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

Clin Cancer Res. 2022 Nov 1;28(21):4702-4713. doi: 10.1158/1078-0432.CCR-22-1115.


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.

Publication types

  • Editorial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Genomics
  • Humans
  • Immunohistochemistry
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Lung Neoplasms* / pathology
  • NF-E2-Related Factor 2 / metabolism
  • Retinal Neoplasms*
  • Retinoblastoma*
  • Small Cell Lung Carcinoma* / genetics
  • Small Cell Lung Carcinoma* / pathology


  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2