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Rb Tumor Suppressor in Small Cell Lung Cancer: Combined Genomic and IHC Analysis with a Description of a Distinct Rb-Proficient Subset

PURPOSE: RB1 mutations and loss of retinoblastoma (Rb) expression represent consistent but not entirely invariable hallmarks of small cell lung cancer (SCLC). The prevalence and characteristics of SCLC retaining wild-type Rb are not well-established. Furthermore, the performance of targeted next-gen...

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Autores principales: Febres-Aldana, Christopher A., Chang, Jason C., Ptashkin, Ryan, Wang, Yuhan, Gedvilaite, Erika, Baine, Marina K., Travis, William D., Ventura, Katia, Bodd, Francis, Yu, Helena A., Quintanal-Villalonga, Alvaro, Lai, W. Victoria, Egger, Jacklynn V., Offin, Michael, Ladanyi, Marc, Rudin, Charles M., Rekhtman, Natasha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9623236/
https://www.ncbi.nlm.nih.gov/pubmed/35792876
http://dx.doi.org/10.1158/1078-0432.CCR-22-1115
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author Febres-Aldana, Christopher A.
Chang, Jason C.
Ptashkin, Ryan
Wang, Yuhan
Gedvilaite, Erika
Baine, Marina K.
Travis, William D.
Ventura, Katia
Bodd, Francis
Yu, Helena A.
Quintanal-Villalonga, Alvaro
Lai, W. Victoria
Egger, Jacklynn V.
Offin, Michael
Ladanyi, Marc
Rudin, Charles M.
Rekhtman, Natasha
author_facet Febres-Aldana, Christopher A.
Chang, Jason C.
Ptashkin, Ryan
Wang, Yuhan
Gedvilaite, Erika
Baine, Marina K.
Travis, William D.
Ventura, Katia
Bodd, Francis
Yu, Helena A.
Quintanal-Villalonga, Alvaro
Lai, W. Victoria
Egger, Jacklynn V.
Offin, Michael
Ladanyi, Marc
Rudin, Charles M.
Rekhtman, Natasha
author_sort Febres-Aldana, Christopher A.
collection PubMed
description PURPOSE: RB1 mutations and loss of retinoblastoma (Rb) expression represent consistent but not entirely invariable hallmarks of small cell lung cancer (SCLC). The prevalence and characteristics of SCLC retaining wild-type Rb are not well-established. Furthermore, the performance of targeted next-generation sequencing (NGS) versus immunohistochemistry for Rb assessment is not well-defined. EXPERIMENTAL DESIGN: A total of 208 clinical SCLC samples were analyzed by comprehensive targeted NGS, covering all exons of RB1, and Rb IHC. On the basis of established coordination of Rb/p16/cyclinD1 expression, p16-high/cyclinD1-low profile was used as a marker of constitutive Rb deficiency. RESULTS: Fourteen of 208 (6%) SCLC expressed wild-type Rb, accompanied by a unique p16-low/cyclinD1-high profile supporting Rb proficiency. Rb-proficient SCLC was associated with neuroendocrine-low phenotype, combined SCLC with non-SCLC (NSCLC) histology and aggressive behavior. These tumors exclusively harbored CCND1 amplification (29%), and were markedly enriched in CDKN2A mutations (50%) and NSCLC-type alterations (KEAP1, STK11, FGFR1). The remaining 194 of 208 SCLC were Rb-deficient (p16-high/cyclinD1-low), including 184 cases with Rb loss (of which 29% lacked detectable RB1 alterations by clinical NGS pipeline), and 10 cases with mutated but expressed Rb. CONCLUSIONS: This is the largest study to date to concurrently analyze Rb by NGS and IHC in SCLC, identifying a 6% rate of Rb proficiency. Pathologic-genomic data implicate NSCLC-related progenitors as a putative source of Rb-proficient SCLC. Consistent upstream Rb inactivation via CDKN2A/p16(↓) and CCND1/cyclinD1(↑) suggests the potential utility of CDK4/6 inhibitors in this aggressive SCLC subset. The study also clarifies technical aspects of Rb status determination in clinical practice, highlighting the limitations of exon-only sequencing for RB1 interrogation. See related commentary by Mahadevan and Sholl, p. 4603
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spelling pubmed-96232362022-11-04 Rb Tumor Suppressor in Small Cell Lung Cancer: Combined Genomic and IHC Analysis with a Description of a Distinct Rb-Proficient Subset Febres-Aldana, Christopher A. Chang, Jason C. Ptashkin, Ryan Wang, Yuhan Gedvilaite, Erika Baine, Marina K. Travis, William D. Ventura, Katia Bodd, Francis Yu, Helena A. Quintanal-Villalonga, Alvaro Lai, W. Victoria Egger, Jacklynn V. Offin, Michael Ladanyi, Marc Rudin, Charles M. Rekhtman, Natasha Clin Cancer Res Translational Cancer Mechanisms and Therapy PURPOSE: RB1 mutations and loss of retinoblastoma (Rb) expression represent consistent but not entirely invariable hallmarks of small cell lung cancer (SCLC). The prevalence and characteristics of SCLC retaining wild-type Rb are not well-established. Furthermore, the performance of targeted next-generation sequencing (NGS) versus immunohistochemistry for Rb assessment is not well-defined. EXPERIMENTAL DESIGN: A total of 208 clinical SCLC samples were analyzed by comprehensive targeted NGS, covering all exons of RB1, and Rb IHC. On the basis of established coordination of Rb/p16/cyclinD1 expression, p16-high/cyclinD1-low profile was used as a marker of constitutive Rb deficiency. RESULTS: Fourteen of 208 (6%) SCLC expressed wild-type Rb, accompanied by a unique p16-low/cyclinD1-high profile supporting Rb proficiency. Rb-proficient SCLC was associated with neuroendocrine-low phenotype, combined SCLC with non-SCLC (NSCLC) histology and aggressive behavior. These tumors exclusively harbored CCND1 amplification (29%), and were markedly enriched in CDKN2A mutations (50%) and NSCLC-type alterations (KEAP1, STK11, FGFR1). The remaining 194 of 208 SCLC were Rb-deficient (p16-high/cyclinD1-low), including 184 cases with Rb loss (of which 29% lacked detectable RB1 alterations by clinical NGS pipeline), and 10 cases with mutated but expressed Rb. CONCLUSIONS: This is the largest study to date to concurrently analyze Rb by NGS and IHC in SCLC, identifying a 6% rate of Rb proficiency. Pathologic-genomic data implicate NSCLC-related progenitors as a putative source of Rb-proficient SCLC. Consistent upstream Rb inactivation via CDKN2A/p16(↓) and CCND1/cyclinD1(↑) suggests the potential utility of CDK4/6 inhibitors in this aggressive SCLC subset. The study also clarifies technical aspects of Rb status determination in clinical practice, highlighting the limitations of exon-only sequencing for RB1 interrogation. See related commentary by Mahadevan and Sholl, p. 4603 American Association for Cancer Research 2022-11-01 2022-07-06 /pmc/articles/PMC9623236/ /pubmed/35792876 http://dx.doi.org/10.1158/1078-0432.CCR-22-1115 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Translational Cancer Mechanisms and Therapy
Febres-Aldana, Christopher A.
Chang, Jason C.
Ptashkin, Ryan
Wang, Yuhan
Gedvilaite, Erika
Baine, Marina K.
Travis, William D.
Ventura, Katia
Bodd, Francis
Yu, Helena A.
Quintanal-Villalonga, Alvaro
Lai, W. Victoria
Egger, Jacklynn V.
Offin, Michael
Ladanyi, Marc
Rudin, Charles M.
Rekhtman, Natasha
Rb Tumor Suppressor in Small Cell Lung Cancer: Combined Genomic and IHC Analysis with a Description of a Distinct Rb-Proficient Subset
title Rb Tumor Suppressor in Small Cell Lung Cancer: Combined Genomic and IHC Analysis with a Description of a Distinct Rb-Proficient Subset
title_full Rb Tumor Suppressor in Small Cell Lung Cancer: Combined Genomic and IHC Analysis with a Description of a Distinct Rb-Proficient Subset
title_fullStr Rb Tumor Suppressor in Small Cell Lung Cancer: Combined Genomic and IHC Analysis with a Description of a Distinct Rb-Proficient Subset
title_full_unstemmed Rb Tumor Suppressor in Small Cell Lung Cancer: Combined Genomic and IHC Analysis with a Description of a Distinct Rb-Proficient Subset
title_short Rb Tumor Suppressor in Small Cell Lung Cancer: Combined Genomic and IHC Analysis with a Description of a Distinct Rb-Proficient Subset
title_sort rb tumor suppressor in small cell lung cancer: combined genomic and ihc analysis with a description of a distinct rb-proficient subset
topic Translational Cancer Mechanisms and Therapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9623236/
https://www.ncbi.nlm.nih.gov/pubmed/35792876
http://dx.doi.org/10.1158/1078-0432.CCR-22-1115
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