A Functional Genomics Review of Non-Small-Cell Lung Cancer in Never Smokers
Abstract
:1. Introduction
2. The Genomic Profile of Lung Cancer in Never Smokers
3. Immunological Changes: Tumour Microenvironment in Never Smokers
4. Abnormalities in Growth-Stimulatory Signalling Pathways
4.1. RAS/MAPK Signalling Pathway
4.2. Mutations in Other EGFR Signalling Pathway Genes
4.2.1. Notch Signalling Pathway Genes
4.2.2. Abnormalities in Tumour Suppressor Gene Pathways: P53 and KRAS
4.2.3. PI3K–AKT–mTOR
4.2.4. microRNAs
5. Application of Molecular Biology and Future Directions
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene | Mutated Samples | Samples Tested | NS % | CS % | RS % | p-Value |
---|---|---|---|---|---|---|
EGFR * | 25,394 | 95,066 | 13.33 | 1.67 | 6.60 | p-value = 0.0046 |
KRAS | 5994 | 37,187 | 6.67 | 14.17 | 16.50 | p-value = 0.095 |
TP53 | 3246 | 9440 | 10.67 | 24.17 | 21.78 | p-value = 0.058 |
PIK3CA | 546 | 13,654 | 1.33 | 3.33 | 2.97 | p-value = 0.800 |
CSMD3 | 543 | 2305 | 1.33 | 7.50 | 9.57 | p-value = 0.059 |
LRP1B * | 497 | 2492 | 1.33 | 15.83 | 15.18 | p-value = 0.0042 |
BRAF | 493 | 24,447 | 0.00 | 5.00 | 4.62 | p-value = 0.14 |
USH2A * | 484 | 2305 | 5.33 | 10.83 | 15.84 | p-value = 0.038 |
RYR2 * | 444 | 2199 | 6.67 | 21.67 | 16.17 | p-value = 0.021 |
CDKN2A | 425 | 5443 | 0.00 | 2.50 | 1.98 | p-value = 0.45 |
MUC16 * | 402 | 2333 | 4.00 | 16.67 | 21.45 | p-value = 0.0018 |
ZFHX4 * | 379 | 2200 | 1.33 | 15.00 | 13.86 | p-value = 0.0071 |
SPTA1 | 308 | 2202 | 6.67 | 10.00 | 13.20 | p-value = 0.24 |
STK11 | 298 | 5856 | 2.67 | 5.83 | 9.90 | p-value = 0.073 |
MUC17 | 288 | 2205 | 4.00 | 12.50 | 8.91 | p-value = 0.13 |
SYNE1 | 287 | 2204 | 0.00 | 5.83 | 3.63 | p-value = 0.072 |
XIRP2 | 283 | 2200 | 0.00 | 10.83 | 10.23 | p-value = 0.014 |
FLG | 282 | 2203 | 5.33 | 15.00 | 12.54 | p-value = 0.12 |
ERBB2 | 275 | 18,935 | 4.00 | 0.00 | 0.99 | p-value = 0.054 |
FAM135B * | 256 | 2303 | 0.00 | 5.00 | 7.92 | p-value = 0.015 |
COL11A1 | 255 | 2302 | 1.33 | 8.33 | 9.57 | p-value = 0.063 |
NAV3 * | 253 | 2203 | 0.00 | 12.50 | 9.24 | p-value = 0.0086 |
RYR3 | 246 | 2199 | 1.33 | 5.00 | 6.93 | p-value = 0.16 |
KEAP1 | 240 | 2993 | 2.67 | 6.67 | 9.57 | p-value = 0.12 |
Gene | Pathway | Findings | References |
---|---|---|---|
TP53 | Notch/ASCL1 axis | Inactivation of TP53 and RB1 participated in the transformation of SCLC in female never smokers. | [15] |
RB1 | [15] | ||
UBA1 | Ubiquitin pathways | Mutations in UBA1 occurred before the corresponding copy number gain. | [1] |
ARID1A | PI3K/AKT pathway | Mutations in ARID1A could promote exit from a quiescent cell state, resulting in high intra-tumoural heterogeneity. | [1] |
CTNNB1 | WNT pathway | Never smokers had a lower TMBs and a higher frequency of mutations in CTNNB1 compared with smokers. | |
BRCA1 | DNA repair | Germline alterations in the listed DNA repair genes were exclusively mutated in never smokers. | [3] |
BRCA2 | |||
FANCG | |||
FANCM | |||
MSH6 | |||
POLD1 | |||
RNF213 | WNT pathway | Somatic mutations were identified as prevalent in Taiwanese study of never smoker lung adenocarcinoma patients. | [16] |
ATP2B3 | [16] | ||
TET2 | [16] | ||
EGFR-Related Mutations | |||
KRAS | RTK–Ras pathway | EGFR and KRAS mutations were mutually exclusive (p = 0.004) | [1] |
Mutations in KRAS were generally early events occurring prior to whole-genome doubling and most other somatic copy number alterations. | [1] | ||
ALK | 6.0% alteration in RTK–Ras pathway. | [1] | |
Never smoker lung adenocarcinomas had a higher proportion of ALK mutations (12%) than former/current smokers (2%) (p < 0.0001). | [17] | ||
MET | 4.3% alteration in RTK–Ras pathway. | [1] | |
ERBB2 | 3.9%, all indels alteration in RTK–Ras pathway. | [1] | |
ROS1 | 2.6% alteration in RTK–Ras pathway. | [1] | |
RET | 1.3% alteration in RTK–Ras pathway. | [1] | |
EGFR | Higher frequency of EGFR mutations in female (31.4%) than in male patients (19.3%) (p = 0.092). | [1] | |
Somatic mutations occurred in 85% of Taiwanese never smoker lung adenocarcinoma patients. | [16] | ||
Statistically significant between NS and CS LUAD (p < 0.005). | [9] | ||
Mutations in EGFR were generally early events occurring prior to whole-genome doubling and most other somatic copy number alterations. | [1] | ||
Never smoker lung adenocarcinomas had a higher proportion of EGFR mutations 37% than former/current smokers 14% (p < 0.0001). | [17] | ||
Erα expression was correlated with the presence of an EGFR mutation in female never smokers. | [18] | ||
RBM10 | Mutations in RBM10 were generally early events occurring prior to whole-genome doubling and most other somatic copy number alterations. | [1] | |
Top ranking mutations in 20% of Taiwanese never smoker lung adenocarcinoma patients. | [16] | ||
TP53 | Top-ranking mutations in 33% of Taiwanese never smoker lung adenocarcinoma patients. | [1] | |
Mutations in TP53 were generally early events occurring prior to whole-genome doubling and most other somatic copy number alterations. | [1] | ||
SETD2 | Significant enrichment of SETD2 mutations in samples with oncogene fusions, particularly in TP53-proficient tumours (p = 0.06). | [1] |
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Hamouz, M.; Hammouz, R.Y.; Bajwa, M.A.; Alsayed, A.W.; Orzechowska, M.; Bednarek, A.K. A Functional Genomics Review of Non-Small-Cell Lung Cancer in Never Smokers. Int. J. Mol. Sci. 2023, 24, 13314. https://doi.org/10.3390/ijms241713314
Hamouz M, Hammouz RY, Bajwa MA, Alsayed AW, Orzechowska M, Bednarek AK. A Functional Genomics Review of Non-Small-Cell Lung Cancer in Never Smokers. International Journal of Molecular Sciences. 2023; 24(17):13314. https://doi.org/10.3390/ijms241713314
Chicago/Turabian StyleHamouz, Mohammad, Raneem Y. Hammouz, Muhammad Ahmed Bajwa, Abdelrahman Waleed Alsayed, Magdalena Orzechowska, and Andrzej K. Bednarek. 2023. "A Functional Genomics Review of Non-Small-Cell Lung Cancer in Never Smokers" International Journal of Molecular Sciences 24, no. 17: 13314. https://doi.org/10.3390/ijms241713314