Distinctive mechanisms underlie the loss of SMARCB1 protein expression in renal medullary carcinoma

morphologic and molecular analysis of 20 cases

Liwei Jia, Maria I. Carlo, Hina Khan, Gouri J. Nanjangud, Satshil Rana, Robert Cimera, Yanming Zhang, A. Ari Hakimi, Amit K. Verma, Hikmat A. Al-Ahmadie, Samson W. Fine, Anuradha Gopalan, S. Joseph Sirintrapun, Satish K. Tickoo, Victor E. Reuter, Benjamin A. Gartrell, Ying Bei Chen

Research output: Contribution to journalArticle

Abstract

Renal medullary carcinoma is a rare but highly aggressive type of renal cancer occurring in patients with sickle cell trait or rarely with other hemoglobinopathies. Loss of SMARCB1 protein expression, a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, has emerged as a key diagnostic feature of these tumors. However, the molecular mechanism underlying this loss remains unclear. We retrospectively identified 20 patients diagnosed with renal medullary carcinoma at two institutions from 1996 to 2017. All patients were confirmed to have sickle cell trait, and all tumors exhibited a loss of SMARCB1 protein expression by immunohistochemistry. The status of SMARCB1 locus was examined by fluorescence in situ hybridization (FISH) using 3-color probes, and somatic alterations were detected by targeted next-generation sequencing platforms. FISH analysis of all 20 cases revealed 11 (55%) with concurrent hemizygous loss and translocation of SMARCB1, 6 (30%) with homozygous loss of SMARCB1, and 3 (15%) without structural or copy number alterations of SMARCB1 despite protein loss. Targeted sequencing revealed a pathogenic somatic mutation of SMARCB1 in one of these 3 cases that were negative by FISH. Tumors in the 3 subsets with different FISH findings largely exhibited similar clinicopathologic features, however, homozygous SMARCB1 deletion was found to show a significant association with the solid growth pattern, whereas tumors dominated by reticular/cribriform growth were enriched for SMARCB1 translocation. Taken together, we demonstrate that different molecular mechanisms underlie the loss of SMARCB1 expression in renal medullary carcinoma. Biallelic inactivation of SMARCB1 occurs in a large majority of cases either via concurrent hemizygous loss and translocation disrupting SMARCB1 or by homozygous loss.

Original languageEnglish (US)
JournalModern Pathology
DOIs
StatePublished - Jan 1 2019

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Medullary Carcinoma
Fluorescence In Situ Hybridization
Sickle Cell Trait
Kidney
Neoplasms
Hemoglobinopathies
Chromatin Assembly and Disassembly
Kidney Neoplasms
Growth
Sucrose
Color
Immunohistochemistry
Mutation
SMARCB1 Protein

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Distinctive mechanisms underlie the loss of SMARCB1 protein expression in renal medullary carcinoma : morphologic and molecular analysis of 20 cases. / Jia, Liwei; Carlo, Maria I.; Khan, Hina; Nanjangud, Gouri J.; Rana, Satshil; Cimera, Robert; Zhang, Yanming; Hakimi, A. Ari; Verma, Amit K.; Al-Ahmadie, Hikmat A.; Fine, Samson W.; Gopalan, Anuradha; Sirintrapun, S. Joseph; Tickoo, Satish K.; Reuter, Victor E.; Gartrell, Benjamin A.; Chen, Ying Bei.

In: Modern Pathology, 01.01.2019.

Research output: Contribution to journalArticle

Jia, L, Carlo, MI, Khan, H, Nanjangud, GJ, Rana, S, Cimera, R, Zhang, Y, Hakimi, AA, Verma, AK, Al-Ahmadie, HA, Fine, SW, Gopalan, A, Sirintrapun, SJ, Tickoo, SK, Reuter, VE, Gartrell, BA & Chen, YB 2019, 'Distinctive mechanisms underlie the loss of SMARCB1 protein expression in renal medullary carcinoma: morphologic and molecular analysis of 20 cases', Modern Pathology. https://doi.org/10.1038/s41379-019-0273-1
Jia, Liwei ; Carlo, Maria I. ; Khan, Hina ; Nanjangud, Gouri J. ; Rana, Satshil ; Cimera, Robert ; Zhang, Yanming ; Hakimi, A. Ari ; Verma, Amit K. ; Al-Ahmadie, Hikmat A. ; Fine, Samson W. ; Gopalan, Anuradha ; Sirintrapun, S. Joseph ; Tickoo, Satish K. ; Reuter, Victor E. ; Gartrell, Benjamin A. ; Chen, Ying Bei. / Distinctive mechanisms underlie the loss of SMARCB1 protein expression in renal medullary carcinoma : morphologic and molecular analysis of 20 cases. In: Modern Pathology. 2019.
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abstract = "Renal medullary carcinoma is a rare but highly aggressive type of renal cancer occurring in patients with sickle cell trait or rarely with other hemoglobinopathies. Loss of SMARCB1 protein expression, a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, has emerged as a key diagnostic feature of these tumors. However, the molecular mechanism underlying this loss remains unclear. We retrospectively identified 20 patients diagnosed with renal medullary carcinoma at two institutions from 1996 to 2017. All patients were confirmed to have sickle cell trait, and all tumors exhibited a loss of SMARCB1 protein expression by immunohistochemistry. The status of SMARCB1 locus was examined by fluorescence in situ hybridization (FISH) using 3-color probes, and somatic alterations were detected by targeted next-generation sequencing platforms. FISH analysis of all 20 cases revealed 11 (55{\%}) with concurrent hemizygous loss and translocation of SMARCB1, 6 (30{\%}) with homozygous loss of SMARCB1, and 3 (15{\%}) without structural or copy number alterations of SMARCB1 despite protein loss. Targeted sequencing revealed a pathogenic somatic mutation of SMARCB1 in one of these 3 cases that were negative by FISH. Tumors in the 3 subsets with different FISH findings largely exhibited similar clinicopathologic features, however, homozygous SMARCB1 deletion was found to show a significant association with the solid growth pattern, whereas tumors dominated by reticular/cribriform growth were enriched for SMARCB1 translocation. Taken together, we demonstrate that different molecular mechanisms underlie the loss of SMARCB1 expression in renal medullary carcinoma. Biallelic inactivation of SMARCB1 occurs in a large majority of cases either via concurrent hemizygous loss and translocation disrupting SMARCB1 or by homozygous loss.",
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AU - Jia, Liwei

AU - Carlo, Maria I.

AU - Khan, Hina

AU - Nanjangud, Gouri J.

AU - Rana, Satshil

AU - Cimera, Robert

AU - Zhang, Yanming

AU - Hakimi, A. Ari

AU - Verma, Amit K.

AU - Al-Ahmadie, Hikmat A.

AU - Fine, Samson W.

AU - Gopalan, Anuradha

AU - Sirintrapun, S. Joseph

AU - Tickoo, Satish K.

AU - Reuter, Victor E.

AU - Gartrell, Benjamin A.

AU - Chen, Ying Bei

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N2 - Renal medullary carcinoma is a rare but highly aggressive type of renal cancer occurring in patients with sickle cell trait or rarely with other hemoglobinopathies. Loss of SMARCB1 protein expression, a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, has emerged as a key diagnostic feature of these tumors. However, the molecular mechanism underlying this loss remains unclear. We retrospectively identified 20 patients diagnosed with renal medullary carcinoma at two institutions from 1996 to 2017. All patients were confirmed to have sickle cell trait, and all tumors exhibited a loss of SMARCB1 protein expression by immunohistochemistry. The status of SMARCB1 locus was examined by fluorescence in situ hybridization (FISH) using 3-color probes, and somatic alterations were detected by targeted next-generation sequencing platforms. FISH analysis of all 20 cases revealed 11 (55%) with concurrent hemizygous loss and translocation of SMARCB1, 6 (30%) with homozygous loss of SMARCB1, and 3 (15%) without structural or copy number alterations of SMARCB1 despite protein loss. Targeted sequencing revealed a pathogenic somatic mutation of SMARCB1 in one of these 3 cases that were negative by FISH. Tumors in the 3 subsets with different FISH findings largely exhibited similar clinicopathologic features, however, homozygous SMARCB1 deletion was found to show a significant association with the solid growth pattern, whereas tumors dominated by reticular/cribriform growth were enriched for SMARCB1 translocation. Taken together, we demonstrate that different molecular mechanisms underlie the loss of SMARCB1 expression in renal medullary carcinoma. Biallelic inactivation of SMARCB1 occurs in a large majority of cases either via concurrent hemizygous loss and translocation disrupting SMARCB1 or by homozygous loss.

AB - Renal medullary carcinoma is a rare but highly aggressive type of renal cancer occurring in patients with sickle cell trait or rarely with other hemoglobinopathies. Loss of SMARCB1 protein expression, a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, has emerged as a key diagnostic feature of these tumors. However, the molecular mechanism underlying this loss remains unclear. We retrospectively identified 20 patients diagnosed with renal medullary carcinoma at two institutions from 1996 to 2017. All patients were confirmed to have sickle cell trait, and all tumors exhibited a loss of SMARCB1 protein expression by immunohistochemistry. The status of SMARCB1 locus was examined by fluorescence in situ hybridization (FISH) using 3-color probes, and somatic alterations were detected by targeted next-generation sequencing platforms. FISH analysis of all 20 cases revealed 11 (55%) with concurrent hemizygous loss and translocation of SMARCB1, 6 (30%) with homozygous loss of SMARCB1, and 3 (15%) without structural or copy number alterations of SMARCB1 despite protein loss. Targeted sequencing revealed a pathogenic somatic mutation of SMARCB1 in one of these 3 cases that were negative by FISH. Tumors in the 3 subsets with different FISH findings largely exhibited similar clinicopathologic features, however, homozygous SMARCB1 deletion was found to show a significant association with the solid growth pattern, whereas tumors dominated by reticular/cribriform growth were enriched for SMARCB1 translocation. Taken together, we demonstrate that different molecular mechanisms underlie the loss of SMARCB1 expression in renal medullary carcinoma. Biallelic inactivation of SMARCB1 occurs in a large majority of cases either via concurrent hemizygous loss and translocation disrupting SMARCB1 or by homozygous loss.

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