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. 2019 Sep;19(9):495-509.
doi: 10.1038/s41568-019-0179-8. Epub 2019 Aug 12.

Co-occurring Genomic Alterations in Non-Small-Cell Lung Cancer Biology and Therapy

Free PMC article

Co-occurring Genomic Alterations in Non-Small-Cell Lung Cancer Biology and Therapy

Ferdinandos Skoulidis et al. Nat Rev Cancer. .
Free PMC article


The impressive clinical activity of small-molecule receptor tyrosine kinase inhibitors for oncogene-addicted subgroups of non-small-cell lung cancer (for example, those driven by activating mutations in the gene encoding epidermal growth factor receptor (EGFR) or rearrangements in the genes encoding the receptor tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and rearranged during transfection (RET)) has established an oncogene-centric molecular classification paradigm in this disease. However, recent studies have revealed considerable phenotypic diversity downstream of tumour-initiating oncogenes. Co-occurring genomic alterations, particularly in tumour suppressor genes such as TP53 and LKB1 (also known as STK11), have emerged as core determinants of the molecular and clinical heterogeneity of oncogene-driven lung cancer subgroups through their effects on both tumour cell-intrinsic and non-cell-autonomous cancer hallmarks. In this Review, we discuss the impact of co-mutations on the pathogenesis, biology, microenvironmental interactions and therapeutic vulnerabilities of non-small-cell lung cancer and assess the challenges and opportunities that co-mutations present for personalized anticancer therapy, as well as the expanding field of precision immunotherapy.

Conflict of interest statement

Competing interests

J.V.H. reports royalties and licensing fees from Spectrum Pharmaceuticals and Biotree; research support from AstraZeneca, Bayer, GlaxoSmithKline and Spectrum Pharmaceuticals; Advisory Committee membership from AstraZeneca, Boehringer-Ingelheim, Exelixis, Genentech, GlaxoSmithKline, Guardant Health, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum Pharmaceuticals, EMD Serono and Synta Pharmaceuticals. F.S. reports honoraria from Bristol-Myers Squibb, outside the scope of this work and consultancy fees from Tango Therapeutics.


Figure 1.
Figure 1.. Single oncogenic driver paradigm of lung adenocarcinoma molecular classification.
The dominant contemporary model of non-small cell lung cancer pathogenesis and molecular classification is based on identification of single and largely non-overlapping oncogenic driver events. Oncogenic pie charts are presented for early-stage (a) and metastatic (b) lung adenocarcinomas (LUADs). The prevalence of individual genomic alterations in early-stage disease is based on combined analysis of whole exome sequencing data from the PanCancer Atlas cohort of The Cancer Genome Atlas (TCGA) (n=785), as well as the cohorts reported by Imielinski et al (n=148) and Kadara et al (n=108), following exclusion of patients with stage 4 disease (n=741 patients in total). The prevalence of MET splice site alterations, MET amplification, ERBB2 amplification, HRAS and NRAS mutations as well as ALK, ROS1 and RET fusions was based on data from the TCGA and Imielinski cohorts only. Oncogenic driver alterations in advanced or metastatic LUAD (encompassing both treatment-naïve patients as well as patients that received prior anti-cancer therapies) are based on next-generation sequencing of pre-defined panels of cancer-relevant genes from patients treated at Memorial Sloan Kettering Cancer Center (N=860,MSK-IMPACT panel) and samples referred to Foundation Medicine (n=4402,FoundationOne panel) (n=5262 patients with advanced/metastatic LUAD in total). The prevalence of alterations in NF1, NRAS, HRAS, MAP2K1, FGFR1/2 and RIT1 is based on data from MSK-IMPACT only. It is notable that although the prevalence of oncogenic KRAS mutations is similar in both early and advanced stage LUADs the frequency of other driver alterations (for example truncating NF1 mutations) differs substantially depending on the disease stage. The increased prevalence of EGFR mutations in the metastatic dataset may partially reflect referral bias. Data were visualized and downloaded from the open source web program cBioPortal, or curated from the scientific literature.
Figure 2.
Figure 2.. Spectrum of major co-occurring genomic alterations in KRAS- and EGFR-mutant lung adenocarcinoma.
Volcano plots (left graphs) summarizing enrichment of individual co-alterations in: KRAS-mutant compared with KRAS-wild-type LUADs (a) and EGFR-mutant compared with EGFR-wild-type LUADs (b). The magnitude of co-mutation enrichment is indicated on the x-axis and is expressed as log2 (% in KRAS-mutant / % in KRAS-wild-type) or log2 (% in EGFR-mutant / % in EGFR-wild-type) respectively, whereas the statistical significance of the association is plotted on the y-axis and is expressed as –log10P value (derived from a Fisher’s exact test). Significantly enriched co-mutations based on a q value <0.05 (derived from Benjamini-Hochberg procedure) are highlighted in red, whereas under-represented genomic events are highlighted in blue. The prevalence of each co-alteration in KRAS-mutant and KRAS-wild-type groups (or EGFR-mutant and EGFR-wild-type groups) is shown in the adjacent frequency plots (right graphs of parts a and b). Targeted next generation sequencing-based molecular profiling (MSK-IMPACT platform) from 860 patients with metastatic LUAD treated at Memorial Sloan Kettering Cancer Center were included in this enrichment analysis that was performed using the cBioPortal web program, . Oncogene-driver specific, non-random patterns of co-occurring alterations in key tumor suppressor genes are evident for both KRAS-mutant and EGFR-mutant tumors.
Figure 3.
Figure 3.. Impact of co-mutations on the microenvironment of KRAS-mutant lung adenocarcinoma.
Schematic representation of co-mutation-associated changes in the immune and non-immune microenvironment of KRAS-mutant lung adenocarcinoma (LUAD). (a) LKB1 inactivation promotes epigenetic suppression of STING and insensitivity to cytosolic DNA that accumulates in the cytoplasm of KRAS- and LKB1-mutant (KL) cells due to dysfunctional mitochondria. KL tumors are further characterized by a pro-inflammatory cytokine milieu with accumulation of immunosuppressive neutrophils, marked paucity of CD4+ and CD8+ T-cells and evidence of T-cell exhaustion, . The potential contributions of immune cell metabolic restriction, altered angiogenesis and acidification of the tumor microenvironment (highlighted in blue) to the immune-inert phenotype of KL tumors remain as yet unexplored, but represent plausible directions for future study. (b) MYC fosters immune evasion of murine KrasG12D- driven LUADs through IL-23- mediated expulsion of T, B and NK cells and CCL9-mediated macrophage recruitment and secretion of immunosuppressive VEGF. (c) KEAP1 mutations, which frequently co-occur with mutations in LKB1, particularly in the context of KRAS-mutant LUAD, have also been associated with low intra-tumoral density of infiltrating T- and B- lymphocytes, although the possible role of KEAP1 loss on NK cell infiltration remains unclear. Stabilization of NRF2 as a result of KEAP1 inactivation may further promote reduced expression of STING through post-transcriptional regulation. (d) Finally, somatic TP53 mutations have been shown to mediate NF-κB pathway activation in Kras-mutant murine models of LUAD. Although TP53 mutations have been associated with reduced production of chemokines required for the recruitment of NK and T cells in some models and human tumors, in the context of KRAS-mutant LUAD TP53 co-alterations promote an inflamed tumor immune microenvironment with increased production of interferon γ (IFNγ) and increased expression of PD-L1 on the surface of tumor cells, , .
Figure 4.
Figure 4.. Next-generation model for the molecular stratification of lung adenocarcinoma.
Oncogenic subgroups of lung adenocarcinoma (LUAD) are divided into smaller subsets on the basis of key co-occurring genomic alterations. Co-mutations constitute major determinants of tumor molecular diversity and can impact both tumor cell-autonomous and non-cell-autonomous cancer hallmarks; determine prognosis; predict response to systemic therapies and influence mechanisms of innate and acquired resistance. For simplicity, only KRAS and EGFR co-alterations are depicted graphically. For KRAS-mutant LUADs the previously identified KL, KP, and KC transcriptome-based subgroups are also indicated; co-mutations in LKB1, KEAP1 and ATM are significantly enriched in the KL subgroup, whereas co-occurring alterations in TP53 and bi-allelic inactivation of CDKN2A/CDKN2B are hallmarks of the KP and KC subgroups respectively. Co-mutations in RBM10 don’t appear to exhibit predilection for any of the three KRAS transcriptomic subgroups. It should therefore be noted that several of the reported co-alterations within oncogene-defined groups are not mutually exclusive. Although co-mutation-defined cohorts are represented as slices of equal size, both the spectrum and prevalence of individual co-mutations evolve according to disease stage, prior treatment exposures, immune editing and the mutational processes that are operational at each stage of carcinogenesis.

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