Genomic Mapping of Metastatic Organotropism in Lung Adenocarcinoma

Authors

Harry B. Lengel

Brooke Mastrogiacomo

James G. Connolly

Kay See Tan

Yuan Liu

Cameron N. Fick

Elizabeth G. Dunne

Di He

Manendra B. Lankadasari

Baby Anusha Satravada

Yichao Sun

Ritika Kundra

Chris Fong

Shaleigh Smith

Gregory J. Riely

Charles M. Rudin

Daniel R. Gomez

David B. Solit

Michael F. Berger

Bob T. Li

Marty W. Mayo

Irina Matei

David C. Lyden

Prasad S. Adusumilli

Nikolaus Schultz

Francisco Sanchez-Vega

David R. Jones

Doi

10.1016/j.ccell.2023.03.018

PMID: 37084736 · DOI: 10.1016/j.ccell.2023.03.018 · Journal: Cancer Cell (2023)

TL;DR

Lengel et al. analyzed 2,532 lung adenocarcinoma (LUAD) specimens from 2,309 MSK patients with matched clinicopathologic and targeted-panel genomic data to identify features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival. Patients developing metastasis were younger and more often male, with primaries enriched for micropapillary/solid histology, higher TMB, chromosomal instability, and fraction of genome doubled. Inactivation of TP53, SMARCA4, and CDKN2A correlated with shorter site-specific time to metastasis; APOBEC signatures were enriched in metastases, especially liver lesions; and only ~4% of metastases harbored actionable alterations not already present in the matched primary PMID:37084736.

Cohort & data

2,532 primary and metastatic LUAD specimens from 2,309 patients profiled at Memorial Sloan Kettering PMID:37084736.
Sites profiled include adrenal gland, bone, CNS, liver/biliary, lung, lymph node, and pleura PMID:37084736.
Targeted sequencing via the MSK-IMPACT panel (luad_mskcc_2023_met_organotropism), with an additional whole-exome sequencing subcohort for mutational signature analysis PMID:37084736.

Key findings

Ever-metastatic primaries had higher TMB, chromosomal instability, and fraction of genome doubled than never-metastatic primaries PMID:37084736.
APOBEC signatures SBS2/SBS13 were more prevalent in metastases than primaries (18% vs 8%, p=0.012), and were particularly enriched in liver metastases in the WES cohort PMID:37084736.
TP53, KEAP1, CDKN2A, MDM2, PIK3CA were among ten genes differentially altered between ever- and never-metastatic primary tumors PMID:37084736.
TP53/EGFR co-alteration with KEAP1 (q<0.001) and STK11 (q<0.001) was significant only in ever-metastatic primaries PMID:37084736.
SMARCA4, STK11, KEAP1, and KRAS alterations were mutually exclusive with EGFR alterations PMID:37084736.
EGFR (p=0.002) and NF1 (p<0.001) alterations were associated with worse metastasis-free survival PMID:37084736.
SMARCA4 alterations were strongly enriched in patients with bone metastasis (OR=6.47) and shortened time to bone metastasis (OR=2.79, 95% CI 1.71–4.56, p<0.001) PMID:37084736.
Adrenal gland metastases had the highest proportion of EGFR activating mutations (133/202, 66%) PMID:37084736.
In primary tumors that metastasized to liver, KRAS G12C was elevated (21%) vs the matched liver metastases (6%, p<0.001) PMID:37084736.
Only ~4% of metastases carried therapeutically actionable alterations undetected in their matched primaries PMID:37084736.

Genes & alterations

TP53 — inactivation correlated with site-specific shorter time to metastasis; co-altered with EGFR in ever-metastatic context PMID:37084736.
SMARCA4 — strong enrichment in bone metastases; shortened time to bone metastasis PMID:37084736.
CDKN2A — inactivation more frequent in CNS and liver metastases than in matched primaries PMID:37084736.
KEAP1, STK11 — co-alteration with TP53/EGFR defines higher-risk metastatic context PMID:37084736.
EGFR — activating mutations enriched at adrenal gland metastases; associated with worse MFS PMID:37084736.
KRAS — G12C preferentially seen in primaries that metastasized to liver vs the liver lesions themselves PMID:37084736.
NF1 — alterations associated with worse MFS PMID:37084736.
Additional genes altered more often in metastases: NKX2-1, FOXA1, MET, ARID1A, MGA; altered less in metastases: MDM2, PIK3CA, ERBB2 PMID:37084736.

Clinical implications

Because only ~4% of metastases carry new actionable alterations not present in the primary, routine re-biopsy of metastases for new targetable drivers yields limited incremental benefit in LUAD PMID:37084736.
Co-alteration patterns (e.g., TP53+EGFR+KEAP1/STK11) and SMARCA4 status may inform site-specific metastatic risk, notably for bone PMID:37084736.

Limitations & open questions

Targeted panel (MSK-IMPACT) limits mutational signature resolution; authors partially address this with a WES subcohort PMID:37084736.
Single-institution (MSK) cohort; external validation was performed but organotropism findings remain cancer-type-specific and may not generalize beyond LUAD PMID:37084736.
Some site-specific analyses (e.g., liver for SMARCA4) were underpowered PMID:37084736.

Citations from this paper used in the wiki

“We analyzed 2532 lung adenocarcinomas (LUAD) to identify clinicopathologic and genomic features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival.” (Summary)
“Inactivation of TP53, SMARCA4, and CDKN2A are correlated with a site-specific shorter time to metastasis. The APOBEC mutational signature is more prevalent among metastases, particularly liver lesions.” (Summary)
“Only 4% of metastases harbor therapeutically actionable alterations undetected in their matched primaries.” (Summary)
“SMARCA4 … associated with shorter time to bone metastasis (OR=2.79, 95% CI 1.71–4.56, p<0.001)” (Results)
“APOBEC-related signatures SBS2 and SBS13 in metastatic tumors (18% vs. 8%, p=0.012)” (Results)

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