Next-Generation Sequencing in Lung Cancer Patients: A Comparative Approach in NSCLC and SCLC Mutational Landscapes
Abstract
:1. Introduction
2. Materials and Methods
2.1. TCGA Datasets and Statistical Analysis
2.2. Patient Cohorts
2.3. Sample Processing and DNA Extraction
2.4. Sequencing Protocol and Data Analysis
2.5. Mutation Validation—SNP Genotyping Assay
3. Results
3.1. Genetic Alterations in the TCGA Datasets
3.2. Clinicopathological Characteristics of the Cohort
3.3. Mutations Identified in the Experimental Cohort
3.4. Mutation Validation
3.5. Statistical Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Training Cohort | Validation Cohort | |
---|---|---|
Characteristics | No. of Patients (%) | No. of Patients (%) |
Total number | 32 | 32 |
Age (years), median | 53–81 (62) | 42–81 (62) |
Gender | ||
Male | 25 (78.2) | 23 (71.9) |
Female | 7 (21.8) | 9 (28.1) |
pT stage | ||
pT1 | 1 (3.1) | - |
pT2 | 4 (12.5) | - |
pT3 | 10 (31.2) | 7 (21.8) |
pT4 | 17 (53.1) | 25 (78.2) |
pN stage | ||
pN0 | 2 (6.2) | 2 (6.2) |
pN1 | - | 2 (6.2) |
pN2 | 20 (62.5) | 22 (68.7) |
pN3 | 10 (31.2) | 6 (18.7) |
pM stage | ||
pM0 | 14 (43.7) | 13 (40.6) |
pM1 | 18 (56.3) | 19 (59.4) |
Stage | ||
IIIB | 14 (43.8) | 11 (34.4) |
IIIC | 1 (3.1) | 2 (6.2) |
IV | 17 (53.1) | 19 (59.4) |
Histological type | ||
NSCLC | 16 (50) | 16 (50) |
SCLC | 16 (50) | 16 (50) |
Smoking status | ||
Active smoker | 16 (50) | 16 (50) |
Former smoker | 13 (40.6) | 13 (40.6) |
Never smoker | 3 (9.4) | 3 (9.4) |
Training Cohort | ||||||||
---|---|---|---|---|---|---|---|---|
Patient | Sex | Age at Diagnosis | TNM | Stage | Histological Type | Active Smoker | Former Smoker | Days to Event |
P8 | F | 58 | T3N2M0 | IIIB | adenocarcinoma | yes | yes | 116 |
P12 | M | 67 | T3N2M0 | IIIB | SCLC | yes | yes | 41 |
P13 | M | 66 | T3N3M0 | IIIB | adenocarcinoma | no | yes | 518 |
P15 | M | 58 | T4N2M0 | IIIB | squamous cell carcinoma | no | yes | 311 |
P16 | F | 76 | T4N3M0 | IIIC | squamous cell carcinoma | yes | yes | 584 |
P19 | F | 67 | T3N3M1 | IV | adenocarcinoma | no | no | 871 |
P20 | F | 81 | T4N2M0 | IIIB | adenocarcinoma | no | yes | 32 |
P22 | M | 58 | T2N2M0 | IIIB | SCLC | yes | yes | 261 |
P23 | M | 60 | T3N2M0 | IIIB | SCLC | no | yes | 336 |
P24 | M | 60 | T4N2M1 | IV | SCLC | no | yes | 111 |
P31 | M | 61 | T4N2M1 | IV | squamous cell carcinoma | no | yes | |
P34 | M | 62 | T3N2M1 | IV | adenocarcinoma | yes | yes | 131 |
P36 | M | 65 | T3N2M0 | IIIB | squamous cell carcinoma | no | yes | 934 |
P37 | F | 63 | T3N3M1 | IV | SCLC | no | no | 408 |
P38 | M | 77 | T4N3M1 | IV | SCLC | no | yes | 44 |
P42 | M | 65 | T4N3M1 | IIIB | SCLC | yes | yes | |
P50 | M | 62 | T4N3M1 | IV | squamous cell carcinoma | yes | yes | 162 |
P63 | M | 66 | T4N2M1 | IV | adenocarcinoma | no | yes | |
P66 | M | 62 | T4N2M1 | IV | SCLC | yes | yes | 62 |
P68 | F | 58 | T3N2M1 | IV | adenocarcinoma | no | no | 582 |
P73 | M | 65 | T4N3M0 | IIIB | SCLC | yes | yes | 116 |
P75 | M | 61 | T4N2M0 | IIIB | SCLC | no | yes | 338 |
P77 | M | 65 | T3N2M1 | IV | SCLC | no | yes | |
P78 | M | 67 | T4N2M0 | IIIB | SCLC | no | yes | 250 |
P80 | M | 67 | T2N2M1 | IV | squamous cell carcinoma | yes | yes | 33 |
P82 | M | 58 | T4N0M0 | IIIB | squamous cell carcinoma | yes | yes | 32 |
P84 | M | 60 | T2N2M1 | IV | SCLC | yes | yes | 227 |
P85 | F | 53 | T4N2M0 | IIIB | squamous cell carcinoma | yes | yes | 70 |
P86 | M | 71 | T2N0M1 | IV | adenocarcinoma | yes | yes | 163 |
P88 | M | 59 | T4N3M1 | IV | SCLC | yes | yes | |
P92 | M | 57 | T1N3M1 | IV | SCLC | yes | yes | |
P107 | M | 56 | T4N2M1 | IV | SCLC | no | yes | 71 |
Validation Cohort | ||||||||
Patient | Sex | Age at Diagnosis | TNM | Stage | Histological Type | Active Smoker | Former Smoker | Days to Event |
P110 | M | 55 | T3N2M1 | IV | squamous cell carcinoma | yes | yes | |
P118 | M | 70 | T3N2M1 | IV | SCLC | no | yes | 46 |
P120 | M | 71 | T4N2M0 | IIIB | SCLC | yes | yes | 185 |
P122 | M | 58 | T4N0M1 | IV | adenocarcinoma | no | yes | 450 |
P124 | M | 61 | T4N3M1 | IV | SCLC | yes | yes | 47 |
P129 | M | 60 | T4N2M0 | IIIB | squamous cell carcinoma | yes | yes | 16 |
P130 | F | 68 | T3N2M1 | IV | adenocarcinoma | no | yes | 143 |
P133 | F | 56 | T4N2M1 | IV | SCLC | yes | yes | 213 |
P136 | F | 67 | T3N2M0 | IIIB | squamous cell carcinoma | no | yes | 73 |
P137 | F | 50 | T4N2M0 | IIIB | adenocarcinoma | no | yes | 286 |
P138 | M | 62 | T4N1M1 | IV | adenocarcinoma | no | no | 231 |
P139 | M | 57 | T4N2M0 | IIIB | SCLC | no | yes | 489 |
P140 | M | 69 | T4N2M1 | IV | SCLC | no | yes | 3 |
P144 | M | 75 | T4N3M1 | IV | SCLC | no | yes | 622 |
P149 | M | 81 | T4N2M1 | IV | SCLC | yes | yes | 816 |
P150 | M | 60 | T3N1M1 | IV | SCLC | no | yes | 304 |
P153 | M | 61 | T4N3M0 | IIIC | adenocarcinoma | no | no | |
P159 | M | 62 | T4N2M0 | IIIB | squamous cell carcinoma | yes | yes | 359 |
P160 | M | 80 | T4N2M1 | IV | squamous cell carcinoma | yes | no | 888 |
P161 | F | 58 | T4N3M1 | IV | SCLC | yes | yes | 302 |
P162 | F | 53 | T4N2M1 | IV | SCLC | yes | yes | 887 |
P163 | F | 68 | T4N2M0 | IIIB | adenocarcinoma | no | yes | 884 |
P164 | M | 57 | T4N2M0 | IIIB | SCLC | no | yes | 883 |
P166 | M | 50 | T4N2M1 | IV | adenocarcinoma | no | yes | 65 |
P170 | M | 75 | T4N3M1 | IV | squamous cell carcinoma | no | no | 59 |
P171 | M | 56 | T4N3M0 | IIIC | SCLC | yes | yes | 153 |
P181 | M | 73 | T4N1M1 | IV | SCLC | no | yes | 278 |
P184 | M | 42 | T4N2M0 | IIIB | SCLC | yes | yes | 23 |
P186 | F | 78 | T4N2M1 | IV | squamous cell carcinoma | yes | yes | 8 |
P191 | M | 75 | T3N2M0 | IIIB | adenocarcinoma | yes | yes | 812 |
P193 | M | 68 | T3N2M0 | IIIB | squamous cell carcinoma | yes | yes | 319 |
P194 | F | 64 | T4N2M1 | IV | SCLC | yes | yes |
Gene | No. Pathogenic Mutations/Gene | Mutation | Amino Acid Change | NSCLC | SCLC (n = 16) | Exon | Variance | Sample | |
---|---|---|---|---|---|---|---|---|---|
LUAD (n = 8) | LUSC (n = 8) | TT/Blood | |||||||
ABL1 | 1 | c.992A>G | p.Asn331Ser | - | - | 1 | 6 | Missense | 1/1 |
CDKN2A | 1 | c.220G>T | p.Asp74Tyr | - | 1 | - | 2 | Missense | 1/0 |
CTNNB1 | 1 | c.136C>G | p.Leu46Val | 1 | - | - | 3 | Missense | 1/0 |
ERBB2 | 1 | c.2329G>A | p.Val777Met | - | - | 1 | 20 | Missense | 1/0 |
IDH2 | 1 | c.419G>A | p.Arg140Gln | 1 | - | - | 4 | Missense | 1/0 |
KIT | 2 | c.1621A>C | p.Met541Leu | 1 | 1 | 2 | 10 | Missense | 1/1 |
c.1588G>A | p.Val530Ile | 1 | - | - | 10 | Missense | 0/1 | ||
NRAS | 2 | c.182A>G | p.Gln61Arg | - | 1 | - | 3 | Missense | 1/0 |
c.182A>T | p.Arg140Gln | - | - | 1 | 3 | Missense | 1/0 | ||
PIK3CA | 3 | c.1624G>A | p.Glu542Lys | - | - | 2 | 10 | Missense | 1/0 |
c.3196G>A | p.Ala1066Thr | 1 | 1 | 4 | 21 | Missense | 1/0 | ||
c.328G>A | p.Glu110Lys | - | - | 1 | 2 | Missense | 1/0 | ||
PTEN | 1 | c.388C>T | p.Arg130Ter | - | - | 1 | 5 | Nonsense | 1/0 |
RB1 | 1 | c.409G>T | p.Glu137Ter | - | - | 1 | 4 | Nonsense | 1/0 |
RET | 1 | c.409G>T | p.Ser649Leu | - | - | 1 | 11 | Missense | 0/1 |
SMAD4 | 2 | c.546C>G | p.Ile182Met | - | - | 1 | 5 | Missense | 1/0 |
c.1081C>T | p.Arg361Cys | - | - | 1 | 9 | Missense | 1/0 | ||
STK11 | 1 | c.465-1G>T | - | - | - | 1 | 4 | Unknown | 1/0 |
TP53 | 23 | c.1000G>T | p.Gly334Trp | 1 | - | - | 10 | Missense | 1/0 |
c.1001G>T | p.Gly334Val | 1 | - | - | 10 | Missense | 1/0 | ||
c.1036G>T | p.Glu346Ter | - | - | 1 | 10 | Nonsense | 1/0 | ||
c.215C>G | p.Pro72Arg | 5 | 4 | 12 | 4 | Missense | 1/1 | ||
c.400T>A | p.Phe134Ile | - | - | 1 | 5 | Missense | 1/0 | ||
c.461G>T | p.Gly154Val | - | - | 1 | 5 | Missense | 1/0 | ||
c.472C>G | p.Arg158Gly | - | - | 1 | 5 | Missense | 1/0 | ||
c.473G>T | p.Arg158Leu | - | 1 | - | 5 | Missense | 1/0 | ||
c.500A>G | p.Gln167Arg | 1 | - | - | 5 | Missense | 0/1 | ||
c.514G>T | p.Val172Phe | - | 1 | - | 5 | Missense | 1/0 | ||
c.559+1G>T | - | 1 | - | - | 5 | unknown | 1/0 | ||
c.575A>G | p.Gln192Arg | - | 1 | - | 6 | Missense | 1/0 | ||
c.713G>T | p.Cys238Phe | - | - | 1 | 7 | Missense | 1/0 | ||
c.722C>T | p.Ser241Phe | - | - | 1 | 7 | Missense | 1/0 | ||
c.725G>T | p.Cys242Phe | - | 1 | - | 7 | Missense | 1/0 | ||
c.742C>T | p.Arg248Trp | - | - | 1 | 7 | Missense | 1/0 | ||
c.797G>T | p.Gly266Val | - | - | 1 | 8 | Missense | 1/0 | ||
c.817C>A | p.Arg273Ser | 1 | - | - | 8 | Missense | 1/0 | ||
c.832C>T | p.Pro278Ser | - | - | 1 | 8 | Missense | 1/0 | ||
c.850A>G | p.Thr284Ala | 1 | - | - | 8 | Missense | 1/0 | ||
c.856G>A | p.Glu286Lys | - | 1 | - | 8 | Missense | 1/0 | ||
c.872A>G | p.Lys291Arg | - | - | 1 | 8 | Missense | 1/0 | ||
c.880G>T | p.Glu294Ter | - | 1 | 1 | 8 | Nonsense | 1/0 |
Datasets TCGA | LUAD | LUSC | SCLC | ||||
---|---|---|---|---|---|---|---|
Gene | Altered/Unaltered | Logrank Test p-Value | Altered/Unaltered | Logrank Test p-Value | Altered/Unaltered | Logrank Test p-Value | |
ABL1 | 3/218 | 0.590 | 5/170 | 0.286 | 1/109 | 0.729 | |
CDKN2A | 55/166 | 0.0576 | 79/96 | 0.0531 | 1/109 | 0.359 | |
CTNNB1 | 9/212 | 0.791 | 5/170 | 0.140 | 0/110 | - | |
ERBB2 | 12/209 | 0.835 | 9/166 | 0.977 | 1/109 | 0.240 | |
IDH2 | 4/217 | 0.0243 | 5/170 | 0.266 | 0/110 | - | |
KIT | 9/212 | 0.976 | 15/160 | 0.360 | 7/103 | 0.528 | |
NRAS | 7/214 | 4.558 × 10−4 | 6/169 | 0.122 | 0/110 | - | |
PIK3CA | 19/202 | 0.793 | 105/70 | 0.938 | 3/107 | 0.574 | |
PTEN | 6/215 | 0.641 | 30/145 | 0.283 | 7/103 | 0.441 | |
RB1 | 17/204 | 0.910 | 18/157 | 0.418 | 80/30 | 0.410 | |
SMAD4 | 11/210 | 0.480 | 10/165 | 0.882 | 2/108 | 0.112 | |
STK11 | 42/179 | 0.412 | 6/169 | 0.0403 | 1/109 | 0.0272 | |
TP53 | 103/118 | 0.173 | 142/33 | 0.0419 | 94/16 | 0.705 |
Altered TP53 | Altered KIT | Altered PIK3CA | Altered STK11 | Stage | Tumor Size | Lymph Node Metastasis | Distant Metastatic Spread | Adenocarcinoma | Squamous Cell Carcinoma | Small-Cell Lung Cancer | Death (Days) | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
altered TP53 | 0.138409 | 0.148581 | 0.185695 | 0.127563 | 0.267435 | −0.06459 | 0.148581 | −0.0619 | −0.0619 | 0.107211 | 0.093676 | |
altered KIT | 0.1384091 | 0.03253 | −0.04969 | 0.074796 | −0.00678 | 0.046953 | 0.060351 | 0.019821 | 0.019821 | −0.03452 | 0.049947 | |
altered PIK3CA | 0.1485808 | 0.03253 | 0.218218 | 0.055228 | 0.217574 | 0.22771 | −0.01587 | −0.50918 | 0.218218 | 0.251976 | −0.03286 | |
altered STK11 | 0.1856953 | −0.04969 | 0.218218 | 0.108465 | 0.110783 | 0.248452 | 0.218218 | 0 | −0.16667 | 0.144338 | 0.056454 | |
Stage | 0.1275627 | 0.074796 | 0.055228 | 0.108465 | −0.10394 | −0.04296 | 0.96862 | 0 | −0.14548 | 0.125988 | −0.00042 | |
Tumor size | 0.2674354 | −0.00678 | 0.217574 | 0.110783 | −0.10394 | 0.06877 | −0.08411 | −0.10585 | 0.052926 | 0.045835 | −0.04025 | |
Lymph node metastasis | −0.06459093 | 0.046953 | 0.22771 | 0.248452 | −0.04296 | 0.06877 | −0.00216 | −0.19687 | −0.03937 | 0.204598 | 0.113633 | |
Distant metastatic spread | 0.1485808 | 0.060351 | −0.01587 | 0.218218 | 0.96862 | −0.08411 | −0.00216 | −0.01827 | −0.1644 | 0.158193 | −0.00042 | |
Adenocarcinoma | −0.06189845 | 0.019821 | −0.50918 | 0 | 0 | −0.10585 | −0.19687 | −0.01827 | −0.33333 | −0.57735 | 0.081326 | |
Squamous cell carcinoma | −0.06189845 | 0.019821 | 0.218218 | −0.16667 | −0.14548 | 0.052926 | −0.03937 | −0.1644 | −0.33333 | −0.57735 | −0.0643 | |
Small-cell lung cancer | 0.1072113 | −0.03452 | 0.251976 | 0.144338 | 0.125988 | 0.045835 | 0.204598 | 0.158193 | −0.57735 | −0.57735 | −0.01636 | |
Death (days) | 0.09367601 | 0.049947 | −0.03286 | 0.056454 | −0.00042 | −0.04025 | 0.113633 | −0.00042 | 0.081326 | −0.0643 | −0.01636 | |
deceased | −0.01491 | 0.085205 | −0.10635 | −0.05723 | 0.085205 | −0.09343 | 0.036155 | 0.051473 | −0.63572 | |||
Active smoker | −0.1072113 | −0.20179 | 0 | 0.144338 | −0.06299 | −0.1375 | 0.068199 | −0.03164 | −0.28868 | 0.216506 | 0.0625 | −0.24329 |
Former smoker | −0.1034483 | −0.13566 | 0.364698 | 0.185695 | −0.1756 | 0.029484 | −0.18279 | −0.16621 | −0.30949 | 0.061898 | 0.214423 | −0.14787 |
never smoker | 0.1034483 | 0.135656 | −0.3647 | −0.1857 | 0.175596 | −0.02948 | 0.182794 | 0.166209 | 0.309492 | −0.0619 | −0.21442 | 0.147874 |
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Pop-Bica, C.; Ciocan, C.A.; Braicu, C.; Haranguș, A.; Simon, M.; Nutu, A.; Pop, L.A.; Slaby, O.; Atanasov, A.G.; Pirlog, R.; et al. Next-Generation Sequencing in Lung Cancer Patients: A Comparative Approach in NSCLC and SCLC Mutational Landscapes. J. Pers. Med. 2022, 12, 453. https://doi.org/10.3390/jpm12030453
Pop-Bica C, Ciocan CA, Braicu C, Haranguș A, Simon M, Nutu A, Pop LA, Slaby O, Atanasov AG, Pirlog R, et al. Next-Generation Sequencing in Lung Cancer Patients: A Comparative Approach in NSCLC and SCLC Mutational Landscapes. Journal of Personalized Medicine. 2022; 12(3):453. https://doi.org/10.3390/jpm12030453
Chicago/Turabian StylePop-Bica, Cecilia, Cristina Alexandra Ciocan, Cornelia Braicu, Antonia Haranguș, Marioara Simon, Andreea Nutu, Laura Ancuta Pop, Ondrej Slaby, Atanas G. Atanasov, Radu Pirlog, and et al. 2022. "Next-Generation Sequencing in Lung Cancer Patients: A Comparative Approach in NSCLC and SCLC Mutational Landscapes" Journal of Personalized Medicine 12, no. 3: 453. https://doi.org/10.3390/jpm12030453