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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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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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 |
format | Online Article Text |
id | pubmed-9623236 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
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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