Is There a Link between Chronic Obstructive Pulmonary Disease and Lung Adenocarcinoma? A Clinico-Pathological and Molecular Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Population
2.2. Morphological Analyses
2.3. DNA Extraction
2.4. Next Generation Sequencing
2.5. Bioinformatics Analysis
- Variants with variant allele frequency (VAF) < 0.05 (5%) were excluded;
- Variants with coverage < 100X were excluded;
- Only exonic and splicing variants were kept;
- Synonymous SNVs were removed;
- Polymorphisms were excluded, defined as variants having minor allele frequency (MAF) > 0.01 according to Exome Sequencing Project (ESP, https://bio.tools/esp, accessed on 14 April 2023) OR Exome Aggregation Consortium (ExAC, https://ngdc.cncb.ac.cn/databasecommons/database/id/3774, accessed on 14 April 2023) OR 1000 Genomes Project (http://www.internationalgenome.org, accessed on 7 August 2024) OR Genome Aggregation Database (https://gnomad.broadinstitute.org/, accessed on 1 June 2024);
- We excluded possibly benign variants and variants with uncertain significance according to ClinVar (database update of 20221231, labels considered: ‘Benign’, ‘Benign/Likely benign’, ‘Likely benign’, ‘Uncertain significance’).
2.6. Statistical Analysis
3. Results
3.1. Study Population
3.2. Distribution of Mutations in COPD, Smokers and Non Smokers Tumor Samples
3.3. Analysis of Matched Pathological/Healthy Tissues
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | COPD/Smoker LUAD N = 38 | Non-COPD/Smoker LUAD N = 54 | Non-COPD/Non-Smoker LUAD N = 18 | p-Value a | q-Value b |
---|---|---|---|---|---|
Sex | 0.001 | 0.015 | |||
males | 30 (79%) | 34 (63%) | 5 (28%) | ||
females | 8 (21%) | 20 (37%) | 13 (72%) | ||
Age | 72 (68, 75) | 69 (62, 73) | 65 (59, 72) | 0.11 | 0.3 |
GOLD stage | >0.9 | >0.9 | |||
I | 18 (47.5%) | 0 (NA%) | 0 (NA%) | ||
II | 18 (47.5%) | 0 (NA%) | 0 (NA%) | ||
III | 2 (5%) | 0 (NA%) | 0 (NA%) | ||
Smoking history (pack years) | 40 (27.5–50) | 36 (22–50) | - | 0.245 | 0.67 |
FEV1 (% of predict) | 76 (64, 87) | 93 (88, 113) | 117 (104, 130) | <0.001 | <0.001 |
FEV1/FV (% of predict) | 67 (58, 70) | 83 (78, 85) | 82 (78, 86) | <0.001 | <0.001 |
FVC (% of predict) | 92 (74, 101) | 92 (82, 105) | 119 (108, 128) | <0.001 | 0.002 |
DLCO/VA (%) | 70 (48, 89) | 80 (65, 91) | 84 (81, 99) | 0.085 | 0.2 |
SUV | 6 (2, 11) | 6 (2, 12) | 2 (1, 5) | 0.061 | 0.2 |
WBC (n × 109/L) | 7.35 (5.78, 8.68) | 6.92 (5.45, 9.30) | 5.52 (4.70, 7.01) | 0.012 | 0.072 |
RBC (n × 1012/L) | 4.50 (4.18, 5.00) | 4.42 (4.14, 4.77) | 4.62 (4.21, 4.96) | 0.7 | 0.8 |
HgB (g/dL) | 13.70 (12.35, 14.65) | 13.70 (12.50, 14.70) | 13.80 (13.03, 14.80) | 0.7 | 0.8 |
Neutrophils (n × 109/L) | 4.40 (3.54, 5.74) | 4.02 (3.06, 6.02) | 2.87 (2.81, 4.52) | 0.046 | 0.2 |
Neutrophils (%) | 64 (56, 69) | 62 (56, 69) | 56 (52, 66) | 0.3 | 0.4 |
Lymphocytes (n × 109/L) | 1.77 (1.48, 2.12) | 1.75 (1.55, 2.06) | 1.62 (1.39, 1.93) | 0.7 | 0.8 |
Lymphocytes (%) | 24 (20, 32) | 26 (20, 32) | 31 (24, 33) | 0.3 | 0.4 |
Monocytes (n × 109/L) | 0.60 (0.49, 0.70) | 0.57 (0.42, 0.70) | 0.49 (0.40, 0.58) | 0.082 | 0.2 |
Monocytes (%) | 8.55 (7.03, 10.05) | 8.00 (7.10, 9.80) | 9.30 (6.90, 10.50) | 0.7 | 0.8 |
Eosinophils (n × 109/L) | 0.16 (0.06, 0.26) | 0.08 (0.05, 0.16) | 0.12 (0.06, 0.26) | 0.079 | 0.2 |
Eosinophils (%) | 2.05 (1.33, 3.63) | 1.30 (0.80, 2.30) | 2.20 (1.30, 3.80) | 0.029 | 0.13 |
Basophils (n × 109/L) | 0.030 (0.020, 0.040) | 0.020 (0.010, 0.030) | 0.020 (0.020, 0.030) | 0.13 | 0.3 |
Basophils (%) | 0.40 (0.30, 0.60) | 0.30 (0.20, 0.50) | 0.40 (0.30, 0.60) | 0.2 | 0.3 |
ESR (mm/h) | 21 (12, 32) | 20 (10, 28) | 14 (9, 20) | 0.090 | 0.2 |
CRP (mg/L) | 2.0 (1.4, 6.9) | 2.9 (1.3, 4.7) | 0.8 (0.3, 2.9) | 0.029 | 0.13 |
Clinical stage | 0.2 | 0.3 | |||
IA | 7 (18.5%) | 17 (31.5%) | 6 (33%) | ||
IB | 16 (42%) | 11 (20.5%) | 9 (50%) | ||
IIA | 4 (10.5%) | 3 (6%) | 0 (0%) | ||
IIB | 7 (18.5%) | 10 (18%) | 2 (11%) | ||
IIIA | 4 (10.5%) | 10 (18%) | 1 (6%) | ||
IIIB | 0 (0%) | 3 (6%) | 0 (0%) |
Characteristic | COPD/Smoker LUAD N = 38 | Non-COPD/Smoker LUAD N = 54 | Non-COPD/Non-Smoker LUAD N = 18 | p-Value a | q-Value b |
---|---|---|---|---|---|
Tumor cells (%) | 70 (50, 80) | 65 (50, 80) | 70 (70, 80) | 0.5 | 0.7 |
Prevalent pattern | 0.3 | 0.4 | |||
Lepidic pattern | 1 (2.5%) | 8 (15%) | 1 (5.6%) | ||
Acinar pattern | 28 (74%) | 32 (59%) | 14 (78%) | ||
Papillary pattern | 1 (2.5%) | 4 (7.5%) | 0 (0%) | ||
Solid pattern | 8 (21%) | 10 (18.5%) | 3 (17%) | ||
Lepidic pattern (%) | 0 (0, 5) | 2 (0, 24) | 18 (5, 30) | 0.008 | 0.057 |
Acinar pattern (%) | 60 (42, 85) | 50 (20, 75) | 60 (45, 84) | 0.14 | 0.3 |
Papillary pattern (%) | 0 (0, 0) | 0 (0, 8) | 0 (0, 8) | 0.7 | 0.8 |
Micropapillary pattern (%) | 0 (0, 2) | 0 (0, 1) | 0 (0, 4) | >0.9 | >0.9 |
Solid pattern (%) | 10 (0, 35) | 0 (0, 32) | 0 (0, 0) | 0.2 | 0.3 |
WHO Grading | |||||
1 | 1 (2%) | 5 (9%) | 1 (5%) | ||
2 | 17 (45%) | 21 (39%) | 14 (78%) | ||
3 | 20 (53%) | 28 (52%) | 3 (17%) | ||
MIB1 (%) | 20 (10, 58) | 40 (20, 70) | 10 (9, 21) | 0.001 | 0.011 |
Necrosis (%) | 0.2 | 0.3 | |||
0 | 6 (16%) | 12 (22%) | 7 (39%) | ||
≤10% | 19 (50%) | 25 (46%) | 7 (39%) | ||
11–30% | 4 (10%) | 7 (13%) | 4 (22%) | ||
>30% | 9 (24%) | 10 (19%) | 0 (0%) | ||
Inflammation (%) | 0.2 | 0.3 | |||
0 | 0 (0%) | 0 (0%) | 1 (6%) | ||
≤10% | 13 (34%) | 24 (44%) | 4 (22%) | ||
11–30% | 18 (47.5%) | 23 (43%) | 11 (61%) | ||
>30% | 7 (18.5%) | 7 (13%) | 2 (11%) | ||
Fibrosis (%) | 0.2 | 0.3 | |||
0 | 3 (8%) | 4 (7%) | 0 (0%) | ||
≤10% | 16 (42%) | 22 (41%) | 3 (17%) | ||
11–30% | 12 (32%) | 18 (33%) | 8 (44%) | ||
>30% | 7 (18%) | 10 (19%) | 7 (39%) | ||
Vascular invasion | 0.5 | 0.7 | |||
No | 18 (47%) | 23 (43%) | 9 (50%) | ||
Yes | 20 (53%) | 31 (57%) | 9 (50%) | ||
Pleural invasion | 0.6 | 0.8 | |||
No | 20 (53%) | 27 (50%) | 11 (61%) | ||
Yes | 18 (47%) | 27 (50%) | 7 (39%) | ||
Type of visceral pleura invasion | >0.9 | >0.9 | |||
PL0 | 20 (53%) | 27 (50%) | 11 (61%) | ||
PL1 | 15 (39%) | 23 (43%) | 6 (33%) | ||
PL2 | 3 (8%) | 4 (7%) | 1 (6%) | ||
Perineural invasion | 0.5 | 0.7 | |||
No | 34 (89%) | 50 (93%) | 18 (100%) | ||
Yes | 4 (11%) | 4 (7%) | 0 (0%) | ||
Lymph node invasion | 0.089 | 0.2 | |||
No | 30 (79%) | 38 (70%) | 17 (94%) | ||
Yes | 8 (21%) | 16 (30%) | 1 (6%) | ||
Type of lymph node invasion | 0.14 | 0.3 | |||
0 | 30 (79%) | 38 (70%) | 17 (94%) | ||
1 | 6 (16%) | 7 (13%) | 1 (6%) | ||
2 | 2 (5%) | 9 (17%) | 0 (0%) |
Gene | COPD/Smoker LUAD N = 38 | Non-COPD/Smoker LUAD N = 54 | Non-COPD/Non-Smoker LUAD N = 18 |
---|---|---|---|
KRAS | 21 (55%) | 27 (50%) | 3 (17%) |
EGFR | 9 (24%) | 12 (22%) | 10 (56%) |
NTRK3 | 8 (21%) | 14 (26%) | 5 (28%) |
TP53 | 10 (26%) | 15 (28%) | 4 (22%) |
NTRK2 | 8 (21%) | 10 (19%) | 1 (6%) |
PIK3CA | 7 (18%) | 9 (17%) | 0 (0%) |
STK11 | 9 (24%) | 13 (24%) | 1 (6%) |
MET | 5 (13%) | 10 (19%) | 0 (0%) |
NOTCH1 | 6 (16%) | 11 (20%) | 2 (11%) |
FBXW7 | 5 (13%) | 5 (9%) | 0 (0%) |
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Lunardi, F.; Nardo, G.; Lazzarini, E.; Tzorakoleftheraki, S.-E.; Comacchio, G.M.; Fonzi, E.; Tebaldi, M.; Vedovelli, L.; Pezzuto, F.; Fortarezza, F.; et al. Is There a Link between Chronic Obstructive Pulmonary Disease and Lung Adenocarcinoma? A Clinico-Pathological and Molecular Study. J. Pers. Med. 2024, 14, 839. https://doi.org/10.3390/jpm14080839
Lunardi F, Nardo G, Lazzarini E, Tzorakoleftheraki S-E, Comacchio GM, Fonzi E, Tebaldi M, Vedovelli L, Pezzuto F, Fortarezza F, et al. Is There a Link between Chronic Obstructive Pulmonary Disease and Lung Adenocarcinoma? A Clinico-Pathological and Molecular Study. Journal of Personalized Medicine. 2024; 14(8):839. https://doi.org/10.3390/jpm14080839
Chicago/Turabian StyleLunardi, Francesca, Giorgia Nardo, Elisabetta Lazzarini, Sofia-Eleni Tzorakoleftheraki, Giovanni Maria Comacchio, Eugenio Fonzi, Michela Tebaldi, Luca Vedovelli, Federica Pezzuto, Francesco Fortarezza, and et al. 2024. "Is There a Link between Chronic Obstructive Pulmonary Disease and Lung Adenocarcinoma? A Clinico-Pathological and Molecular Study" Journal of Personalized Medicine 14, no. 8: 839. https://doi.org/10.3390/jpm14080839