Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy

In the paper

“While the full extent to which mutational processes account for unique combinations of somatic genomic alterations in NSCLC is currently unknown, there is evidence that APOBEC-mediated mutagenesis fuels sub-clonal diversification and branched evolution78, 79.”

What the sources say

• Supported

  The paper’s APOBEC analysis (section labeled Abstract; page unavailable) reports an APOBEC-like signature and a trend toward its enrichment in later, non-trunk mutations. Its phylogenetic analysis identifies non-trunk mutations with branches, supporting the citing sentence’s cautious statement that there is evidence for a role in subclonal diversification and branched evolution. The enrichment was statistically significant in only one of 11 patients. (LLM, conf=0.84)

  cites [78] Zhang, J. et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 346, 256–259 (2014). source
• Not checked yetcites [79] de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251–256 (2014). source

In the paper

“Nkx2–1 haplo-insufficiency promotes both initiation and progression of invasive mucinous adenocarcinomas124”

What the sources say

• ?Could not verify

  The Methods (Patient Selection; page unavailable) describe profiling EGFR, KRAS, PIK3CA and other alterations, while the Discussion (page unavailable) addresses PIK3CA-related tumorigenesis. Searches for NKX2-1 haplo-insufficiency and mucinous adenocarcinoma found no passage addressing whether reduced NKX2-1 dosage promotes its initiation or progression. (LLM, conf=0.76)

  cites [124] Eng, J. et al. Impact of concurrent PIK3CA mutations on response to EGFR tyrosine kinase inhibition in EGFR-mutant lung cancers and on prognosis in oncogene-driven lung adenocarcinomas. J. Thorac. Oncol. 10, 1713–1719 (2015). sourceExperimental — accuracy not yet measured

In the paper

“both RET and ROS1 fusion-positive LUAD are characterized by high rates of concurrent CDKN2A loss (29.8% and 30.4% for RET and ROS1-rearranged tumors respectively)”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• ?Could not verify

  The Results sections on mutation findings and co-mutation analysis report RET rearrangements and examine other concurrent alterations, but do not report CDKN2A loss in RET-positive tumors. Searches for CDKN2A and the claimed 29.8% rate found no supporting passage in our copy. (LLM, conf=0.76)

  cites [131] Aisner, D. L. et al. The impact of smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations—the Lung Cancer Mutation Consortium (LCMC2). Clin. Cancer Res. 24, 1038–1047 (2018). sourceExperimental — accuracy not yet measured

In the paper

“relative paucity of TP53 mutations”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Supported

  The Results section, under “Co-mutation plot and analysis,” reports that TP53 mutations were rare in tumors with ALK, ROS1, or RET rearrangements. It contrasts this with TP53 mutations in 40% of EGFR-mutant and 50% of KRAS-mutant tumors, supporting the claimed relative paucity in RET- and ROS1-fusion-positive lung adenocarcinoma. (LLM, conf=0.93)

  cites [131] Aisner, D. L. et al. The impact of smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations—the Lung Cancer Mutation Consortium (LCMC2). Clin. Cancer Res. 24, 1038–1047 (2018). source

In the paper

“LKB1 deficient cells are selectively vulnerable to inhibition of the ATP1A1 Na+/K+-ATPase by cardiac glycosides162”

What the sources say

• Partly supported

  The Discussion reports that targeting Na+/K+-ATPase with cardiac glycosides was synthetic lethal with LKB1 loss in a lung-cancer xenograft model. It does not identify ATP1A1 specifically, and the cited evidence is narrower than a claim about LKB1-deficient cells generally. (LLM, conf=0.86)

  cites [162] Liu, Y. et al. Gemcitabine and Chk1 inhibitor AZD7762 synergistically suppress the growth of Lkb1-deficient lung adenocarcinoma. Cancer Res. 77, 5068–5076 (2017). sourceExperimental — accuracy not yet measured

In the paper

“NSCLCs driven by the same dominant oncogenic alteration can vary considerably in their histological appearance and immunohistochemical profile.”

In the paper

“There is mounting evidence that substantial molecular and clinical heterogeneity exists within oncogenic driver-defined subgroups of NSCLC (“intra-driver heterogeneity”).”

In the paper

“recent studies have revealed considerable phenotypic diversity downstream of tumor-initiating oncogenes”

In the paper

“Co-occurring genomic alterations, particularly in tumor 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 tumor cell-intrinsic and non-cell-autonomous cancer hallmarks.”

In the paper

“accumulating evidence points towards the existence of substantial clinical heterogeneity within oncogenic-driver defined NSCLC subgroups that is currently incompletely accounted for by the single oncogenic driver model”

In the paper

“KRAS-mutant lung adenocarcinomas (LUADs) demonstrate dual propensity towards either solid growth pattern with positivity for the NKX2–1 homeobox transcription factor (also known as TTF1) or, alternatively, invasive mucinous adenocarcinoma histology and corresponding lack of NKX2–1 expression33.”

What the sources say

• Not checked yetcites [33] Rekhtman, N., Ang, D. C., Riely, G. J., Ladanyi, M. & Moreira, A. L. KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma. Mod. Pathol. 26, 1307–1319 (2013). source

In the paper

“Importantly, large-scale profiling studies utilizing either whole exome sequencing or broad targeted sequencing panels in NSCLC tumors have revealed multiple non-random patterns of co-occurring or mutually exclusive mutations, which typically vary depending on the particular oncogenic driver mutation15, 34, 58–62.”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source
• Not checked yetcites [58] Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017). source
• Not checked yetcites [59] Jordan, E. J. et al. prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609 (2017). This article and Frampton et al. (2015) are the largest reported studies of comprehensive genomic profiling in patients with advanced LUAD. source
• Not checked yetcites [60] Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008). source
• Not checked yetcites [61] Campbell, J. D. et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet. 48, 607–616 (2016). source
• Not checked yetcites [62] Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012). source

In the paper

“Although passenger mutations account for the largest fraction of this mutational burden, combinations of somatic mutations in bona fide cancer driver genes are identified in the majority of LUAD and a substantial fraction of LUSC, even when next generation sequencing platforms are limited to the evaluation of pre-defined sets of cancer-relevant genes.”

In the paper

“Phenotypic variability and therapeutic response heterogeneity are particularly evident within KRAS-mutant LUAD.”

In the paper

“The compendium of co-occurring genomic alterations in NSCLC are potentially more impactful than distinct mutations in oncogenic drivers with regard to determining tumor heterogeneity.”

In the paper

“Thus, from its inception, NSCLC develops through a network of evolving genetic interactions that collectively determine cancer hallmark traits65, 66.”

What the sources say

• Not checked yetcites [65] Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000). source
• Not checked yetcites [66] Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011). source

In the paper

“The pervasive diversity of this oncogenotype was aptly demonstrated in a study that applied affinity propagation clustering analysis36 to mRNA expression data from 106 genomically-annotated NSCLC cell lines; strikingly, variation in mRNA expression within KRAS-mutant NSCLC cell lines was equivalent to that observed across the entire cell line panel37.”

What the sources say

• Not checked yetcites [36] Dueck, D. & Frey, B. J. Non-metric affinity propagation for unsupervised image categorization. 2007 IEEE 11th International Conference on Computer Vision 1-6, 198–205 (2007).
• Not checked yetcites [37] Kim, J. et al. XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature 538, 114–117 (2016). source

In the paper

“It is important to note, however, that even genomic alterations that do not show statistically significant patterns of co-occurrence may still have important interactions biologically.”

In the paper

“Nonetheless, distinct types of somatic mutations or gene rearrangements appear to only partially account for intra-driver heterogeneity because marked differences in biological behavior can also be observed between NSCLC that bear identical oncogenic alterations in driver genes.”

In the paper

“For example, the PRKAR1A-ALK fusion was consistently demonstrated to be less sensitive to first, second and third generation ALK TKIs48.”

What the sources say

• Not checked yetcites [48] Childress, M. A. et al. ALK fusion partners impact response to ALK inhibition: differential effects on sensitivity, cellular phenotypes, and biochemical properties. Mol. Cancer Res. 16, 1724–1736 (2018). source

In the paper

“The importance of co-mutations as mediators of diverse NSCLC phenotypes has only recently attracted focus and their functional impact remains largely uncaptured within current molecular stratification frameworks.”

In the paper

“In particular, it is critical to distinguish between early-stage, surgically resected tumors and locally advanced or metastatic disease because several distinct patterns of co-mutations are enriched in metastatic disease, likely reflecting acquisition of traits that promote tumor progression and metastatic dissemination72, 73.”

What the sources say

• Not checked yetcites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source
• Not checked yetcites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source

In the paper

“Taken together, these studies challenge the single-oncogene paradigm in NSCLC by unveiling multiple layers of heterogeneity within oncogenic subgroups that can only partially be attributed to the driver oncoprotein itself.”

In the paper

“Multiple studies have affirmed the favorable prognostic impact of exon 19 EGFR deletions compared with exon 21 L858R amino acid substitution, although the molecular basis for this association has not been conclusively determined44, 45.”

What the sources say

• Not checked yetcites [44] Jackman, D. M. et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin. Cancer Res. 12, 3908–3914 (2006). source
• Not checked yetcites [45] Choi, Y. W. et al. EGFR exon 19 deletion is associated with favorable overall survival after first-line gefitinib therapy in advanced non-small cell lung cancer patients. Am. J. Clin. Oncol. 41, 385–390 (2018). source

In the paper

“In many cases, divergent clinical behavior can be directly attributed to the distinct effects of individual oncogenic alleles.”

In the paper

“Even more variable are duration of response to targeted therapy, progression-free survival and overall survival16–26, 28–32, 35.”

What the sources say

• Not checked yetcites [16] Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009). source
• Not checked yetcites [17] Zhou, C. et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12, 735–742 (2011). source
• Not checked yetcites [18] Rosell, R. et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13, 239–246 (2012). source
• Not checked yetcites [19] Yang, J. C. et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 16, 141–151 (2015). source
• Not checked yetcites [20] Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018). source
• Not checked yetcites [21] Mok, T. S. et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376, 629–640 (2017). source
• Not checked yetcites [22] Mok, T. S. et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J. Clin. Oncol. 36, 2244–2250 (2018). source
• Not checked yetcites [23] Peters, S. et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 377, 829–838 (2017). source
• Not checked yetcites [24] Solomon, B. J. et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 371, 2167–2177 (2014). source
• Not checked yetcites [25] Soria, J. C. et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 389, 917–929 (2017). source

In the paper

“In addition, selective pressure imposed by previous anticancer therapy can substantially influence patterns of co-mutations; therefore, detailed knowledge of prior therapeutic exposures is critical for accurate interpretation and understanding of the functional effect of co-mutation patterns.”

In the paper

“The unique metabolic phenotypes associated with combined expression of oncogenic KRAS and LKB1 inactivation – but not with mutations in either gene alone - may at least partially explain their preferential co-occurrence in human NSCLC.”

In the paper

“Mechanistically, trans-differentiation [G] is mediated by LKB1 loss-triggered down-regulation of the Polycomb Repressive Complex 2 (PRC2) subunit EED and relief of PRC2-mediated repression of squamous differentiation genes86.”

What the sources say

• Not checked yetcites [86] Zhang, H. et al. Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb repressive complex 2. Nat. Commun. 8, 14922 (2017).

In the paper

“As noted previously, KRAS-mutant LUADs are intrinsically heterogeneous in their biology and clinical behavior.”

In the paper

“Activating mutations in KRAS are the most prevalent oncogenic driver event in both early-stage and metastatic LUAD, occurring in 25–32% of tumors34, 59, 60, 62, 67.”

What the sources say

• Not checked yetcites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source
• Not checked yetcites [59] Jordan, E. J. et al. prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609 (2017). This article and Frampton et al. (2015) are the largest reported studies of comprehensive genomic profiling in patients with advanced LUAD. source
• Not checked yetcites [60] Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008). source
• Not checked yetcites [62] Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012). source
• Not checked yetcites [67] Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015). This article identifies co-alterations in LKB1, TP53 and CDKN2A/CDKN2B as key determinants of the molecular diversity of KRAS -mutant LUAD and is the first report linking LKB1 co-mutations with a non-T cell-inflamed tumour immune microenvironment in LUAD. source

In the paper

“Epigenetic reprogramming upon LKB1 loss in KRAS-mutant cells is further fueled by a metabolic network, that promotes increased flux of glucose-derived carbon towards serine biosynthesis and the methionine salvage pathway, bolstering synthesis of S-adenosyl methionine (SAM), a critical substrate for DNA methylation87.”

What the sources say

• Not checked yetcites [87] Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumourigenesis. Nature 539, 390–395 (2016). source

In the paper

“Landmark large scale sequencing studies have established a census of major KRAS co-mutations in both early-stage and advanced LUAD15, 34, 59, 62.”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source
• Not checked yetcites [59] Jordan, E. J. et al. prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609 (2017). This article and Frampton et al. (2015) are the largest reported studies of comprehensive genomic profiling in patients with advanced LUAD. source
• Not checked yetcites [62] Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012). source

In the paper

“We previously identified three robust and reproducible transcriptomic sub-groups of KRAS-mutant LUAD by applying non-negative matrix factorization consensus clustering81–83 to RNASeq data from 68 tumors from The Cancer Genome Atlas (TCGA) dataset67.”

What the sources say

• Not checked yetcites [67] Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015). This article identifies co-alterations in LKB1, TP53 and CDKN2A/CDKN2B as key determinants of the molecular diversity of KRAS -mutant LUAD and is the first report linking LKB1 co-mutations with a non-T cell-inflamed tumour immune microenvironment in LUAD. source
• Not checked yetcites [81] Brunet, J. P., Tamayo, P., Golub, T. R. & Mesirov, J. P. Metagenes and molecular pattern discovery using matrix factorization. Proc. Natl Acad. Sci. USA 101, 4164–4169 (2004). source
• Not checked yetcites [82] Devarajan, K. Nonnegative matrix factorization: an analytical and interpretive tool in computational biology. PLOS Comput. Biol 4, e1000029 (2008). source
• Not checked yetcites [83] Monti, S., Tamayo, P., Mesirov, J. & Golub, T. Consensus clustering: A resampling-based method for class discovery and visualization of gene expression microarray data. Mach. Learn. 52, 91–118 (2003). source

In the paper

“one subgroup was dominated by co-occurring TP53 alterations (thereafter referred to as KP)”

What the sources say

• Not checked yetcites [67] Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015). This article identifies co-alterations in LKB1, TP53 and CDKN2A/CDKN2B as key determinants of the molecular diversity of KRAS -mutant LUAD and is the first report linking LKB1 co-mutations with a non-T cell-inflamed tumour immune microenvironment in LUAD. source

In the paper

“Furthermore, evidence from other tumor types supports the notion that within a network of epistatic oncogenic interactions the chronology – or order – of individual genomic alterations can impart distinct phenotypic outcomes.”

In the paper

“However, co-mutations in a set of core genes including LKB1, KEAP1, ATM and RBM10 are consistently enriched in KRAS-mutant LUAD (Figure 2).”

In the paper

“Remarkably, superimposition of somatic genetic alterations of key tumor suppressor genes revealed non-overlapping patterns of co-occurring genomic alterations in the three subgroups”

What the sources say

• Not checked yetcites [67] Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015). This article identifies co-alterations in LKB1, TP53 and CDKN2A/CDKN2B as key determinants of the molecular diversity of KRAS -mutant LUAD and is the first report linking LKB1 co-mutations with a non-T cell-inflamed tumour immune microenvironment in LUAD. source

In the paper

“Furthermore, tumor genomes can be shaped by immunosurveillance through early elimination of clones that present strong antigenic neo-peptides.”

In the paper

“Thus, NRF2- mediated metabolic reprogramming and regulation of redox homeostasis likely underpin the strong co-selection of KEAP1 with LKB1 and KRAS mutations in NSCLC at least partially because oncogenic KRAS itself promotes oxidative stress and anabolic metabolism and because KL NSCLC cells depend on the pentose phosphate pathway for NAPDH generation and for detoxification of reactive oxygen”

What the sources say

• Not checked yetcites [94] Singh, A. et al. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumourigenesis. J. Clin. Invest. 123, 2921–2934 (2013). source
• Not checked yetcites [97] Galan-Cobo, A. et al. LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence in KRAS-mutant lung adenocarcinoma. Cancer Res. 79, 3251–3267 (2019). source
• Not checked yetcites [98] Ying, H. et al. Oncogenic Kras maintains pancreatic tumours through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012). source

In the paper

“Mutations in other established drivers within the receptor tyrosine kinase-RAS-RAF network including EGFR, ERBB2, BRAF, NF1, as well as ALK, ROS1 and RET rearrangementsare largely non-overlapping with KRAS, although the strength of their negative association varies depending on the individual gene.”

In the paper

“Generation of SAM via this pathway, coupled with up-regulation of DNA methyl-transferases, underpins an increase in global levels of CpG methylation in KL cells that is critical for tumor maintenance.”

What the sources say

• Not checked yetcites [87] Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumourigenesis. Nature 539, 390–395 (2016). source

In the paper

“Several distinct mutational signatures sculpt the genome of NSCLC – including signatures of tobacco exposure and APOBEC-mediated cytidine deamination57.”

What the sources say

• Not checked yetcites [57] Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013). source

In the paper

“These findings established co-mutations as major determinants of the molecular diversity of KRAS-mutant LUAD.”

In the paper

“Additional significantly co-altered genes reported in some studies include PTPRD, U2AF1, POLE, NTRK3 and LRP1B.”

In the paper

“Interestingly, Kras-driven lung carcinogenesis is accelerated by incomplete Atm loss in a p53 deficient setting”

What the sources say

• Not checked yetcites [104] Nahar, R. et al. Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat. Commun. 9, 216 (2018). This article provides a comprehensive evaluation of the clonal and subclonal genomic landscape of early-stage EGFR -mutant LUAD in patients of Asian descent. source

In the paper

“Mutations in ATM, encoding an apical kinase in the DNA damage response pathway, also significantly co-occur with mutant KRAS.”

In the paper

“This notion is further supported by identification of TP53 mutational inactivation as a clonal and predominantly early event in established NSCLC that precedes genome doubling and subsequent branched evolution74, 103.”

What the sources say

• Not checked yetcites [74] Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017). This landmark study establishes a census of clonal and subclonal alterations in early-stage NSCLC and identifies copy number heterogeneity as an independent predictor of short relapse-free survival following surgical resection. source
• Not checked yetcites [103] Muzumdar, M. D. et al. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685 (2016). source

In the paper

“The majority of RB1-mutant tumors also harbor TP53 co-alterations, underscoring the critical contributions of these archetypal tumor suppressor genes to cell cycle control.”

In the paper

“Intriguingly, analysis of patterns of co-occurrence and mutual exclusivity between a set of 505 pre-selected candidate functional genomic events in 6456 tumors from the Pan-Cancer TCGA Dataset using a novel algorithmic approach (SELECT algorithm) identified somatic mutations in RBM10 as the top-scoring KRAS co-occurrence motif in both NSCLC and colorectal adenocarcinoma63.”

What the sources say

• Not checked yetcites [63] Mina, M. et al. Conditional selection of genomic alterations dictates cancer evolution and oncogenic dependencies. Cancer Cell 32, 155–168 (2017). This study describes a novel algorithmic approach for assessment of cancer evolutionary dependencies and is the most comprehensive pancancer analysis of co-alteration patterns reported to date. source

In the paper

“In murine models the impact of Atm inactivation on Kras-driven lung carcinogenesis is context-dependent and varies according to the functional status of p53104.”

What the sources say

• Not checked yetcites [104] Nahar, R. et al. Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat. Commun. 9, 216 (2018). This article provides a comprehensive evaluation of the clonal and subclonal genomic landscape of early-stage EGFR -mutant LUAD in patients of Asian descent. source

In the paper

“This suggests that up-regulation of a NRF2-driven transcriptional program may represent a bottleneck in the evolution of LKB1-deficient NSCLC.”

In the paper

“Prior therapy is associated with increased average number of co-alterations.”

In the paper

“Although EGFR –mutant tumors represent the prototypical oncogene-addicted LUAD subgroup that spearheaded adoption of the single-driver model, the overwhelming majority of EGFR-mutant lung tumors harbor one or more co-mutations, even when the analysis is limited to pre-defined sets of cancer-relevant genes within established panels (FoundationOne, Guardant360, MSK-IMPACT)15, 59, 72, 73.”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [59] Jordan, E. J. et al. prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609 (2017). This article and Frampton et al. (2015) are the largest reported studies of comprehensive genomic profiling in patients with advanced LUAD. source
• Not checked yetcites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source
• Not checked yetcites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source

In the paper

“Thus, data from genetically engineered mouse models (GEMMs) point towards a context-dependent, conditional haplo-insufficient role for Atm loss in KrasG12D-driven lung tumorigenesis.”

What the sources say

• Not checked yetcites [104] Nahar, R. et al. Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat. Commun. 9, 216 (2018). This article provides a comprehensive evaluation of the clonal and subclonal genomic landscape of early-stage EGFR -mutant LUAD in patients of Asian descent. source

In the paper

“In contrast, complete Atm inactivation is incompatible with cellular viability in the context of KrasG12D expression and bi-allelic Trp53 inactivation, suggesting that excessive DNA damage in this context removes incipient cancer cells from the proliferative pool.”

What the sources say

• Not checked yetcites [104] Nahar, R. et al. Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat. Commun. 9, 216 (2018). This article provides a comprehensive evaluation of the clonal and subclonal genomic landscape of early-stage EGFR -mutant LUAD in patients of Asian descent. source

In the paper

“Somatic mutations in TP53 represent by far the most prevalent co-alteration in EGFR-mutant LUAD (54.6%−64.5%) and their clinical significance has been evaluated in several studies.”

In the paper

“Therefore, TP53 co-mutations impact the natural history of EGFR-mutant NSCLC at least partially by allowing tolerance of a greater degree of genomic instability that results in both larger numbers of co-occurring truncal drivers as well as late sub-clonal diversification with focal emergence of high amplitude amplifications and deletions in mediators of therapeutic resistance103.”

What the sources say

• Not checked yetcites [103] Muzumdar, M. D. et al. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685 (2016). source

In the paper

“Loss of p53 or expression of either dominant negative or dominant gain-of-function Trp53 mutants also co-operate with oncogenic Kras to induce LUADs with shortened latency and increased metastatic proclivity, although these tumors are less aggressive than those with Lkb1 loss69–71, 84.”

What the sources say

• Not checked yetcites [69] Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001). source
• Not checked yetcites [70] Jackson, E. L. et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65, 10280–10288 (2005). source
• Not checked yetcites [71] Fisher, G. H. et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumour suppressor genes. Genes Dev. 15, 3249–3262 (2001). source
• Not checked yetcites [84] Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007). source

In the paper

“In vivo depletion of Rbm10 in mice using CRISPR/Cas9- mediated gene editing concurrently with activation of endogenous oncogenic KrasG12D confers a modest fitness advantage that is lost when Trp53 or Lkb1 are also inactivated108.”

What the sources say

• Not checked yetcites [108] Zhao, J. et al. Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing. Sci. Rep. 7, 40488 (2017).

In the paper

“Mutational inactivation of RB1 is a clonal and early genetic event in 9.5%−12.5% of EGFR-mutant LUAD72, 73, 103, 117.”

What the sources say

• Not checked yetcites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source
• Not checked yetcites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source
• Not checked yetcites [103] Muzumdar, M. D. et al. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685 (2016). source
• Not checked yetcites [117] Jakobsen, J. N., Santoni-Rugiu, E., Grauslund, M., Melchior, L. & Sorensen, J. B. Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment. Oncotarget 9, 26195–26208 (2018). source

In the paper

“The spectrum and prevalence of co-mutations does not appear to vary depending on the specific initiating EGFR mutation and is similar across the three most common subtypes (EGFR exon 19 deletion, EGFRL858R and EGFR exon 20 insertions)47.”

What the sources say

• Not checked yetcites [47] Riess, J. W. et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J. Thorac. Oncol. 13, 1560–1568 (2018). source

In the paper

“Several of these features are recapitulated in mice where endogenous expression of oncogenic KrasG12D is coupled with bi-allelic deletion of Cdkn2a/Cdkn2b, resulting in concurrent abrogation of p16, p19ARF and p15.”

In the paper

“hemizygous Nkx2–1 loss suppresses EgfrL858R-driven lung carcinogenesis”

What the sources say

• Not checked yetcites [125] Winslow, M. M. et al. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature 473, 101–104 (2011). source

In the paper

“advanced-stage ALK-rearrangement -positive LUAD are enriched in somatic alterations in CDKN2A (32.5%)”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [128] Lee, J. J. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857 (2019). e21. source

In the paper

“and CDKN2B (26.5%)”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [128] Lee, J. J. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857 (2019). e21. source

In the paper

“NKX2–1 amplification is significantly enriched in EGFR-mutant LUAD”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

In the paper

“constitutes a classical example of a context-dependent genetic interaction.”

In the paper

“PIK3CA mutations, including classical kinase (H1074R and H1074L) and helical (E545K and E542K) domain mutations are observed in 9%−12.4% of advanced stage EGFR-mutant LUAD”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source
• Not checked yetcites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source

In the paper

“CTNNB1 mutations are rare in early-stage EGFR-mutant LUAD (1.8% in the TCGA cohort)”

What the sources say

• Not checked yetcites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source

In the paper

“Mutant EGFR has further been shown to directly tyrosine phosphorylate β-catenin resulting in its stabilization and nuclear accumulation120.”

What the sources say

• Not checked yetcites [120] Marcoux, N. et al. EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes. J. Clin. Oncol. 37, 278–285 (2019). source

In the paper

“TP53 co-mutations promote genomic instability”

What the sources say

• Not checked yetcites [128] Lee, J. J. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857 (2019). e21. source
• Not checked yetcites [129] Kron, A. et al. Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer. Ann. Oncol. 29, 2068–2075 (2018). source
• Not checked yetcites [130] Alidousty, C. et al. Genetic instability and recurrent MYC amplification in ALK-translocated NSCLC: a central role of TP53 mutations. J. Pathol. 246, 67–76 (2018). source

In the paper

“earlier studies that identified a central role for WNT signaling in LUAD metastasis”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source
• Not checked yetcites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source

In the paper

“Activating mutations in CTNNB1 represent one of the most consistently co-selected alterations in EGFR-mutant LUAD across different studies.”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source
• Not checked yetcites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source

In the paper

“experimental data demonstrating increased invasive potential of EGFR and CTNNB1 co-mutated NSCLC cells in vitro15, 34, 72, 73, 120, 121”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source
• Not checked yetcites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source

In the paper

“In mouse models of Kras-mutant LUAD, Nkx2–1 loss fosters metastasis”

What the sources say

• Not checked yetcites [124] Eng, J. et al. Impact of concurrent PIK3CA mutations on response to EGFR tyrosine kinase inhibition in EGFR-mutant lung cancers and on prognosis in oncogene-driven lung adenocarcinomas. J. Thorac. Oncol. 10, 1713–1719 (2015). source

In the paper

“like CTNNB1 mutations, are encountered preferentially in advanced-stage tumors15, 34, 72, 73”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source
• Not checked yetcites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source

In the paper

“but are less likely to harbor TP53 alterations (23.8%−26.5%) compared with other driver subgroups15, 128.”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [128] Lee, J. J. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857 (2019). e21. source

In the paper

“do not appear to impact response rates and progression-free survival with first or second line EGFR TKI therapy73, 115, 123”

What the sources say

• Not checked yetcites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source
• Not checked yetcites [115] Labbe, C. et al. Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Lung Cancer 111, 23–29 (2017). source
• Not checked yetcites [123] Pacheco-Pinedo, E. C. et al. Wnt/β-catenin signalling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium. J. Clin. Invest. 121, 1935–1945 (2011). source

In the paper

“in vivo they are associated with worse overall survival in some studies”

What the sources say

• Not checked yetcites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source
• Not checked yetcites [115] Labbe, C. et al. Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Lung Cancer 111, 23–29 (2017). source
• Not checked yetcites [123] Pacheco-Pinedo, E. C. et al. Wnt/β-catenin signalling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium. J. Clin. Invest. 121, 1935–1945 (2011). source

In the paper

“In vitro, co-occurring PIK3CA mutations promote cellular invasion and migration”

What the sources say

• Not checked yetcites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source
• Not checked yetcites [115] Labbe, C. et al. Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Lung Cancer 111, 23–29 (2017). source
• Not checked yetcites [123] Pacheco-Pinedo, E. C. et al. Wnt/β-catenin signalling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium. J. Clin. Invest. 121, 1935–1945 (2011). source

In the paper

“do not appear to impact response rates and progression-free survival with first or second line EGFR TKI therapy73, 115, 123”

What the sources say

• Not checked yetcites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source
• Not checked yetcites [115] Labbe, C. et al. Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Lung Cancer 111, 23–29 (2017). source
• Not checked yetcites [123] Pacheco-Pinedo, E. C. et al. Wnt/β-catenin signalling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium. J. Clin. Invest. 121, 1935–1945 (2011). source

In the paper

“NKX2–1 transactivates the receptor ROR1”

What the sources say

• Not checked yetcites [126] Maeda, Y. et al. Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. J. Clin. Invest. 122, 4388–4400 (2012). source

In the paper

“indicating that sustained NKX2–1 expression is essential for tumor initiation downstream of mutant Egfr125.”

In the paper

“their prevalence increases in late-stage tumors (5.3% - 9.6%)”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source
• Not checked yetcites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source

In the paper

“mutations in CTNNB1 have been reported to occur more frequently in LUAD with the EGFRT790M mutation following exposure to first or second generation EGFR TKIs”

What the sources say

• Not checked yetcites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source

In the paper

“therefore, in this genomic background Nkx2–1 functions as a tumor suppressor gene.”

In the paper

“these tumors are characterized by highly significant enrichment of MDM2 and CDK4 amplification (41.6%) compared with other driver oncogenes”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

In the paper

“whereas loss of CDKN2A (24.1%) and CDKN2B (17.5%) occur with similar frequencies to that in the overall population of patients with NSCLC15.”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

In the paper

“In a conditional GEMM of LUAD (Keap1Fl/Fl;PtenFl/Fl), co-deletion of Keap1 and Pten resulted in immunologically cold tumors, akin to Lkb1-mutant NSCLC141.”

What the sources say

• Not checked yetcites [141] Okon, I. S. et al. Protein kinase LKB1 promotes RAB7-mediated neuropilin-1 degradation to inhibit angiogenesis. J. Clin. Inves.t 124, 4590–4602 (2014). source

In the paper

“The spectrum of co-occurring alterations in BRAF-mutant NSCLC mirrors the background frequency of alterations in TP53 (53.3%), LKB1 (16.2%), ATM (5.8%), NF1 (6.9%), PIK3CA (6.6%), KEAP1 (6.6%), MYC (10.8%), NKX2–1 (7.3%)”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

In the paper

“NRF2 was recently identified as a negative regulator of STING expression via effects on STING mRNA stability142”

What the sources say

• Not checked yetcites [142] Best, S. A. et al. Synergy between the KEAP1/NRF2 and PI3K pathways drives non-small-cell lung cancer with an altered immune microenvironment. Cell Metab. 27, 935–943.e4 (2018). source

In the paper

“LKB1 inactivation induces epigenetic repression of STING (also known as TMEM173), thus promoting insensitivity to cytosolic dsDNA accumulation136.”

What the sources say

• Not checked yetcites [136] Koyama, S. et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumour microenvironment. Cancer Res. 76, 999–1008 (2016). source

In the paper

“The prevalence of additional co-mutations in this group is low,128”

What the sources say

• Not checked yetcites [128] Lee, J. J. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857 (2019). e21. source

In the paper

“patients with ERBB2-mutant NSCLC exhibit preferential amplification of NKX2–1 (19.4%) and ERBB2 itself (14.4%)”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

In the paper

“although alterations in RB1, MDM2, CDKN2A (16.6%) and CDKN2B (11.2%) are less frequent within this molecular subgroup15.”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

In the paper

“In contrast, mutations in TP53 (33.57%) are under-represented”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

In the paper

“as well as frequent mutations in RB1 (8.9%)”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

In the paper

“but the frequencies of co-mutations in TP53 (51.7%), CDKN2A (27.2%), CDKN2B (17.2%), PIK3CA (5%), CTNNB1 (4.4%) and MDM2 amplification (7.2%) are similar to that observed in the overall population of patients with NSCLC15.”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

In the paper

“increased peri-tumoral accumulation of natural killer (NK) cells in KEAP1-mutant tumors was reported in a cohort of surgically resected early-stage LUAD132.”

What the sources say

• Not checked yetcites [132] Michels, S. et al. Clinicopathological characteristics of RET rearranged lung cancer in European patients. J. Thorac. Oncol. 11, 122–127 (2016). source

In the paper

“although the frequency of TP53 mutations appears to be somewhat higher compared to ALK-rearranged tumors (34.6%−45.5% for RET-and 45.6% for ROS1- rearranged tumors)15, 131.”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [131] Aisner, D. L. et al. The impact of smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations—the Lung Cancer Mutation Consortium (LCMC2). Clin. Cancer Res. 24, 1038–1047 (2018). source

In the paper

“TP53 co-mutations are associated with an inflamed tumor immune microenvironment and increased tumor cell PD-L1 expression in KRAS-mutant NSCLC and GEMMs.”

What the sources say

• Not checked yetcites [143] Olagnier, D. et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506 (2018). source
• Not checked yetcites [144] Petitjean, A. et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumour phenotype: lessons from recent developments in the IARC TP53 database. Hum. Mutat. 28, 622–629 (2007). source
• Not checked yetcites [145] Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumour mutational burden. Genome Med. 9, 34 (2017). source

In the paper

“both RET and ROS1 fusion-positive LUAD are characterized by high rates of concurrent CDKN2A loss (29.8% and 30.4% for RET and ROS1-rearranged tumors respectively)”

What the sources say

• Not checked yetcites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source
• Not checked yetcites [131] Aisner, D. L. et al. The impact of smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations—the Lung Cancer Mutation Consortium (LCMC2). Clin. Cancer Res. 24, 1038–1047 (2018). source

In the paper

“The key finding that TP53 somatic mutations are underrepresented across LUAD driven by different oncogenic fusions was validated in a subsequent study”

What the sources say

• Not checked yetcites [127] Yamaguchi, T. et al. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signalling in lung adenocarcinoma. Cancer Cell. 21, 348–361 (2012). source