SDH-deficient renal cell carcinoma associated with biallelic mutation in succinate dehydrogenase A: comprehensive genetic profiling and its relation to therapy response

McEvoy, Christopher R. E.; Koe, Lisa; Choong, David Y.H.; Leong, Huei San; Xu, Huiling; Karikios, Deme; Plew, Jeffrey D; Prall, Owen W.J.; Fellowes, Andrew; Fox, Stephen B.

doi:10.1038/s41698-018-0053-2

Cited by 29 publications

(48 citation statements)

References 27 publications

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“…Most reported cases with the classic morphology of SDH‐deficient RCCs have been associated with germline mutations in SDHB and SDHC . To date, only four cases have been reported to be associated with SDHA mutation, which, in addition to the loss of SDHB on immunohistochemistry, showed also a loss of SDHA . On the basis of the limited experience from these cases, SDHA‐deficient RCCs show higher nuclear grades, and a combination of variable morphologies that are different from that of typical SDH‐deficient RCC, including papillary, solid, cribriform and desmoplastic morphologies …”

Section: Sdh‐deficient Rccmentioning

confidence: 99%

“…6 To date, only four cases have been reported to be associated with SDHA mutation, which, in addition to the loss of SDHB on immunohistochemistry, showed also a loss of SDHA. [9][10][11]26 On the basis of the limited experience from these cases, SDHA-deficient RCCs show higher nuclear grades, and a combination of variable morphologies that are different from that of typical SDHdeficient RCC, including papillary, solid, cribriform and desmoplastic morphologies. [9][10][11]26 The differential diagnosis of SDH-deficient RCC includes primarily oncocytoma and chromophobe RCC.…”

Section: Sdh-deficient Rccmentioning

confidence: 99%

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New and emerging renal entities: a perspective post‐WHO 2016 classification

2018

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Renal tumours include a heterogeneous and diverse spectrum of neoplasms. Recent advances in this field have significantly improved our understanding of the morphological, immunohistochemical, molecular, epidemiological and clinical characteristics of renal tumours, which led to the new Vancouver classification of renal neoplasia and the new World Health Organization (WHO) classification of renal cell tumours. This review aims to summarise the new information and evidence on several new and emerging/provisional renal entities, which were mostly generated after the recent classification of renal neoplasia. We include in this review the following new and emerging/provisional renal entities: succinate dehydrogenase‐deficient renal cell carcinoma, thyroid‐like follicular carcinoma of the kidney, anaplastic lymphoma kinase rearrangement‐associated renal cell carcinoma, renal cell carcinomas with prominent smooth muscle stroma, fumarate hydratase‐deficient renal cell carcinoma, biphasic squamoid papillary renal cell carcinoma, eosinophilic solid and cystic renal cell carcinoma, atrophic kidney‐like renal cell carcinoma, clear cell renal cell carcinoma with giant cells and emperipolesis, Warthin‐like papillary renal cell carcinoma, and low‐grade oncocytic renal tumour (CD117‐negative; cytokeratin 7‐positive). Some of these entities, such as succinate dehydrogenase‐deficient renal cell carcinoma, have already been recognised as new entities in the WHO classification, and some have been recognised as provisional/emerging entities. However, we include in this review several additional entities that, on the basis of the published evidence, also warrant this designation. We hope that this review will ease the navigation through this complex and evolving field, and will inform and stimulate new studies and discussions.

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Section: Sdh‐deficient Rccmentioning

confidence: 99%

Section: Sdh-deficient Rccmentioning

confidence: 99%

New and emerging renal entities: a perspective post‐WHO 2016 classification

2018

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“…SDH‐deficient renal carcinomas were first identified in 2004 (Vanharanta, et al, ) and accepted as a unique subtype of renal tumor in 2016 (Moch, Cubilla, Humphrey, Reuter, & Ulbright, ). Two recent studies have identified the variant SDHA p.Arg31stop, previously defined as the most prevalent mutation observed in SDH‐deficient (GISTs) (Miettinen & Lasota, ), in renal cancer patients (Carlo, et al, ; McEvoy, et al, ). Association of SDHx germline variants with thyroid cancer risk has also been described (Neumann, et al, ; Ni, et al, ), of particular relevance to the proband in this study.…”

Section: Resultsmentioning

confidence: 99%

“…Comprehensive reviews of SDHA variants over a large disease spectrum in various databases have been published (Bannon, et al, ; Casey, et al, ; Evenepoel, et al, ). To date, there have been few reports of SDHA mutations in sporadic renal cancer: for example, a 17 kbp homozygous deletion leading to the loss of 9 exons of SDHA (Yakirevich, et al, ), a heterozygous germline mutation in the initiation codon (Jiang, et al, ), a splice site deletion (Ozluk, et al, ), and a combined germline/somatic biallelic loss (McEvoy, et al, ). The SDHA Ala45Thr variant was previously reported in a case of thoracic paraganglioma (Casey, et al, ) but was largely uncharacterized.…”

Section: Discussionmentioning

confidence: 99%

Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma

Nicolas

Demidova

Iqbal

et al. 2019

Molec Gen & Gen Med

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Background Identification of genetic factors causing predisposition to renal cell carcinoma has helped improve screening, early detection, and patient survival. Methods We report the characterization of a proband with renal and thyroid cancers and a family history of renal and other cancers by whole‐exome sequencing (WES), coupled with WES analysis of germline DNA from additional affected and unaffected family members. Results This work identified multiple predicted protein‐damaging variants relevant to the pattern of inherited cancer risk. Among these, the proband and an affected brother each had a heterozygous Ala45Thr variant in SDHA , a component of the succinate dehydrogenase (SDH) complex. SDH defects are associated with mitochondrial disorders and risk for various cancers; immunochemical analysis indicated loss of SDHB protein expression in the patient’s tumor, compatible with SDH deficiency. Integrated analysis of public databases and structural predictions indicated that the two affected individuals also had additional variants in genes including TGFB2 , TRAP1 , PARP1 , and EGF , each potentially relevant to cancer risk alone or in conjunction with the SDHA variant. In addition, allelic imbalances of PARP1 and TGFB2 were detected in the tumor of the proband. Conclusion Together, these data suggest the possibility of risk associated with interaction of two or more variants.

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“…Sporadic tumours can also arise because of somatic SDH mutations, as in the example of SDH‐deficient GISTs . The combination of a germline mutation with a ‘second‐hit’ somatic mutation seems to be the molecular background of the majority of SDH‐deficient renal cell carcinomas . Carney triad tumours are characterised by functional SDH deficiency, without SDH gene mutation .…”

Section: Introductionmentioning

confidence: 99%

Loss of succinate dehydrogenase B immunohistochemical expression distinguishes pulmonary chondromas from hamartomas

et al. 2019

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Aims Pulmonary chondromas, which are rare cartilaginous neoplasms that often arise in the setting of Carney triad, are morphologically similar to pulmonary hamartomas, which are much more common. There is evidence that succinate dehydrogenase (SDH) deficiency drives neoplasia in patients with Carney triad, and SDHB immunohistochemistry can be used as a surrogate marker to detect SDH deficiency. The aim of this study was to investigate the utility of SDHB immunohistochemistry in distinguishing pulmonary chondromas from hamartomas. Methods and results Immunohistochemistry for SDHB (clone 21A11AE7) was performed on histological sections from six cases of pulmonary chondroma and 33 cases of pulmonary hamartoma. SDHB expression was retained in all 33 pulmonary hamartomas, and lost in the majority of evaluable chondromas (five of six). Of the five patients with chondromas showing SDHB loss, four had definitive Carney triad. Most patients with pulmonary hamartomas were older males with small solitary masses, whereas chondromas often presented as multiple masses in young females. Conclusion Loss of SDHB immunohistochemical expression can be useful for differentiating pulmonary chondromas from hamartomas, and potentially identifying patients with Carney triad.

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SDH-deficient renal cell carcinoma associated with biallelic mutation in succinate dehydrogenase A: comprehensive genetic profiling and its relation to therapy response

Cited by 29 publications

References 27 publications

New and emerging renal entities: a perspective post‐WHO 2016 classification

New and emerging renal entities: a perspective post‐WHO 2016 classification

Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma

Loss of succinate dehydrogenase B immunohistochemical expression distinguishes pulmonary chondromas from hamartomas

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