Maignan Aurelie, Guerin Carole, Julliard Valentin, Paladino Nunzia-Cinzia, Kim Edward, Roche Philippe, Castinetti Fréderic, Essamet Wassim, Mancini Julien, Imperiale Alessio, Clifton-Bligh Roderick, Romanet Pauline, Barlier Anne, Pacak Karel, Sebag Fréderic, Taïeb David
Department of Endocrine Surgery, Conception Hospital, APHM, Aix Marseille Univ, Marseille, France.
Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, and University of Sydney, Sydney, New South Wales, Australia.
Langenbecks Arch Surg. 2017 Aug;402(5):787-798. doi: 10.1007/s00423-017-1564-y. Epub 2017 Feb 22.
Succinate dehydrogenase B (SDHB) associated pheochromocytomas (PHEOs) are associated with a higher risk of tumor aggressiveness and malignancy. The aim of the present study was to evaluate (1) the frequency of germline SDHB mutations in apparently sporadic patients with PHEO who undergo preoperative genetic testing and (2) the ability to predict pathogenic mutations.
From 2012 to 2016, 82 patients underwent a PHEO surgical resection. Sixteen were operated in the context of hereditary PHEO and were excluded from analysis. Among the 66 remaining cases, 48 were preoperatively screened for an SDHB mutation. In addition to imaging studies with specific radiopharmaceuticals (I-MIBG or F-FDOPA) for exclusion of multifocality/metastases, 36 patients underwent F-FDG PET/CT.
From the 48 genetically screened patients, genetic testing found a germline SDHB variant in two (4.2%) cases: a variant of unknown significance, exon 1, c.14T>G (p.Val5Gly), and a most likely pathogenic mutation, exon 5, c.440A>G (p.Tyr147Cys), according to in silico analysis. Structural and functional analyses of the protein predicted that p.Tyr147Cys mutant was pathogenic. Both tumors exhibited moderate F-FDG PET uptake with similar uptake patterns to non-SDHB mutated PHEOs. The two patients underwent total laparoscopic adrenalectomies. Of the remaining patients, 44 underwent a laparoscopic adrenalectomy, and two had an open approach. Pathological analysis of the tumors from patients bearing two germline SDHB variants revealed a typical PHEO (PASS 0 and 2). Ex-vivo analyses (metabolomics, SDHB immunohistochemistry, loss of heterozygosity analysis) allowed a reclassification of the two SDHB variants as probably non-pathogenic variants.
This study illustrates that SDHx mutational analysis can be misleading, even if structural and functional analyses are done. Surgeons should be aware of the difficulty of classifying new SDHB variants prior to implementing SDHB mutation status into a tailored surgical management strategy of a patient.
琥珀酸脱氢酶B（SDHB）相关的嗜铬细胞瘤（PHEO）具有更高的肿瘤侵袭性和恶性风险。本研究的目的是评估（1）接受术前基因检测的散发性PHEO患者中胚系SDHB突变的频率，以及（2）预测致病突变的能力。
2012年至2016年，82例患者接受了PHEO手术切除。16例在遗传性PHEO背景下接受手术，被排除在分析之外。在其余66例病例中，48例术前进行了SDHB突变筛查。除了使用特定放射性药物（I-MIBG或F-FDOPA）进行影像学研究以排除多灶性/转移外，36例患者接受了F-FDG PET/CT检查。
在48例进行基因筛查的患者中，基因检测在2例（4.2%）中发现了胚系SDHB变异：根据计算机分析，一个意义不明的变异，位于外显子1，c.14T>G（p.Val5Gly），以及一个最可能致病的突变，位于外显子5，c.440A>G（p.Tyr147Cys）。对该蛋白的结构和功能分析预测p.Tyr147Cys突变体具有致病性。这两个肿瘤均表现出中等程度的F-FDG PET摄取，摄取模式与未发生SDHB突变的PHEO相似。这两名患者接受了全腹腔镜肾上腺切除术。其余患者中，44例接受了腹腔镜肾上腺切除术，2例采用开放手术。对携带两个胚系SDHB变异的患者的肿瘤进行病理分析，显示为典型的PHEO（PASS 0和2）。体外分析（代谢组学、SDHB免疫组织化学、杂合性缺失分析）使这两个SDHB变异重新分类为可能的非致病变异。
本研究表明，即使进行了结构和功能分析，SDHx突变分析也可能产生误导。在将SDHB突变状态纳入患者的个体化手术管理策略之前，外科医生应意识到对新的SDHB变异进行分类的困难。
