# The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer

Source: https://onco.cc/key-papers/paper-schoenfeld-smarca4-alterations-lung-ccr-2020/  
OnCo record `paper-schoenfeld-smarca4-alterations-lung-ccr-2020` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

One of the most commonly mutated genes in lung cancer turns out to come in two kinds: one that destroys the protein and carries the worst prognosis, and one that leaves it intact. Both do worse than average, and both do better than average on immunotherapy.

## Summary

Genomic, protein expression and clinical outcome data were analysed for patients with SMARCA4-altered lung cancer treated at one centre. Among 4,813 patients with non-small-cell lung cancer, 407, 8%, carried a SMARCA4 alteration. Two categories were described: class 1 (truncating mutations, fusions and homozygous deletion) and class 2 (missense mutations). Loss of protein expression was associated with class 1 alterations, 81% against 0%. Both classes co-occurred more frequently with KRAS, STK11 and KEAP1 mutations than in SMARCA4 wild-type tumours. In metastatic disease, SMARCA4 alterations were associated with shorter overall survival, with class 1 the shortest. Treatment with immune checkpoint inhibitors was associated with improved outcomes in SMARCA4-altered tumours, with class 1 responding best.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Clinical Cancer Research
- Year: 2020
- DOI: 10.1158/1078-0432.CCR-20-1825
- Authors: Schoenfeld AJ, Bandlamudi C, Lavery JA, et al.
- Findings: SMARCA4 alterations in 407 of 4,813 lung cancers, 8%, in two genomically and clinically distinct classes.; Protein loss in 81% of class 1 alterations and none of class 2.; Both classes co-occur with KRAS, STK11 and KEAP1 and are independent predictors of poor prognosis.; Checkpoint inhibitor outcomes were better in SMARCA4-altered tumours, class 1 best.
- What it means: It turned a frequently reported variant into an interpretable one: the class decides whether the stain will be negative, how poor the prognosis is, and whether immunotherapy is more rather than less likely to help.
- Caveats: Single centre and retrospective.; Immunotherapy comparison is not randomised and is confounded by co-mutation.; Class 2 missense variants include variants of unknown significance.

## Sources

- Schoenfeld et al., Clin Cancer Res 2020: the genomic landscape of SMARCA4 alterations in 4,813 lung cancers: https://doi.org/10.1158/1078-0432.CCR-20-1825
- PubMed: https://pubmed.ncbi.nlm.nih.gov/32709715/

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [KEAP1](https://onco.cc/targets/keap1/), [KRAS](https://onco.cc/targets/kras/), [SMARCA4](https://onco.cc/targets/smarca4/), [STK11](https://onco.cc/targets/stk11/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- pathways: [SWI/SNF chromatin remodelling](https://onco.cc/pathways/swi-snf-chromatin/), [T-cell exhaustion](https://onco.cc/pathways/t-cell-exhaustion/)
- terms: [Driver mutation](https://onco.cc/terms/driver-mutation/), [Immunohistochemistry (IHC)](https://onco.cc/terms/ihc/), [STK11 / KEAP1 co-mutations](https://onco.cc/terms/stk11-keap1/), [Variant of uncertain significance (VUS)](https://onco.cc/terms/vus/)
- people: [Gregory J. Riely](https://onco.cc/people/gregory-riely/)
- journals: [Clinical Cancer Research](https://onco.cc/journals/clinical-cancer-research/)

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