Rb tumor suppressor in small cell lung cancer: Combined genomic and IHC analysis with a description of a distinct Rb-proficient subset Editorial
| Authors: | Febres-Aldana, C. A.; Chang, J. C.; Ptashkin, R.; Wang, Y.; Gedvilaite, E.; Baine, M. K.; Travis, W. D.; Ventura, K.; Bodd, F.; Yu, H. A.; Quintanal-Villalonga, A.; Lai, W. V.; Egger, J. V.; Offin, M.; Ladanyi, M.; Rudin, C. M.; Rekhtman, N. |
| Title: | Rb tumor suppressor in small cell lung cancer: Combined genomic and IHC analysis with a description of a distinct Rb-proficient subset |
| Abstract: | 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. ©2022 The Authors; Published by the American Association for Cancer Research. |
| Keywords: | immunohistochemistry; genetics; metabolism; carcinoma, non-small-cell lung; lung neoplasms; retinoblastoma; pathology; retina tumor; retinal neoplasms; lung tumor; genomics; small cell lung cancer; small cell lung carcinoma; non small cell lung cancer; transcription factor nrf2; kelch like ech associated protein 1; humans; human; nf-e2-related factor 2; kelch-like ech-associated protein 1 |
| Journal Title: | Clinical Cancer Research |
| Volume: | 28 |
| Issue: | 21 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-11-01 |
| Start Page: | 4702 |
| End Page: | 4713 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-22-1115 |
| PUBMED: | 35792876 |
| PROVIDER: | scopus |
| PMCID: | PMC9623236 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work