Molecularly defined renal carcinomas
2022-12-01 Paola Dal Cin, PhD , Michelle S. Hirsch, MD Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
Keywords
molecular diagnostic techniques , genetic alterations , targetable therapyClassification
Definition
The extensive application of molecular diagnostic techniques in the recent years has made it possible to detect genetic alterations that are relatively specific to various renal neoplasm subtypes. Many of these tumors have been previously misdiagnosed or diagnosed as other RCC subtypes or reported as an unclassified RCC. An accurate diagnosis of these tumors is of primary importance for the correct management of the patients; more specifically, a correct and specific diagnosis can lead to potential targetable therapy and/or genetic testing of patients and family members for familial syndromes in a subset of cases.
| Molecularly defined renal tumors | Genetic marker(s) |
|---|---|
| TFE3-rearranged renal cell carcinomas | TFE3 rearrangement at Xp11.2. with several partners genes, with the most frequent been ASPSCR1, PRCC, and SFPQ. Other genes NONO, CLTC, LUC7L3, KHSRP, PARP14, DVL2, RBM10 ,MED15, MATR3, FUBP1, GRIPAP1, ARID1, NEAT1, KAT6A, and EWSR1. 1 The immunohistochemical stain for TFE3 is not always reliable, but strong and diffuse expression can be of help to screen and /or identify the rearrangement, especially in those cases with false negative by FISH analysis due to intrachromosomal rearrangements as NONO, GRIPAP1 and RBM10. 2 The morphological spectrum of Xp11 translocation RCCs can mimic other renal cell tumors (eg, CCRCC and PRCC). The reported outcome of patients with Xp11.2 translocation RCC is variable and it has not been firmly established whether biological potential differs for the various fusion types. However, certain microscopic features have been described, but are not entirely specific, with a specific gene fusion partners.3 |
| TFEB -rearranged renal cell carcinomas | t(6;11)(p21.1;q12) associated with MALAT1::TFEB rearrangement in both children and adults has been described.4,5 Several TFEB partners genes e.g., ACTB, EWSR1, CLTC,PPP1R10 , KHDRBS2, COL21A1, CADM2 and NEAT1 are mainly reported as single case reports by NGS. 6,7 False-negative TFEB FISH results can ocurr by intrachromosomal inversions involving TFEB and PPP1R10, KHDRBS2, or COL21A1. 6 |
| TFEB amplification with and without TFEB rearrangement at 6p21.1, 8, has also been described as an unique RCC subtype with poor outcome and aggressive behavior. 9 The aggressive biological behavior of such amplified renal tumors might be secondary to other closed genes that are co-amplified, such as VEGFA and CCND3, or other genetic alterations.10-12 | |
| ELOC (formerly TCEB1)-mutated renal cell carcinoma | Complete inactivation of Elongin C (ELOC) at 8q21, results when there a combination of ELOC mutation and chromosome 8q/-8 loss. ELOC-mutated RCCs have morphologic overlap with clear cell RCC , but with wild-type VHL, papillary RCC, translocation RCC, and clear cell tubulopapillary tumors. ELOC-mutated RCC lacks 3p loss and there are no alterations affecting the function of PBRM1, SETD2 or BAP1. 13-15 |
| ELOC Inactivation increases HIF stabilisation via the same mechanism as VHL inactivation. ELOC mutations exclusively affected two residues: Y79C/S/F/N or A100P, both essential for the interaction between Elongin C and pVHL.42. 16 Genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL varian. 17 | |
| Fumarate hydratase-deficient renal cell carcinoma | Mutations of the fumarate hydratase FH gene, located at 1q42.3-q43, results in either complete loss or reduction of the FH enzymatic activity, with accumulation of intracellular fumarate and increased protein succination. 18-20 The identification of FH-deficient RCC is very important, not only because they are very aggressive tumors, but also due to their hereditary association with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome OMIM:15080021 |
| Highly variable copy number variation pattern affecting mainly chrs 4, 9, 13, 14, 15, but not a useful diagnostic tool in identifying these cases.22 | |
| Succinate deydrogenase-deficient renal cell carcinoma | SDH-deficient RCC results when ther eis a germline mutations in one of the a SDH gene subunits: most commonly SDHB , less commonly SDHC and rarely SDHA ; SDHD -deficient RCCs have not yet reported).23 Diagnosis can be made when there is an absence of SDHB immunoreactivity and/or with molecular analysis.24 |
| ALK-rearranged renal cell carcinomas | t(2;10)(p23;q22) associated with VCL::ALK fusion in pediatric patients with sickle cell trait. 25,26 |
| ALK rearrangement in adolescents or adults without sickle cell trait with other gene partners, including TPM3, EML4,STRN, HOOK1, CLIP1, KIF5B and PLEKHA7. 26-30 | |
| A single case in adult patient without sickle cell trait showed VCL::ALK gene fusion co-occurring with pathogenic mutations in EP300 and TRRAP. 31 | |
| Patients with ALK-rearranged RCC may benefit from targeted ALK inhibitor therapy. 32 | |
| SMARCB1 -deficient renal medullary carcinoma | Biallelic inactivation of SMARCB1 at 22q11.23 occurs in a large majority of cases either via concurrent hemizygous loss and translocation disrupting SMARCB1 or by homozygous loss. Both mechanisms correlate with the loss of the nuclear SMARCB1 expression. 33-35 It should be noted that several other non-renal SMARCB1 deficient neoplasms have also been reported, all showing loss of INI1 protein expression. |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 3269911 | 1988 | Diagnostic and surgical arthroscopy of the temporomandibular joint. Historical perspective & preliminary results. | Geist ET et al |
| 2 | 28296677 | 2017 | RBM10-TFE3 Renal Cell Carcinoma: A Potential Diagnostic Pitfall Due to Cryptic Intrachromosomal Xp11.2 Inversion Resulting in False-negative TFE3 FISH. | Argani P et al |
| 3 | 34009777 | 2021 | Key Renal Neoplasms With a Female Predominance. | Baniak N et al |
| 4 | 11395386 | 2001 | A distinctive pediatric renal neoplasm characterized by epithelioid morphology, basement membrane production, focal HMB45 immunoreactivity, and t(6;11)(p21.1;q12) chromosome translocation. | Argani P et al |
| 5 | 12719541 | 2003 | Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation. | Davis IJ et al |
| 6 | 31764220 | 2020 | Clinicopathologic and Molecular Analysis of the TFEB Fusion Variant Reveals New Members of TFEB Translocation Renal Cell Carcinomas (RCCs): Expanding the Genomic Spectrum. | Xia QY et al |
| 7 | 33208882 | 2021 | TFEB rearranged renal cell carcinoma. A clinicopathologic and molecular study of 13 cases. Tumors harboring MALAT1-TFEB, ACTB-TFEB, and the novel NEAT1-TFEB translocations constantly express PDL1. | Caliò A et al |
| 8 | 27565001 | 2016 | TFEB-amplified Renal Cell Carcinomas: An Aggressive Molecular Subset Demonstrating Variable Melanocytic Marker Expression and Morphologic Heterogeneity. | Argani P et al |
| 9 | 30706129 | 2019 | Histological and molecular characterization of TFEB-rearranged renal cell carcinomas. | Wyvekens N et al |
| 10 | 28338654 | 2017 | TFEB-VEGFA (6p21.1) co-amplified renal cell carcinoma: a distinct entity with potential implications for clinical management. | Gupta S et al |
| 11 | 30206412 | 2019 | VEGFA amplification/increased gene copy number and VEGFA mRNA expression in renal cell carcinoma with TFEB gene alterations. | Caliò A et al |
| 12 | 31600176 | 2019 | TFEB Expression Profiling in Renal Cell Carcinomas: Clinicopathologic Correlations. | Gupta S et al |
| 13 | 23797736 | 2013 | Integrated molecular analysis of clear-cell renal cell carcinoma. | Sato Y et al |
| 14 | 25676555 | 2015 | TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype. | Hakimi AA et al |
| 15 | 35653922 | 2022 | Analysis of clinicopathological and molecular features of ELOC(TCEB1)-mutant renal cell carcinoma. | Wang Y et al |
| 16 | 30565303 | 2019 | Clear cell renal cell carcinoma with wild-type von Hippel-Lindau gene: a non-existent or new tumour entity? | Batavia AA et al |
| 17 | 35323939 | 2022 | Elongin C (ELOC/TCEB1)-associated von Hippel-Lindau disease. | Andreou A et al |
| 18 | 26900816 | 2016 | Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome. | Trpkov K et al |
| 19 | 28300276 | 2017 | Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers. | Muller M et al |
| 20 | 34448900 | 2021 | [FH-deficient renal cell carcinoma expands the spectrum of renal papillary tumors]. | Rupp N et al |
| 21 | 32744123 | 2020 | Fumarate hydratase as a therapeutic target in renal cancer. | Kancherla P et al |
| 22 | 30785029 | 2019 | Fumarate hydratase deficient renal cell carcinoma: Chromosomal numerical aberration analysis of 12 cases. | Pivovarcikova K et al |
| 23 | 31026220 | 2019 | Succinate Dehydrogenase-Deficient Renal Cell Carcinoma. | Tsai TH et al |
| 24 | 32016042 | 2019 | Immunohistochemical screening for the diagnosis of succinate dehydrogenase-deficient renal cell carcinoma and fumarate hydratase-deficient renal cell carcinoma. | Trpkov K et al |
| 25 | 19774614 | 2010 | Fine needle aspiration cytology of ALK1(-), CD30+ anaplastic large cell lymphoma post renal transplantation: a case report and literature review. | Balachandran I et al |
| 26 | 26773439 | 2016 | ALK-rearranged renal cell carcinomas in children. | Cajaiba MM et al |
| 27 | 23542520 | 2013 | Distinct ALK-rearranged and VCL-negative papillary renal cell carcinoma variant in two adults without sickle cell trait. | Hodge JC et al |
| 28 | 30351856 | 2018 | A review of ALK-rearranged renal cell carcinomas with a focus on clinical and pathobiological aspects. | Kuroda N et al |
| 29 | 31993771 | 2020 | ALK-rearranged renal cell carcinoma with a novel PLEKHA7-ALK translocation and metanephric adenoma-like morphology. | Hang JF et al |
| 30 | 33729862 | 2021 | ALK-rearranged Renal Cell Carcinoma (RCC): A Report of 2 Cases and Review of the Literature Emphasizing the Distinction Between VCL-ALK and Non-VCL-ALK RCC. | Wangsiricharoen S et al |
| 31 | 31563285 | 2019 | Targeted next-generation sequencing revealed distinct clinicopathologic and molecular features of VCL-ALK RCC: A unique case from an older patient without clinical evidence of sickle cell trait. | Wang XT et al |
| 32 | 28122866 | 2017 | Targeting ALK: Precision Medicine Takes on Drug Resistance. | Lin JJ et al |
| 33 | 30656488 | 2019 | Renal Medullary Carcinoma: a Report of the Current Literature. | Blas L et al |
| 34 | 32359397 | 2020 | Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma. | Msaouel P et al |
| 35 | 34609565 | 2021 | [SMARCB1(INI1)-deficient renal cell carcinoma: medullary and beyond : Evolving concepts]. | Agaimy A et al |
Citation
Paola Dal Cin, PhD ; Michelle S. Hirsch, MD
Molecularly defined renal carcinomas
Atlas Genet Cytogenet Oncol Haematol. 2022-12-01
Online version: http://atlasgeneticsoncology.org/solid-tumor/208976/molecularly-defined-renal-carcinomas
