| Autor: |
Natasha Rekhtman, Charles M. Rudin, Marc Ladanyi, Michael Offin, Jacklynn V. Egger, W. Victoria Lai, Alvaro Quintanal-Villalonga, Helena A. Yu, Francis Bodd, Katia Ventura, William D. Travis, Marina K. Baine, Erika Gedvilaite, Yuhan Wang, Ryan Ptashkin, Jason C. Chang, Christopher A. Febres-Aldana |
| Rok vydání: |
2023 |
| ISSN: |
1078-0432 |
| DOI: |
10.1158/1078-0432.c.6532947.v1 |
| Popis: |
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 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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