K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways
Open accessAbstract
INTRODUCTION: Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes. METHODS: Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients. RESULTS: We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds. CONCLUSION: KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design.
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Written from the paper’s full text.
TL;DR
In a large diagnostic NSCLC cohort, KRAS-mutated tumors were genetically heterogeneous: 53.5% had at least one additional mutation, and co-occurring aberrations differed by KRAS subtype. Co-mutations included TP53, STK11, KEAP1, ATM, MET amplification, and ERBB2 amplification, with some associations to G12C and survival differences.
Key findings
- Among 1078 evaluable KRAS-mutated NSCLC patients, 577 (53.5%) had at least one additional mutation; TP53 mutations occurred in 425 patients (39.4%), and targetable EGFR and BRAF mutations each occurred in 1.2%.
- In the extended 101-patient analysis, co-occurring mutations included STK11 (19.8%), KEAP1 (12.9%), and ATM (11.9%); 77 patients (76.2%) had additional mutations.
- FISH showed MET amplification in 93 of 606 analyzed samples (15.4%) and ERBB2 amplification in 9 of 65 analyzed samples (13.8%), with all detected ERBB2 amplifications occurring in G12C tumors (p = 0.002); all ERBB4 mutations also occurred in G12C (p = 0.025).
- In stage IV patients, STK11 mutations were associated with worse median OS (3.2 months vs 10.0 months, p = 0.002), and ROS1 mutations with worse median OS (2.0 months vs 10.0 months, p = 0.004), though only three patients accounted for the ROS1 group.
Methods
- Diagnostic samples from 4507 patients with NSCLC were analyzed by NGS with a 14-gene panel; 101 patients were analyzed with an extended panel of 14 additional genes, and FISH was performed in subsets for MET, ERBB2, FGFR1, ALK, ROS1, and RET.
- Molecular data were correlated with clinical characteristics including age, sex, stage, smoking status, pack-years, therapy, and overall survival; survival was calculated by Kaplan-Meier methods, and categorical associations used chi-square or Fisher’s exact tests.
- Whole-exome sequencing was performed in two patients, with cancer cell fractions used to assess clonality of KRAS and co-occurring PIK3CA/TP53 mutations.
Limitations
- The paper states that FISH for amplifications was performed only in a subset of the KRAS-mutant cohort, follow-up was short, and the initial 14-gene NGS panel was restricted and did not include KEAP1, NFE2L2, or STK11, requiring a new 22-gene panel in 101 patients.
- The paper states that the ROS1 survival finding needs further evaluation because only three patients accounted for that group.
- Evident from the text: extended-panel co-mutation frequencies are based on only 101 patients, and the WES clonality conclusions are based on two patients.
Model-written summary. Check it against the paper before relying on it.
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0 of 21 cited sources checked · 0 supported · 0 flagged
- Findingown data
EGFR mutations occurred in 13 patients (1.2%).
“Of the 13 patients with EGFR mutation (1.2%), two harbored L858R (one with an additional T790M de novo), one an exon 19delins, one G719C, one S768I, and one an E709* nonsense mutation.”
Quote in the paperNot a substantial claim - Findingown data
The remaining 24 patients had three (n=20) or four (n=4) co-occurring aberrations.
“The remaining 24 patients had three (n ¼ 20) or four (n ¼ 4) co-occurring aberrations.”
Quote in the paperNot a substantial claim - Findingown data
The most frequent KRAS mutation, G12C, was present in 449 samples (41.7%).
“The most frequent KRAS mutation, G12C, was present in 449 samples (41.7%) (Fig. 1B).”
Quote in the paperNot a substantial claim - Findingown data
In multiple logistic regression analyses including smoking status, age, sex, stage, and histologic subtype, only tumor stage was significantly associated with the co-occurrence of additional mutations.
“In multiple logistic regression analyses using the initial gene panel and including smoking status (qualitatively and quantitatively), age, sex, stage, and histologic subtype, only tumor stage was significantly associated with the co-occurrence of additional mutations (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
G12X mutations were by far the most common mutations (n=916 [85.0%]).
“G12X mutations were by far the most common mutations (n ¼ 916 [85.0%]), and 1074 patients (99.6%) carried G12X, G13X, or Q61X mutations.”
Quote in the paperNot a substantial claim
- Findingown data
On the basis of 4507 samples analyzed, 1207 patients (26.8%) harbored a KRAS mutation.
“On the basis of 4507 samples analyzed, 1207 patients (26.8%) harbored a KRAS mutation and 1078 patients (89.3%) were eligible for analysis (Fig. 1A).”
Quote in the paperNot a substantial claim - Findingown data
Transversions accounted for 76.5% of these mutations (n=826).
“Transversions accounted for 76.5% of these mutations (n ¼ 826).”
Quote in the paperNot a substantial claim - Findingown data
All mutations detected with the initial approach were able to be confirmed with the extended panel.
“All mutations detected with the initial approach were able to be confirmed (Figure 1C and Table 2).”
Quote in the paperNot a substantial claim - Findingown data
425 patients (39.4%) had at least one additional TP53 mutation.
“In al, 425 patients (39.4%) had at least one additional TP53 mutation, whereas aberrations of the other genes were present in 277 patients (25.7%).”
Quote in the paperNot a substantial claim - Findingown data
1078 patients (89.3%) were eligible for analysis.
“On the basis of 4507 samples analyzed, 1207 patients (26.8%) harbored a KRAS mutation and 1078 patients (89.3%) were eligible for analysis (Fig. 1A).”
Quote in the paperNot a substantial claim - Findingown data
Of the 101 samples analyzed with the extended NGS panel, 77 (76.2%) had additional mutations.
“Of the 101 samples analyzed with the extended NGS panel including genes that had already been shown to co-occur frequently with KRAS mutations such as KEAP1 or STK11, 77 (76.2%) had additional mutations.”
Quote in the paperNot a substantial claim - Findingown data
Aberrations of other genes were present in 277 patients (25.7%).
“In al, 425 patients (39.4%) had at least one additional TP53 mutation, whereas aberrations of the other genes were present in 277 patients (25.7%).”
Quote in the paperNot a substantial claim - Findingown data
1074 patients (99.6%) carried G12X, G13X, or Q61X mutations.
“G12X mutations were by far the most common mutations (n ¼ 916 [85.0%]), and 1074 patients (99.6%) carried G12X, G13X, or Q61X mutations.”
Quote in the paperNot a substantial claim - Findingown data
Of the initial cohort, 577 patients (53.5%) had at least one additional mutation.
“Of the initial cohort, 577 patients (53.5%) had at least one additional mutation, with 412 of them (71.4%)having one and 141 (24.4%) having two.”
Quote in the paperNot a substantial claim - Findingown data
Co-occurring mutations, with both already-proven and still-unproven therapeutic relevance, are present in a substantial amount of these patients.
“co-occurring mutations, with both with alreadyproven and still-unproven therapeutic relevance, are present in a substantial amount of these patients.”
Quote in the paperSubstantial claim - Findingown data
In the other patient, we found a subclonal KRAS mutation.
“In one patient, we found a clonal KRAS mutation, and in the other, we found a subclonal KRAS mutation.”
Quote in the paperNot a substantial claim - Findingown data
Patients with KEAP1/NFE2L2 mutations showed a trend toward worse outcome (p=0.051).
“Patients with KEAP1/ NFE2L2 mutations showed a trend toward worse outcome (p ¼ 0.051).”
Quote in the paperNot a substantial claim - Findingown data
In sample C13-39572, a TP53 mutation (R248L) together with subclonal loss was detected in a minor subclone.
“A tumor protein p53 gene (TP53) mutation (R248L) together with subclonal loss was detected in a minor subclone, thus showing a biallelic deactivation of TP53 in about 59% of the tumor cells.”
Quote in the paperNot a substantial claim - Findingown data
Co-occurring genetic aberrations have a significantly higher prevalence in patients with metastasis.
“Our evaluation of 1078 KRAS-mutated patients analyzed in routine diagnostics with NGS supplemented by FISH analyses in a subset of these patients shows that co-occurring genetic aberrations can be found frequently, with a significantly higher prevalence in patients with metastasis.”
Quote in the paperSubstantial claim - Findingown data
BRAF mutations occurred in 14 patients (1.3%).
“Of the 14 patients (1.3%) harboring BRAF mutations, one had V600E, one G596V, beside G464V (n ¼ 2) and G469V (n ¼ 3).”
Quote in the paperNot a substantial claim - Findingown data
In sample C13-39572, the KRAS mutation (G12C) was clonal.
“In sample C13-39572, the KRAS mutation (G12C) was clonal, whereas the PIK3CA E545K mutation was subclonal.”
Quote in the paperNot a substantial claim - Findingown data
In both WES cases, E545K mutations in PIK3CA were subclonal.
“In both cases, the E545K mutations in PIK3CA were subclonal, whereas one KRAS mutation was clonal (G12C [sample C13-39572]) and the other was present in the same subclonal population that harbored the PIK3CA mutation (Q61L [sample C12-3094]).”
Quote in the paperSubstantial claim - Findingown data
Of 606 samples analyzed by FISH for MET amplification, 93 (15.4%) were amplified.
“Of the 606 samples analyzed by FISH for MET amplification, 93 (15.4%) were amplified.”
Quote in the paperNot a substantial claim - Findingown data
Other drivers such as PIK3CA and TP53 were found to be subclonal in these two cases.
“Other drivers such as PIK3CA and TP53 were found to be subclonal in these two cases”
Quote in the paperSubstantial claim - Findingown data
FGFR1 amplifications were found in 3 (4.9%) of 61 analyzed samples.
“FGFR1 amplifications were found in three (4.9%) of the 61 analyzed samples.”
Quote in the paperNot a substantial claim - Findingown data
In one WES case, the KRAS G12C mutation was clonal.
“In both cases, the E545K mutations in PIK3CA were subclonal, whereas one KRAS mutation was clonal (G12C [sample C13-39572]) and the other was present in the same subclonal population that harbored the PIK3CA mutation (Q61L [sample C12-3094]).”
Quote in the paperNot a substantial claim - Findingown data
The prevalence of co-occurring mutations was substantially higher with the extended NGS panel than with the initial panel.
“Within this analysis, the prevalence of co-occurring mutations was substantially higher than in our initial panel, demonstrating the need for advanced panels in routine setting.”
Quote in the paperSubstantial claim - Findingown data
G12C occurred more frequently with CTNNB1 mutations and FGFR1 amplifications, albeit not significantly.
“Patients with G12C harbored all detected ERBB2 amplifications (p ¼ 0.002) as well as all detected ERBB4 mutations (p ¼ 0.025), April 2019 Heterogeneity of KRAS-mutated NSCLC occurred more frequently with CTNNB1 mutations and FGFR1 amplifications, albeit not significantly owing to low patient numbers (Fig. 2B).”
Quote in the paperNot a substantial claim - Findingown data
Patients with G12C harbored all detected ERBB2 amplifications (p=0.002).
“Patients with G12C harbored all detected ERBB2 amplifications (p ¼ 0.002) as well as all detected ERBB4 mutations (p ¼ 0.025), April 2019 Heterogeneity of KRAS-mutated NSCLC occurred more frequently with CTNNB1 mutations and FGFR1 amplifications, albeit not significantly owing to low patient numbers (Fig. 2B).”
Quote in the paperSubstantial claim - Findingown data
In the second WES case, KRAS Q61L was present in the same subclonal population that harbored the PIK3CA mutation.
“In both cases, the E545K mutations in PIK3CA were subclonal, whereas one KRAS mutation was clonal (G12C [sample C13-39572]) and the other was present in the same subclonal population that harbored the PIK3CA mutation (Q61L [sample C12-3094]).”
Quote in the paperNot a substantial claim - Findingown data
In sample C13-39572, the PIK3CA E545K mutation was subclonal.
“In sample C13-39572, the KRAS mutation (G12C) was clonal, whereas the PIK3CA E545K mutation was subclonal.”
Quote in the paperNot a substantial claim - Findingown data
In one patient, we found a clonal KRAS mutation.
“In one patient, we found a clonal KRAS mutation, and in the other, we found a subclonal KRAS mutation.”
Quote in the paperNot a substantial claim - Findingown data
Patients with G12C harbored all detected ERBB4 mutations (p=0.025).
“Patients with G12C harbored all detected ERBB2 amplifications (p ¼ 0.002) as well as all detected ERBB4 mutations (p ¼ 0.025), April 2019 Heterogeneity of KRAS-mutated NSCLC occurred more frequently with CTNNB1 mutations and FGFR1 amplifications, albeit not significantly owing to low patient numbers (Fig. 2B).”
Quote in the paperSubstantial claim - Findingown data
In sample C12-3094, the KRAS Q61L mutation was present in the same subclonal population that harbors the PIK3CA mutation (E545K).
“In C12-3094, the KRAS Q61L mutation was present in the same subclonal population that harbors the PIK3CA mutation (E545K).”
Quote in the paperNot a substantial claim - Findingown data
Co-occurring genetic aberrations can be found frequently in KRAS-mutated patients.
“Our evaluation of 1078 KRAS-mutated patients analyzed in routine diagnostics with NGS supplemented by FISH analyses in a subset of these patients shows that co-occurring genetic aberrations can be found frequently, with a significantly higher prevalence in patients with metastasis.”
Quote in the paperSubstantial claim - Findingown data
In patients with stage IV disease, different KRAS mutations did not show differences in mOS.
“We further focused on patients with stage IV disease, for whom the different KRAS mutations did not show differences in mOS (see Fig. 3B and Supplement 3 for details on the whole cohort).”
Quote in the paperSubstantial claim - Findingown data
There were no targetable mutations in DDR2, MET, ERBB2, or ALK.
“There were no targetable mutations in DDR2, MET, ERBB2, or ALK (see Supplement 2).”
Quote in the paperNot a substantial claim - Findingown data
No rearrangements were found in ALK, ROS1, and RET.
“No rearrangements were found in ALK, ROS1 and RET.”
Quote in the paperNot a substantial claim - Findingown data
With the new panel, mOS did not differ significantly between stage IV patients without additional mutation and those with co-occurring mutation (log-rank p=0.687).
“With use of our new panel, mOS did not differ significantly between patients in stage IV without additional mutation and those with co-occurring mutation (log-rank, p ¼ 0.687 [Fig.3C]).”
Quote in the paperSubstantial claim - Findingown data
A TP53 mutation together with subclonal loss was detected in a minor subclone, showing biallelic deactivation of TP53 in about 59% of the tumor cells.
“In addition, a TP53 mutation together with subclonal loss was detected in a minor subclone, thus showing a biallelic deactivation of TP53 in about 59% of the tumor cells.”
Quote in the paperNot a substantial claim - Interpretationown data
KRAS-mutated NSCLC represents a genetically heterogeneous subgroup.
“KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of cooccurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes.”
- Also stated in: § Discussion · hedged
“The present data not only suggest that KRAS-mutated NSCLC should no longer be understood and managed as a homogenous genetic subgroup but also underline the fact that routine testing for co-occurring mutations might already now be of therapeutic relevance in a substantial”
Quote in the paperSubstantial claim- Rests on an assumption: A systematic analysis of co-occurring mutations in a large patient cohort is still lacking.
- Also stated in: § Discussion · hedged
- Interpretationown data
In a fraction of NSCLC cases, strong oncogenic events may develop late in tumor evolution.
“suggesting that in a fraction of NSCLC cases strong oncogenic events may develop late in tumor evolution.”
Quote in the paperSubstantial claim - Interpretationown data
Mutations in KRAS, and similarly in TP53 and PIK3CA, may be subclonal and therefore represent late events in tumor evolution in a fraction of NSCLC tumors.
“These two examples suggest that mutations in KRAS, and similarly in TP53 and PIK3CA, may be subclonal and therefore represent late events in tumor evolution in a fraction of NSCLC tumors.”
Quote in the paperSubstantial claim - Premisecitation
There is growing evidence that KRAS-mutated lung cancer does not represent a homogeneous NSCLC subgroup.
“According to recent molecular findings, there is growing evidence that KRASmutated lung cancer does not represent a homogeneous NSCLC subgroup.15,22,39,40”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [15] Arbour, 2018, Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer, Clin Cancer Res source
Not checked in the free run.
- cites [22] Skoulidis, 2015, Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities, Cancer Discov source
Not checked in the free run.
- cites [39] Zer, 2016, Pooled analysis of the prognostic and predictive value of KRAS mutation status and mutation subtype in patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors, J Thorac Oncol source
Not checked in the free run.
- cites [40] Scheffler, 2015, PIK3CA mutations in non-small cell lung cancer (NSCLC): genetic heterogeneity, prognostic impact and incidence of prior malignancies, Oncotarget source
Not checked in the free run.
- Premisecitation
There is growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup.
“There is growing evidence for genetic heterogeneity of KRAS-mutated NSCLC.15”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Arbour, 2018, Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer, Clin Cancer Res source
Not checked in the free run.
- Interpretationown data
NSCLC comprises a strongly heterogeneous group on the genomic level.
“our data show that NSCLC comprises a strongly heterogeneous group on the genomic level”
Quote in the paperSubstantial claim - Premisecitation
Kinase inhibitors targeting molecules downstream of KRAS-like MEK inhibitors have shown modest efficacy, with response rates of 11% for selumetinib and 12% for trametinib.
“Kinase inhibitors targeting molecules downstream of KRAS-like MEK inhibitors have shown modest efficacy, with response rates of 11% for selumetinib 16 and 12% for trametinib.17”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [16] Lopez-Chavez, 2015, Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial, J Clin Oncol source
Not checked in the free run.
- cites [17] Blumenschein, 2015, A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†, Ann Oncol source
Not checked in the free run.
- Study design and conductnone given
FISH analysis for assessment of amplification was done only in a subset of the total cohort of patients with KRAS mutation.
“One limitation of our study concerning an accurate determination of the frequency of targetable comutations is that the FISH analysis for assessment of amplification was done only in a subset of the total cohort of patients with KRAS mutation.”
Quote in the paperSubstantial claim - Premisecitation
The RAF-MEK-ERK pathway is not the only pathway controlled by KRAS.
“Obviously, the RAF-MEK-ERK pathway is not the only pathway controlled by KRAS, 18 which is supported by findings demonstrating enhanced efficacy of combining MEK inhibitors with phosphoinositide 3-kinase inhibitors in NSCLC models.19,20”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Pylayeva-Gupta, 2011, RAS oncogenes: weaving a tumorigenic web, Nat Rev Cancer source
Not checked in the free run.
- Premisecitation
Co-occurring KEAP1/NFE2L2 mutations are an independent negative prognostic factor regarding survival and response to platinum-based chemotherapy.
“Recent work has revealed co-occurring kelch like ECH associated protein 1 gene (KEAP1)/ nuclear factor erythroid 2, like 2 gene (NFE2L2) mutations as an independent negative prognostic factor regarding survival and response to platinum-based chemotherapy 15,24 and leading to dependence on glutaminolysis, whereas co-occurrence of serine/threonine kinase 11 deficiency promotes activation of pro”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [15] Arbour, 2018, Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer, Clin Cancer Res source
Not checked in the free run.
- cites [24] Frank, 2018, Clinical and pathological characteristics of KEAP1- and NFE2L2- mutated non-small cell lung carcinoma (NSCLC), Clin Cancer Res
Not checked in the free run.
- Premisecitation
KRAS mutations can occur both clonally or subclonally in NSCLC.
“KRAS mutations can occur both clonally or subclonally in NSCLC, 21”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] McGranahan, 2015, Clonal status of actionable driver events and the timing of mutational processes in cancer evolution, Sci Transl Med source
Not checked in the free run.
- Interpretationown data
Cancer cell fractions indicate the diverse clonality status of the driver mutations.
“Cancer cell fractions indicate the diverse clonality status of the driver mutations.”
Quote in the paperNot a substantial claim - Premisecitation
Co-occurrence of STK11 deficiency promotes activation of proinflammatory cytokine production.
“Recent work has revealed co-occurring kelch like ECH associated protein 1 gene (KEAP1)/ nuclear factor erythroid 2, like 2 gene (NFE2L2) mutations as an independent negative prognostic factor regarding survival and response to platinum-based chemotherapy 15,24 and leading to dependence on glutaminolysis, whereas co-occurrence of serine/threonine kinase 11 deficiency promotes activation of pro”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Koyama, 2016, STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment, Cancer Res source
Not checked in the free run.
- Study design and conductreasoning
The 14-gene NGS panel was restricted and did not include genes such as KEAP1, NFE2L2, and STK11.
“A second clear limitation is the restricted number of genes in our 14-gene NGS panel, which was established for routine diagnostics in 2013 to widen targetable therapy in NSCLC, although so far, not all the genes analyzed have been proved to be targetable and new targetable genes such as neurotrophic receptor tyrosine kinase 1 gene (NTRK1), neurotrophic receptor tyrosine kinase 2 gene (NTRK2), and”
Quote in the paperSubstantial claim - Premisecitation
Co-mutations of KRAS and TP53 are correlated with expression of PD-L1 in NSCLC.
“Further therapeutic considerations might arise from the finding that co-mutations of KRAS and tumor protein p53 gene (TP53) are correlated with expression of programmed death ligand 1 in NSCLC, 27,28 suggesting that these tumors might be predictive for antiprogrammed death 1/programmed death ligand 1 immunotherapy.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27] Scheel, 2016, PD-L1 expression in non-small cell lung cancer: correlations with genetic alterations, Oncoimmunology source
Not checked in the free run.
- cites [28] Dong, 2017, Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma, Clin Cancer Res source
Not checked in the free run.
- Interpretationown data
In sample C13-39572, TP53 was biallelically deactivated in about 59% of tumor cells.
“A tumor protein p53 gene (TP53) mutation (R248L) together with subclonal loss was detected in a minor subclone, thus showing a biallelic deactivation of TP53 in about 59% of the tumor cells.”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 27
- May combine two claims. 10
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown data93.2% of patients had a history of smoking, with a mean of 35.9 pack-years (SD=23.7).
“In all, 93.4% of patients had ADC and 93.2% a history of smoking (a mean of 35.9 pack-years [SD ¼ 23.7 pack-years]) (Table 1).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataMedian age was 65 years (range 34-92 years).
“There were slightly more male than female patients (51.5% versus 48.5%), with a median age of 65 years (range 34-92 years).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataMost patients (64.9%) had stage IV NSCLC.
“Most patients (64.9%) had stage IV NSCLC.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOf those with additional mutations, 412 (71.4%) had one and 141 (24.4%) had two.
“Of the initial cohort, 577 patients (53.5%) had at least one additional mutation, with 412 of them (71.4%)having one and 141 (24.4%) having two.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataFor former smokers, the mean time between smoking cessation and first diagnosis of lung cancer was 14.8 years (SD=11.3 years).
“For former smokers, the mean time between smoking cessation and first diagnosis of lung cancer was 14.8 years (SD ¼ 11.3 years).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPIK3CA mutations occurred in 35 patients (3.2%), most affecting exon 9 (n=31).
“Most of the 35 patients (3.2%) with PIK3CA mutation had mutations affecting exon 9 (n ¼ 31), with the remaining representing H1047X (exon 20) mutations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThere were slightly more male than female patients (51.5% versus 48.5%).
“There were slightly more male than female patients (51.5% versus 48.5%), with a median age of 65 years (range 34-92 years).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data93.4% of patients had ADC.
“In all, 93.4% of patients had ADC and 93.2% a history of smoking (a mean of 35.9 pack-years [SD ¼ 23.7 pack-years]) (Table 1).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataSample C13-39572 contained a total of 1197 mutations, and most (90.2%) were subclonal.
“Furthermore, sample C13-39572, which contained a total of 1197 mutations, showed a particularly high mutational burden, but most of these mutations (90.2%) were found to be subclonal.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataIn sample C13-39572, 90.2% of mutations were subclonal.
“This case had a total of 1197 mutations, but 90.2% of these mutations were subclonal.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataOf the MET amplifications, 60 were low-level and 30 were high-level.
“Of these, 60 were low-level and 30 were high-level amplifications.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMedian OS was 56.2 months for stage II, 59.3 months for stage III, and 12.0 months for stage IV; not reached for stage I.
“Although the median OS (mOS) was not reached for stage I, the mOS times were 56.2 months (95% CI: 53.8-58.6)for stage II, 59.3 months (95% CI, 31.4-87.3)for stage III, and 12.0 months (95% CI: 10.0-14.0)for stage IV (Fig. 3A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOf 65 patients with known ERBB2 amplification status, 9 (13.8%) were amplified, all from patients with ADC.
“The samples from nine of the 65 patients (13.8%) with known ERBB2 amplification status were amplified, all of them from patients with ADC.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataIn sample C13-39572, there were a total of 1197 mutations.
“This case had a total of 1197 mutations, but 90.2% of these mutations were subclonal.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataSurvival was assessable for 609 patients, with a median follow-up time of 12.5 months (95% CI: 10.5-14.4).
“Survival was assessable for 609 patients, with a median follow-up time of 12.5 months (95% confidence interval [CI]: 10.5-14.4).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationDetected mutations were analyzed by following a published workflow.
“The detected mutations were analyzed by following a published workflow.36”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenAll primary diagnoses were done per the current WHO classification by experienced pathologists.
“All primary diagnoses were done per the current WHO classification by experienced pathologists (R. B. and A. S.).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAn additional KRAS mutation could be detected in a patient with activating EGFR mutation, leading to acquired resistance to third-generation EGFR tyrosine kinase inhibitors.
“Also, an additional KRAS mutation could be detected in a patient with activating EGFR mutation, leading to acquired resistance to third-generation EGFR tyrosine kinase inhibitors.30”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Ortiz-Cuaran, 2016, Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors, Clin Cancer Res source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThe study had a short follow-up.
“Another limitation of our study, namely, the short follow-up, was anticipated in advance, as we set out this study to gain an overview on KRAS heterogeneity in”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataTissue samples from 4507 patients with NSCLC were sent consecutively to the central diagnostics platform and routinely analyzed between August 2013 and May 2015.
“Tissue samples from 4507 patients with NSCLC that were sent consecutively to the central diagnostics platform of Network Genomic Medicine in Cologne, Germany, were routinely analyzed between August 2013 and May 2015 (Supplement 1).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationAdditional immunohistochemical stainings were performed to corroborate the diagnosis.
“Additional immunohistochemical stainings (cytokeratin 5/6, cytokeratin7, p40, and thyroid transcription factor 1) were performed to corroborate the diagnosis.31”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMutations in KRAS represent the longest-known and most frequent oncogenic mutations in NSCLC and are still considered undruggable.
“Mutations in KRAS represent the longest-known and most frequent oncogenic mutations in NSCLC and are still considered undruggable.38”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] June, 2016, Drugging the undruggable Ras - immunotherapy to the rescue?, N Engl J Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo preselection of patients was performed.
“No preselection of patients was performed.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationIn an analysis of cohorts with KRAS-mutated lung cancer that differed in clinical stage and preceding therapy, three major subgroups could be defined on the basis of RNA expression patterns and correlated with different patterns of co-occurring mutations in transformation-associated genes.
“In an analysis of cohorts with KRAS-mutated lung cancer that differed in clinical stage and preceding therapy, three major subgroups could be defined on the basis of RNA expression patterns and correlated with different patterns of co-occurring mutations in transformationassociated genes.22”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Skoulidis, 2015, Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities, Cancer Discov source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNGS was performed only if more than 10% of the tumor cells were available.
“NGS was performed only if more than 10% of the tumor cells were available.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationIntronic variants and silent mutations were identified and excluded from the results by using an in-house pipeline.
“Intronic variants and silent mutations were identified and excluded from the results by using an in-house pipeline 37 (Supplement 2 and see also Supplement 1).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationKRAS mutations occur both clonally and subclonally in human cancer.
“KRAS mutations occur both clonally and subclonally in human cancer, arguing against a unique presentation as”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] McGranahan, 2015, Clonal status of actionable driver events and the timing of mutational processes in cancer evolution, Sci Transl Med source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone givenAllelic fractions of somatic mutations were corrected for purity and copy number changes to determine cancer cell fractions.
“In brief, allelic fractions of somatic mutations were corrected for purity and copy number changes to determine cancer cell fractions.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
Study design and conductnone givenAll samples were analyzed with a validated gene panel of 102 amplicons of 14 genes.
“All samples were analyzed with a validated gene panel 32 of 102 amplicons of the following 14 genes: KRAS, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma gene (PIK3CA), BRAF, EGFR, erb-b2 receptor tyrosine kinase 2 gene (ERBB2), NRAS, discoidin domain receptor tyrosine kinase 2 gene (DDR2), TP53, ALK, catenin beta 1 gene (CTNNB1), MET, AKT/serine threonine kinase 1 gene (AK”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationDifferent KRAS proteins exert different effects on transformation of downstream signal transduction pathways.
“In addition, different KRAS proteins have been described as exerting different effects on transformation of downstream signal transduction pathways.23”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Ihle, 2012, Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome, J Natl Cancer Inst source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCo-occurrence of KRAS mutations and MET amplifications has been described in therapy-naive NSCLC.
“For instance, the co-occurrence of KRAS mutations and MNNG HOS Transforming gene (MET) amplifications has been described in therapy-naive NSCLC.29”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Schildhaus, 2015, MET amplification status in therapy-naïve adeno- and squamous cell carcinomas of the lung, Clin Cancer Res source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRecent efforts have tried to connect evolutionary heterogeneity with treatment approaches.
“recent efforts have tried to connect this evolutionary heterogeneity with treatment approaches.45”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] McGranahan, 2015, Biological and therapeutic impact of intratumor heterogeneity in cancer evolution, Cancer Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe distribution of cancer cell fractions was searched for distinct subpopulations by using a nonparametric method to deconvolute the noise in the cancer cell fractions.
“Next, the distribution of cancer cell fractions was searched for distinct subpopulations by using a nonparametric method to deconvolute the noise in the cancer cell fractions.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
A systematic analysis of co-occurring mutations in a large patient cohort is still lacking.
“Nevertheless, a systematic analysis of co-occurring mutations in a large patient cohort is still lacking.”
The paper relies on this without support.
KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time.
“Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRASmutated NSCLC represents a genetically heterogeneous subgroup.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In a dataset of 1078 patients with KRAS-mutant NSCLC, 577 (53.5%) had at least one additional co-mutation.
“In a dataset of 1078 patients with KRAS-mutant NSCLC, 577 (53.5%) patients had at least one additional co-mutation [52].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [52]
Co-occurring genomic changes profoundly affect biological behaviors, clinical outcomes, and therapeutic vulnerabilities of KRAS-mutant cancers.
“Compelling evidence showed that co-occurring genomic changes could profoundly affect biological behaviors (29–31), clinical outcomes (32), and therapeutic vulnerabilities of KRAS-mutant cancers (33, 34).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [32]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
MET amplification analysis has two sample counts
MinorThe results state that 606 samples were analyzed for MET amplification, while Table 2 gives 604 for that analysis.
“Of the 606 samples analyzed by FISH for MET amplification, 93 (15.4%) were amplified.”
“| MET amplification | 93 | 604 | 15.4 | 12.7-18.6 |”
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Cited by
Sorted by citations
Sotorasib for Lung Cancers with <i>KRAS</i> p.G12C Mutation
Skoulidis, F., Li, B. T., Dy, G. K., Price, T. J., Falchook, G. S., Wolf, J., Italiano, A., Schuler, M., Borghaei, H., Barlesi, F., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2103695 · Cited by 1,849 · see citing works
Self-citationKRAS Mutation: From Undruggable to Druggable in Cancer
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Self-citationTargeting KRAS in non-small-cell lung cancer: recent progress and new approaches
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Molecular epidemiology and diagnostics of KRAS mutations in human cancer
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KRAS: From undruggable to a druggable Cancer Target
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- Authors
- Scheffler, M., Ihle, M. A., Hein, R., Merkelbach-Bruse, S., Scheel, A. H., Siemanowski, J., Brägelmann, J., Kron, A., Abedpour, N., Ueckeroth, F., Schüller, M., Koleczko, S., Michels, S., Fassunke, J., Pasternack, H., Heydt, C., Serke, M., Fischer, R., Schulte, W., Gerigk, U., Nogova, L., Ko, Y.-D., Abdulla, D. S. Y., Riedel, R., Kambartel, K.-O., Lorenz, J., Sauerland, I., Randerath, W., Kaminsky, B., Hagmeyer, L., Grohé, C., Eisert, A., Frank, R., Gogl, L., Schaepers, C., Holzem, A., Hellmich, M., Thomas, R. K., Peifer, M., Sos, M. L., Büttner, R., & Wolf, J.
- Affiliations
- University Hospital Cologne (DE)
- University of Cologne (DE)
- University Hospital Schleswig-Holstein (DE)
- Lungenklinik Hemer (DE)
- St. Marien-Hospital Bonn (DE)
- Johanniter-Krankenhaus Bonn (DE)
- Bethanien Krankenhaus Moers (DE)
- Klinikum Lüdenscheid (DE)
- Krankenhaus Bethanien (DE)
- Evangelische Lungenklinik Berlin (DE)
- Corresponding author
- Wolf, Jürgen
- ORCID
- Scheffler, Matthias
- Ihle, Michaela A.
- Scheel, Andreas H.
- Siemanowski, Janna
- Brägelmann, Johannes
- Kron, Anna
- Abedpour, Nima
- Michels, Sebastian
- Fassunke, Jana
- Pasternack, Helen
- Heydt, Carina
- Fischer, Rieke
- Riedel, Richard
- Kambartel, Karl-Otto
- Randerath, Winfried
- Hagmeyer, Lars
- Grohé, Christian
- Eisert, Anna
- Holzem, Alessandra
- Hellmich, Martin
- Thomas, Roman K.
- Peifer, Martin
- Sos, Martin L.
- Büttner, Reinhard
- Wolf, Jürgen
- Venue
- Journal of Thoracic Oncology
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 14
- Issue
- 4
- Pages
- 606-616
- ISSN
- 1556-0864 (ISSN-L)
- OpenAlex
- W2906754611
- Cited by
- 264
- References
- 42
- Citations by year
- 2026: 20 · 2025: 27 · 2024: 32 · 2023: 50 · 2022: 48 · 2021: 51 · 2020: 25 · 2019: 9
- FWCI
- 16.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Thoracic Oncology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Funders
- AstraZeneca
- Boehringer Ingelheim
- Pfizer
- Celgene
- Bayer
- Novartis Pharma
- British Microcirculation Society
- Meso Scale Diagnostics
- Roche
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- KRAS mutation, non-small cell lung cancer, co-occurring mutations, genetic heterogeneity, TP53, STK11, Keap1, ATM, MET amplification, ERBB2 amplification, EGFR, BRAF, PIK3CA, clonality, driver mutations
- MeSH terms
- Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Proto-Oncogene Proteins p21(ras)
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
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