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Comprehensive Molecular Analysis of NSCLC; Clinicopathological Associations.

Chatziandreou I, Tsioli P, Sakellariou S, Mourkioti I, Giannopoulou I, Levidou G, Korkolopoulou P, Patsouris E, Saetta AA - PLoS ONE (2015)

Bottom Line: The heterogeneity of molecular alterations in lung cancer has led to the ongoing discovery of potential biomarkers and targets in order to improve survival.KRAS mutations were associated with histology, the most common mutation being p.Gly12Cys (38%).In conclusion, only 89 patients were eligible for EGFR -TKIs and ALK inhibitors therapy, whereas 257 patients showed other alterations, highlighting the necessity for a detailed molecular profiling potentially leading to more efficient individualized therapies for NSCLC patients.

View Article: PubMed Central - PubMed

Affiliation: First Department of Pathology, Laikon General Hospital, Athens University Medical School, Athens, Greece.

ABSTRACT

Background: Selection of NSCLC patients for targeted therapy is currently based upon the presence of sensitizing mutations in EGFR and EML4/ALK translocations. The heterogeneity of molecular alterations in lung cancer has led to the ongoing discovery of potential biomarkers and targets in order to improve survival.

Aim: This study aimed to detect alterations in EGFR, KRAS, BRAF, PIK3CA, MET-gene copy number and ALK rearrangements in a large cohort of 956 NSCLC patients of Hellenic origin using highly sensitive techniques and correlations with clinicopathological characteristics.

Results: Mutations were detected in EGFR 10.6% (101 out of 956 samples), KRAS 26.5% (191 out of 720 samples), BRAF 2.5% (12 out of 471 samples), PIK3CA 3.8% (7 out of 184 samples), MET gene amplification was detected in 18% (31 out of 170) and ALK rearrangements in 3.7% (4 out of 107 samples). EGFR mutations were detected in exon 19 (61.4% of mutant cases), exon 21 p.Leu858Arg (19.8%), exon 20 (15.8%), exon 18 (2.9%) and were correlated with gender histology, smoking status and TTF1 staining. p.Thr790Met mutant cases (3.9%) displayed concurrent mutations in exons 19 or 21. Negative TTF-1 staining showed strong negative predictive value for the presence of EGFR mutations. KRAS mutations were associated with histology, the most common mutation being p.Gly12Cys (38%).

Discussion: In conclusion, only 89 patients were eligible for EGFR -TKIs and ALK inhibitors therapy, whereas 257 patients showed other alterations, highlighting the necessity for a detailed molecular profiling potentially leading to more efficient individualized therapies for NSCLC patients.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the distribution (%) of different KRAS mutations.
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pone.0133859.g003: Schematic representation of the distribution (%) of different KRAS mutations.

Mentions: In order to further examine the mutational profile of the patients, as far as MAPK and PI3K/AKT signaling pathways are concerned, HRM analysis and Pyrosequencing/sanger sequencing were applied to detect mutations in KRAS (exon 2), BRAF (exon 15) and PIK3CA (exons 9 and 20) genes. KRAS mutational analysis was performed for 720 samples and 26.5% (191 out of 720) of the cases were mutated, mainly adenocarcinomas (29.9%, 164 out of 549 adenocarcinomas). Regarding the adenocarcinoma groups the presence of KRAS mutations was more common in Invasive mucinous AdCa (5 out of 11 samples, Table 5), but no statistical correlations were elicited. In the other NSCLC histological types KRAS mutation frequency was 3% in squamous cell carcinomas (2 out of 66, Table 3) and 19% in NOS and other histologies (25 out of 105 Fig 2). Interestingly, a statistically significant relation (p<0.0001) depicting the association of KRAS mutations with tumors’ histological type in NSCLC patients was determined. In contrast with EGFR, KRAS mutations were equally distributed between the two sexes, observed in 26.4% of males and 25.9% of females. KRAS mutations mainly affected codon 12 (92%) and the distribution of mutations was the following: the most frequent mutation was p.Gly12Cys (38% of mutant cases) which has been reported to be smoking related and p.Gly12Val (24%). In detail, ten different mutations were identified in total namely: p.Gly12Cys, p.Gly12Val, p.Gly12A, p.Gly12Asp, p.Gly12Arg. p.Gly12Ser, p.Gly12Phe, p.Gly12Gly, p.Gly13Asp and p.Gly13Cys (Fig 3). From the cases analysed for KRAS, smoking status was available for only 84 patients. KRAS was mutated in 21 of 70 smokers (30%) and 1 of 14 (7.1%) non- smokers; although 21 out of 22 mutations were found in smokers, this finding was not statistical significant (p = 0.1), probably due to the small number of cases and in particular the limited number of non-smoking patients (14 patients). No clinicopathological associations were found between KRAS mutations and stage (p = 0.586), grade (p = 0.582) or age (p = 0.294).


Comprehensive Molecular Analysis of NSCLC; Clinicopathological Associations.

Chatziandreou I, Tsioli P, Sakellariou S, Mourkioti I, Giannopoulou I, Levidou G, Korkolopoulou P, Patsouris E, Saetta AA - PLoS ONE (2015)

Schematic representation of the distribution (%) of different KRAS mutations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4514742&req=5

pone.0133859.g003: Schematic representation of the distribution (%) of different KRAS mutations.
Mentions: In order to further examine the mutational profile of the patients, as far as MAPK and PI3K/AKT signaling pathways are concerned, HRM analysis and Pyrosequencing/sanger sequencing were applied to detect mutations in KRAS (exon 2), BRAF (exon 15) and PIK3CA (exons 9 and 20) genes. KRAS mutational analysis was performed for 720 samples and 26.5% (191 out of 720) of the cases were mutated, mainly adenocarcinomas (29.9%, 164 out of 549 adenocarcinomas). Regarding the adenocarcinoma groups the presence of KRAS mutations was more common in Invasive mucinous AdCa (5 out of 11 samples, Table 5), but no statistical correlations were elicited. In the other NSCLC histological types KRAS mutation frequency was 3% in squamous cell carcinomas (2 out of 66, Table 3) and 19% in NOS and other histologies (25 out of 105 Fig 2). Interestingly, a statistically significant relation (p<0.0001) depicting the association of KRAS mutations with tumors’ histological type in NSCLC patients was determined. In contrast with EGFR, KRAS mutations were equally distributed between the two sexes, observed in 26.4% of males and 25.9% of females. KRAS mutations mainly affected codon 12 (92%) and the distribution of mutations was the following: the most frequent mutation was p.Gly12Cys (38% of mutant cases) which has been reported to be smoking related and p.Gly12Val (24%). In detail, ten different mutations were identified in total namely: p.Gly12Cys, p.Gly12Val, p.Gly12A, p.Gly12Asp, p.Gly12Arg. p.Gly12Ser, p.Gly12Phe, p.Gly12Gly, p.Gly13Asp and p.Gly13Cys (Fig 3). From the cases analysed for KRAS, smoking status was available for only 84 patients. KRAS was mutated in 21 of 70 smokers (30%) and 1 of 14 (7.1%) non- smokers; although 21 out of 22 mutations were found in smokers, this finding was not statistical significant (p = 0.1), probably due to the small number of cases and in particular the limited number of non-smoking patients (14 patients). No clinicopathological associations were found between KRAS mutations and stage (p = 0.586), grade (p = 0.582) or age (p = 0.294).

Bottom Line: The heterogeneity of molecular alterations in lung cancer has led to the ongoing discovery of potential biomarkers and targets in order to improve survival.KRAS mutations were associated with histology, the most common mutation being p.Gly12Cys (38%).In conclusion, only 89 patients were eligible for EGFR -TKIs and ALK inhibitors therapy, whereas 257 patients showed other alterations, highlighting the necessity for a detailed molecular profiling potentially leading to more efficient individualized therapies for NSCLC patients.

View Article: PubMed Central - PubMed

Affiliation: First Department of Pathology, Laikon General Hospital, Athens University Medical School, Athens, Greece.

ABSTRACT

Background: Selection of NSCLC patients for targeted therapy is currently based upon the presence of sensitizing mutations in EGFR and EML4/ALK translocations. The heterogeneity of molecular alterations in lung cancer has led to the ongoing discovery of potential biomarkers and targets in order to improve survival.

Aim: This study aimed to detect alterations in EGFR, KRAS, BRAF, PIK3CA, MET-gene copy number and ALK rearrangements in a large cohort of 956 NSCLC patients of Hellenic origin using highly sensitive techniques and correlations with clinicopathological characteristics.

Results: Mutations were detected in EGFR 10.6% (101 out of 956 samples), KRAS 26.5% (191 out of 720 samples), BRAF 2.5% (12 out of 471 samples), PIK3CA 3.8% (7 out of 184 samples), MET gene amplification was detected in 18% (31 out of 170) and ALK rearrangements in 3.7% (4 out of 107 samples). EGFR mutations were detected in exon 19 (61.4% of mutant cases), exon 21 p.Leu858Arg (19.8%), exon 20 (15.8%), exon 18 (2.9%) and were correlated with gender histology, smoking status and TTF1 staining. p.Thr790Met mutant cases (3.9%) displayed concurrent mutations in exons 19 or 21. Negative TTF-1 staining showed strong negative predictive value for the presence of EGFR mutations. KRAS mutations were associated with histology, the most common mutation being p.Gly12Cys (38%).

Discussion: In conclusion, only 89 patients were eligible for EGFR -TKIs and ALK inhibitors therapy, whereas 257 patients showed other alterations, highlighting the necessity for a detailed molecular profiling potentially leading to more efficient individualized therapies for NSCLC patients.

No MeSH data available.


Related in: MedlinePlus