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MLH1 V384D polymorphism associates with poor response to EGFR tyrosine kinase inhibitors in patients with EGFR L858R-positive lung adenocarcinoma.

Chiu CH, Ho HL, Doong H, Yeh YC, Chen MY, Chou TY, Tsai CM - Oncotarget (2015)

Bottom Line: A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy.Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001).Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001).

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

ABSTRACT
A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.

No MeSH data available.


Related in: MedlinePlus

Genetic variations of EGFR L858R lung adenocarcinomas in 46 cancer-related genesThe mutation profiles in hotspot regions of 46 cancer-related genes in individual EGFR L858R tumors are shown on the left in 2 groups, according to the progression-free survival of patients. A positive result for mutation is indicated by a filled box. The percentage of mutation identified in each group for each gene is shown on the right.
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Figure 1: Genetic variations of EGFR L858R lung adenocarcinomas in 46 cancer-related genesThe mutation profiles in hotspot regions of 46 cancer-related genes in individual EGFR L858R tumors are shown on the left in 2 groups, according to the progression-free survival of patients. A positive result for mutation is indicated by a filled box. The percentage of mutation identified in each group for each gene is shown on the right.

Mentions: NGS was used to interrogate mutations within hotspot regions of 46 cancer-related genes in lung adenocarcinoma samples from 13 and 16 EGFR-TKI-treated patients who had short (< 3 months) and long (> 1 year) PFS, respectively. Differential mutation patterns were revealed in these two groups (Fig. 1 and more details in the Supplementary Appendix). All 29 tumors were confirmed to harbor the activating EGFR L858R mutation without the simultaneous presence of the T790M allele that predicts EGFR-TKI resistance. Among the 46 genes, KDR (which encodes for vascular endothelial growth factor receptor 2) was the most commonly mutated gene coexisting with EGFR L858R, regardless of the patient's treatment response. Mutation rates of ABL1, APC, and PDGFRA were disproportionately high in the patient with long PFS. In contrast, mutations in FGFR2 (K368E), KRAS (G12D), MLH1 (V384D), and TP53 occurred more often in patients with short PFS. Derepression of FGFR2 expression has been implicated in the mechanism for rapidly acquired EGFR-TKI resistance in NSCLC cells [12]. KRAS G12C is linked to poor outcomes of EGFR-TKI therapy in NSCLC patients [13]. A study shows higher p53 mutation rates in advanced-stage than in early-stage lung cancers and suggests that the concurrent occurrence of p53 mutations with EGFR mutations may foster the development of therapeutic resistance [25]. However, the DNA mismatch repair gene MLH1 has not been associated with EGFR-TKI resistance yet.


MLH1 V384D polymorphism associates with poor response to EGFR tyrosine kinase inhibitors in patients with EGFR L858R-positive lung adenocarcinoma.

Chiu CH, Ho HL, Doong H, Yeh YC, Chen MY, Chou TY, Tsai CM - Oncotarget (2015)

Genetic variations of EGFR L858R lung adenocarcinomas in 46 cancer-related genesThe mutation profiles in hotspot regions of 46 cancer-related genes in individual EGFR L858R tumors are shown on the left in 2 groups, according to the progression-free survival of patients. A positive result for mutation is indicated by a filled box. The percentage of mutation identified in each group for each gene is shown on the right.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480762&req=5

Figure 1: Genetic variations of EGFR L858R lung adenocarcinomas in 46 cancer-related genesThe mutation profiles in hotspot regions of 46 cancer-related genes in individual EGFR L858R tumors are shown on the left in 2 groups, according to the progression-free survival of patients. A positive result for mutation is indicated by a filled box. The percentage of mutation identified in each group for each gene is shown on the right.
Mentions: NGS was used to interrogate mutations within hotspot regions of 46 cancer-related genes in lung adenocarcinoma samples from 13 and 16 EGFR-TKI-treated patients who had short (< 3 months) and long (> 1 year) PFS, respectively. Differential mutation patterns were revealed in these two groups (Fig. 1 and more details in the Supplementary Appendix). All 29 tumors were confirmed to harbor the activating EGFR L858R mutation without the simultaneous presence of the T790M allele that predicts EGFR-TKI resistance. Among the 46 genes, KDR (which encodes for vascular endothelial growth factor receptor 2) was the most commonly mutated gene coexisting with EGFR L858R, regardless of the patient's treatment response. Mutation rates of ABL1, APC, and PDGFRA were disproportionately high in the patient with long PFS. In contrast, mutations in FGFR2 (K368E), KRAS (G12D), MLH1 (V384D), and TP53 occurred more often in patients with short PFS. Derepression of FGFR2 expression has been implicated in the mechanism for rapidly acquired EGFR-TKI resistance in NSCLC cells [12]. KRAS G12C is linked to poor outcomes of EGFR-TKI therapy in NSCLC patients [13]. A study shows higher p53 mutation rates in advanced-stage than in early-stage lung cancers and suggests that the concurrent occurrence of p53 mutations with EGFR mutations may foster the development of therapeutic resistance [25]. However, the DNA mismatch repair gene MLH1 has not been associated with EGFR-TKI resistance yet.

Bottom Line: A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy.Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001).Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001).

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

ABSTRACT
A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.

No MeSH data available.


Related in: MedlinePlus