • K. A. Schneider • J. L. Hornick • H. Q. Rana • K. A. Janeway

Ó Springer Science+Business Media Dordrecht 2014

Abstract The succinate dehydrogenase (SDH) complex exerts a fundamental role in mitochondrial cellular respiration and mutations in its encoding genes (SDHA, SDHB, SDHC, SDHD, collectively referred to as SDHx) lead to a number of inherited endocrine cancer predisposition syndromes, including familial paraganglioma/pheochromocytoma. Recent studies suggest a possible role for the SDH complex and other mitochondrial enzymes in the pathogenesis of hematological malignancy. Our aim was to search and identify pedigrees of patients affected by germline SHDx mutations treated at our institution for endocrine and other tumors, and seek to identify cases of hematological malignancy. We also analyzed cancer

genome databases for reported cases of SDHx mutations outside of endocrine neoplasms. We report of two unrelated pedigrees carrying SDHx mutations with members affected by lymphomas. Sequencing data revealed one case of chronic lymphocytic leukemia with a SDHB mutation. This novel set of observations demonstrates the need for collaborative databases of patients with endocrine cancers with SDHx mutations, and the investigation of their role in hematological (lymphoid) malignancy. Keywords Lymphoma  Malignancy  Cancer predisposition  Succinate dehydrogenase

Introduction R. Renella (&)  J. Carnevale  K. A. Janeway Department of Pediatric Oncology, Dana Farber Cancer Institute, 450 Brookline Ave, Boston, MA, USA e-mail: [email protected]; [email protected] R. Renella  J. L. Hornick  H. Q. Rana  K. A. Janeway Harvard Medical School, Boston, MA, USA Present Address: R. Renella Department of Pediatric Oncology, Dana Farber Cancer Institute, 450 Brookline Ave, Boston, MA, USA K. A. Schneider Pediatric Cancer Risk Program (PCRP), Dana-Farber Cancer Institute, Boston, MA, USA J. L. Hornick Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA H. Q. Rana Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

Mutations in genes encoding for the succinate dehydrogenase (SDH)–ubiquinone complex II (a multi-subunit component of the Krebs cycle and mitochondrial respiratory chain) predispose to hereditary paraganglioma (PGL) and pheochromocytoma (PHEO), and are associated with an increased risk for other malignancies [1–5]. A non-negligible fraction of simplex cases of PGL or PHEO carry germline inactivating mutations in SDHB, SDHC or SDHD [1, 3], but lesions in these genes can also be associated with other neoplasms, including renal cell carcinoma (RCC), pituitary tumors, papillary thyroid cancer, and gastrointestinal stromal tumors (GIST) [6–9]. Evidence is accumulating to suggest the possible role for the SDHx genes in neoplastic transformation by alteration of the cellular epigenetic landscape [4, 10]. Interestingly, a recent study has also highlighted a possible role for recurrent, inactivating SDHB mutations in the pre-adaptation of leukemic clones to hypoxia [11]. To date, a predisposition to lymphoid malignancies has not been reported. In fact, the full

123

R. Renella et al.

spectrum of associated malignancies has not been established as the SDHx genes (i.e SDHA, B, C or D) are not routinely evaluated in individuals with non-endocrine cancers. Here, we report two pedigrees with individuals with SDHx mutations and lymphoid neoplasms, which suggest those may be involved in the pathogenesis of hematological malignancies.

Materials and methods We searched our databases for patients with PGL/PHEO and SDHx mutations, and extensively reviewed the literature for associations with hematological malignancy. We also performed mutation database searches via available large-scale cancer genome sequencing repositories. For patients, CLIA-certified genetic testing was performed within the context of genetic counseling by a licensed genetic counselor and documentation of informed consent. The patients reported herein are enrolled in IRB-approved studies of hereditary cancer risk. Pathological samples were stained as previously reported [12]. Due to the rarity of SDHx mutations, pedigrees were de-identified with removal of clinically irrelevant information that might compromise patient privacy.

Results Our literature review revealed no previously reported cases of hematological malignancy in patients with PGL/PHEO and confirmed, known SDHx mutations. A detailed analysis seeking for SDHx mutations in cancer cell-based exomes revealed, in the Catalogue of Somatic Mutations in cancer (COSMIC v67, cancer.sanger.ac.uk), one patient whose chronic lymphocytic leukemia (CLL) tumor material presented a somatic SHDB mutation [13]. This patient’s CLL was sequenced as part of a large, comprehensive whole exome study of subclonal somatic mutations in the progression of chronic lymphocytic leukemia [14]. In our cohort, we identified 2 out of 7 total SDHx mutation positive pedigrees with members affected by endocrine and lymphoid neoplasms. Six families had 13 members agreeing to SDHx mutation screening (proband, both parents, multiple siblings), while in one family only two members could be tested (proband, one parent). In the first pedigree, a previously healthy 12-year-old girl, presented with a non-tender enlarged submental lymphadenopathy (family history is shown in Fig. 1a). The resected lymph node showed nodular lymphocyte predominant HL. At disease extension work-up, an isolated enlarged retrocaval lymph node displayed avid 18FDG uptake at PET (Fig. 2a). The patient received standard of

123

care ABVD chemotherapy. Restaging after 2 cycles and 4 cycles showed decreased and then negative uptake in the pharynx and neck, but retroperitoneal activity was persistent. A laparotomic biopsy of the retroperitoneal mass revealed a PGL. Radiation therapy was administered, and re-imaging was negative for any residual tumor. Eighteen months after completion of planned therapy a follow-up PET scan displayed recurrent FDG uptake in the spinal T12-L1 region, concerning for residual/recurrent PGL. This area was monitored with biannual imaging. CT, PET, and MRI all consistently showed a retrocaval mass (11 9 6 mm in size). The patient remained in remission without evidence for recurrent lymphoma. CT imaging 2.5 years off treatment showed progression of the retrocaval mass and surgical resection confirmed the diagnosis of PGL. Due to the high likelihood of a hereditary PGL syndrome, the patient underwent genetic counseling and testing of the SDHx genes, which revealed a pathogenic SDHB mutation (p.C196Y). The patient is currently without PGL or HL recurrence and suffers from no treatmentrelated toxicity. The PGL was composed of a nested population of large polygonal cells with abundant eosinophilic cytoplasm (Fig. 2b, c). By immunohistochemistry, the PGL cells displayed markedly reduced immunoreactivity for SDHB (indicating loss of SDHB enzymatic function), compared to the strong, granular cytoplasmic staining in adjacent brown fat (Fig. 2e, f) and normal control tissue (skeletal muscle, panel E inset). In NLPHL (Fig. 2d), the vast majority of lesional cells are non-neoplastic B-lymphocytes, with only small numbers of large atypical lymphoid cells (so-called ‘‘popcorn’’ cells), which represent the neoplastic component. It is therefore exceedingly difficult to assess SDHB protein expression in the neoplastic cells in this tumor type. Moreover, little is known about SDHB immunoreactivity in normal lymph nodes. Therefore, as a control, a normal lymph node was also stained with SDHB. Both the NLPHL section (Fig. 2g) and the normal lymph node displayed minimal SDHB staining, precluding definitive assessment of SDHB protein loss. In the second pedigree, a family was ascertained through a 15-year-old diagnosed with metastatic GIST/ PHEO. She was found to harbor a truncating SDHC mutation (p.R15X). Her maternal aunt, who carried the same mutation, was diagnosed with stage IV-B HL at age 24 years (Fig. 1b, arrow). Staging laparatomy revealed lymphatic (para-aortic, pericaval, porta-hepatis and splenic hilar), hepatic and splenic involvement. On pathology, histologic features were consistent with nodular sclerosis HL. She was treated with splenectomy and chemotherapy (6 cycles of MOPP and ABVD each), which were curative. Lymphoma specimen was not available for immunohistochemistry. Interestingly, family history revealed a maternal grandmother diagnosed with NHL at age 88 years.

SDH complex mutations and lymphoid malignancy Fig. 1 Pedigrees: a Pedigree of Family 1. b Pedigree of Family 2. Highlighted in red are all the individuals affected by neoplasia. Age at diagnosis as well as tissue type are given when available. Dot indicates individuals with confirmed SDH mutations. NOS not otherwise specified, Pheo pheochromocytoma, PG paraganglioma, GIST gastrointestinal stromal tumor, H&N head and neck carcinoma. (Color figure online)

Fig. 2 a Radiological assessment disease sites in case 1 by whole body FDG-PET with an anterior view indicating cervical sites of involvement by HL and showing the paravertebral 18FDG-avid mass, constituted by paraganglioma. b–g Histology and Immunohistochemistry (IHC) of tumor samples of index case 1. b PGL and brown fat 940 HE stain, c PGL 9100 HE stain, d NLPHL 9100 HE stain,

e PGL and brown fat 940 SDHB stain (inset: Normal muscle 9100 SDHB stain), f PGL 9100 weak SDHB stain, g NLPHL 9100 weak SDHB stain. PGL paraganglioma, HE hematoxilin-eosin, SDHB succinate dehydrogenase-B IHC antibody, NLPHL nodular lymphocyte predominant Hodgkin Lymphoma. Magnification is indicated in 9 = times

123

R. Renella et al.

Discussion Hereditary susceptibility to PGL has been recognized for decades, but the specific association of SDHx mutations with other malignancies is progressively expanding [6, 15]. In particular, SDHB mutations can be associated with broader cancer risks than previously recognized [8]. SDHx mutations lead to the functional impairment of the citric acid cycle and the mitochondrial respiratory chain. Their association with neoplasia has ignited new interest in the molecular underpinnings of the Warburg phenomenon, a classical oncogenesis hypothesis stating that cancer cells rely on aerobic glycolysis for the generation of ATP [5, 6, 16]. Evidence suggests that hypoxia inducible factor (HIF) plays a critical role in the induction of aerobic glycolysis in tumor cells, and that dysfunction of SDH complex results in increased levels of reactive oxygen species as well as succinate, which have both been shown to induce HIF stabilization [17–20]. In addition, succinate accumulation in SDH deficiency was shown inhibit histone demethylation by JMJD3 and TET2-dependent 5-methylcytosine oxidation, which could potentially lead to altered epigenomic landscapes favoring oncogenesis [4, 10]. Taken altogether, these data suggest that SDH-associated constitutive activation of hypoxia-sensing and signaling pathways, accumulation of reactive oxygen species, succinate and/or another messenger molecules, may underlie neoplastic development at-large. If SDHx mutations truly play a role in the pathogenesis of lymphoma/leukemia, patients with germline SDHx mutations should have an increased incidence of these tumors. Interestingly, mutations in the SDHB (case 1), have been associated with more aggressive PGL and with increased frequency of non-neural crest derived neoplasms [8]. Case 2 presents a truly novel finding, i.e. the association of SDHC mutations and a positive family history for lymphoma. In fact, our cancer-genome database analysis revealed one patient whose chronic lymphocytic leukemia (CLL) tumor material presented a somatic SHDB mutation [13]. Several limitations to this report need to be discussed. First, PGL syndromes are exceedingly rare, and finding hematological malignancies in pedigrees with PGL could be indicative of a normal incidence and prevalence, independent from SDHx-mutations. In particular, HL is relatively common in young adults, comprising roughly 7 % of all childhood cancers. However, NLPHL is rare within this group. Second, we were only able to obtain pathological material from one patient, and genetic confirmations were limited by the fraction of consenting individuals within the pedigrees. Regarding the immunohistochemical staining, unfortunately no other lymph node material was available from the patients to allow for further analysis. However, staining from lymph nodes from other patients (with and

123

without SDHx mutations, data not shown), the extent of immunoreactivity was comparable suggesting that the limited amount of cytoplasm and the lower density of mitochondria (relatively to other cell types) could represent technical limitations. Overall, both limitations are closely related to the rarity of the conditions studied, but it remains striking to be observe that a third of our pedigrees with SDHx mutations seem to be affected by such non-endocrine sneoplasms. At this time, the data does not imply a putative role for SDH mutations, but simply highlights association. Nonetheless, we believe that this report is of importance to practicing clinicians in term of awareness of possible expansion of the SDHx-associated neoplastic spectrum. In addition to opening new avenues for investigation on the putative role of SDHx mutations in hematological malignancies, it demonstrates the need for large collaborative databases of patients with SDHx mutations, so that specific cancer risks involved may be delineated definitively. Conflict of interest The authors have no conflict of interest to disclose.

References 1. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW 3rd, Cornelisse CJ, Devilee P, Devlin B (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287(5454):848–851 2. Niemann S, Muller U (2000) Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26(3):268–270. doi:10.1038/81551 3. Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER (2001) Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69(1):49–54. doi:10.1086/ 321282 4. Killian JK, Kim SY, Miettinen M, Smith C, Merino M, Tsokos M, Quezado M, Smith WI, Jahromi MS, Xekouki P, Szarek E, Walker RL, Lasota J, Raffeld M, Klotzle B, Wang Z, Jones L, Zhu Y, Wang Y, Waterfall JJ, O'Sullivan MJ, Bibikova M, Pacak K, Stratakis C, Janeway KA, Schiffman JD, Fan J-B, Helman L, Meltzer PS (2013) Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov 3(6):648–657. doi:10.1158/2159-8290. CD-13-0092 5. Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E, Munnich A, Rotig A (1995) Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 11(2):144–149. doi:10. 1038/ng1095-144 6. King A, Selak MA, Gottlieb E (2006) Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25(34):4675–4682. doi:10.1038/sj.onc. 1209594 7. Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, Maher ER (2008) Germline SDHB mutations and familial

SDH complex mutations and lymphoid malignancy

8.

9.

10.

11.

12.

13.

renal cell carcinoma. J Natl Cancer Inst 100(17):1260–1262. doi:10.1093/jnci/djn254 Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C (2004) Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292(8):943–951. doi:10.1001/jama.292.8.943 Gill AJ, Pachter NS, Chou A, Young B, Clarkson A, Tucker KM, Winship IM, Earls P, Benn DE, Robinson BG, Fleming S, Clifton-Bligh RJ (2011) Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol 35(10):1578–1585. doi:10.1097/PAS.0b013e318227e7f4 Letouze´ E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, Janin M, Menara M, Nguyen AT, Benit P, Buffet A, Marcaillou C, Bertherat J, Amar L, Rustin P, De Reynie`s A, Gimenez-Roqueplo A-P, Favier J (2013) SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23(6):739–752. doi:10.1016/j.ccr.2013.04.018 Baysal BE (2007) A recurrent stop-codon mutation in succinate dehydrogenase subunit B gene in normal peripheral blood and childhood T-cell acute leukemia. PLoS ONE 2(5):e436. doi:10. 1371/journal.pone.0000436 Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J, Dahia PL, Liegl B, Ball ER, Raygada M, Lai AH, Kelly L, Hornick JL, Pediatric NIH, Wild-Type GC, O’Sullivan M, de Krijger RR, Dinjens WN, Demetri GD, Antonescu CR, Fletcher JA, Helman L, Stratakis CA (2011) Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci USA 108(1):314–318. doi:10.1073/pnas.1009199108 Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, Teague JW, Campbell PJ, Stratton MR, Futreal PA (2011) COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Res 39(Database issue):D945–950. doi:10.1093/ nar/gkq929

14. Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, Sougnez C, Stewart C, Sivachenko A, Wang L, Wan Y, Zhang W, Shukla SA, Vartanov A, Fernandes SM, Saksena G, Cibulskis K, Tesar B, Gabriel S, Hacohen N, Meyerson M, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ (2013) Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 152(4):714–726. doi:10.1016/j.cell. 2013.01.019 15. Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul J-L, Strompf L, Schlumberger M, Bertagna X, Plouin P-F, Jeunemaitre X, Gimenez-Roqueplo A-P (2005) Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23(34): 8812–8818. doi:10.1200/JCO.2005.03.1484 16. Warburg O (1956) On the origin of cancer cells. Science 123(3191): 309–314 17. Lum JJ, Bui T, Gruber M, Gordan JD, DeBerardinis RJ, Covello KL, Simon MC, Thompson CB (2007) The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev 21(9):1037–1049. doi:10.1101/gad.1529107 18. Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7(1):77–85. doi:10.1016/j.ccr.2004.11.022 19. Semenza GL, Roth PH, Fang HM, Wang GL (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269(38):23757–23763 20. Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL (2007) HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11(5):407–420. doi:10.1016/j.ccr.2007.04.001

123

Exploring the association of succinate dehydrogenase complex mutations with lymphoid malignancies.

The succinate dehydrogenase (SDH) complex exerts a fundamental role in mitochondrial cellular respiration and mutations in its encoding genes (SDHA, S...
657KB Sizes 0 Downloads 3 Views