Detection of TP53 and PIK3CA Mutations in Circulating Tumor DNA Using Next-Generation Sequencing in the Screening Process for Early Breast Cancer Diagnosis
Abstract
:1. Introduction
2. Experimental Section
2.1. Study Design and Patient Population
2.2. DNA Extraction
2.3. Targeted Sequencing
2.4. Plasma DNA Sequencing (SafeSEQ)
2.5. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. Analysis of PIK3CA and TP53 Mutations in Fresh Frozen Tissue Samples of Primary Breast
3.3. PIK3CA and TP53 Mutations Detected in ctDNA
3.4. Comparison of PIK3CA and TP53 Mutations Detection Results from Tumor Tissue and ctDNA
3.5. Clinicopathological Variables Associated with the Detectability of Tumor-Derived PIK3CA and TP53 Mutations in Blood
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
BC | Breast cancer; |
BIRADS | Breast Imaging-Reporting and Data System; |
ctDNA | Circulating tumor DNA; |
NGS | Next generation sequencing; |
TCGA | Cancer Genome; |
TP53 | tumor protein p53; |
PIK3CA | phosphatidylinositol-4;5-bisphosphate 3-kinase catalytic subunit alpha; |
dPCR | Digital-PCR; |
GIST | Gastrointestinal stromal tumors; |
IHC | Immunohistochemical; |
HER2 | human epidermal growth factor receptor 2; |
HR | Hormone receptors; |
ER | Estrogen receptor; |
PR | Progesterone receptor; |
SISH | Silver in situ hybridization; |
VAF | Variant allele frequency; |
CDI | Invasive ductal carcinoma; |
CLI | Invasive lobular carcinoma; |
EBV | Epstein–Barr Virus; |
OR | Odds ratio; |
CI | Confidence interval; |
COSMIC | Catalog of somatic mutations in cancer; |
CHIP | Clonal hematopoiesis of indeterminate potential |
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Diagnostic Age (years) Median (range) | 64 years (44–92) |
---|---|
Mammographic Tumor Size n (%) | |
<2 cm | 15 (51.7) |
2 to 5 cm | 13 (44.8) |
>5 cm | 1 (3.4) |
Tumor type | |
CDI | 24 (82.7) |
CLI | 2 (6.9) |
Papilar carcinoma | 2 (6.9) |
Tubular carcinoma | 1 (3.4) |
Tumor grade n (%) | |
I | 5 (17.2) |
II | 16 (55.2) |
III | 7 (24.13) |
Unknown | 1 (3.4) |
Axilar lymph node | |
Positive | 9 (31.3) |
Negative | 20 (68.9) |
Progesterone receptor n (%) | |
Positive | 12 (41.4) |
Negative | 17 (58.6) |
Estrogen receptor n (%) | |
Positive | 25 (86.20) |
Negative | 4 (13.79) |
HER2 status n (%) | |
Positive | 1 (3.4) |
Negative | 28 (96.6) |
IHC subtype n (%) | |
Luminal A tumor | 14 (48.3) |
Luminal B tumor | 11 (37.9) |
HER2-positive tumor | 1 (3.4) |
Triple negative tumor | 3 (10.3) |
BIRADS category | |
4c | 14 (48.3) |
5 | 15 (51.7) |
Patient ID | Gene | HGVS | Protein | Chr | hg19 | Tumor VAF (%) | COSMIC |
---|---|---|---|---|---|---|---|
2MS | PIK3CA | c.3140A > T | p.H1047L | 3 | 178952085 | 31.2 | COSM776 |
2MS | TP53 | c.524G > A | p.R175H | 17 | 7578406 | 58.3 | COSM10648 |
7MS | PIK3CA | c.3140A > G | p.H1047R | 3 | 178952085 | 31 | COSM775 |
9MS | TP53 | c.637C > T | p.R213Ter | 17 | 7578212 | 46.9 | COSM10654 |
10MS | PIK3CA | c.3140A > G | p.H1047R | 3 | 178952085 | 17 | COSM775 |
13MS | TP53 | c.398T > A | p.M133K | 17 | 7578532 | 75.2 | COSM11781 |
14MS | PIK3CA | c.3140A > G | p.H1047R | 3 | 178952085 | 25.3 | COSM775 |
16MS | PIK3CA | c.3140A > T | p.H1047L | 3 | 178952085 | 28.2 | COSM776 |
16MS | TP53 | c.743G > T | p.R248L | 17 | 7577538 | 43.1 | COSM6549 |
17MS | PIK3CA | c.3140A > G | p.H1047R | 3 | 178952085 | 30.1 | COSM775 |
19MS | PIK3CA | c.1624G > A | p.E542K | 3 | 178936082 | 47.7 | COSM760 |
22MS | TP53 | c.1028_1029delAG | p.E343AfsTer3 | 17 | 7573997 | 73.5 | COSM5752326 |
23MS | PIK3CA | c.1633G > A | p.E545K | 3 | 178936091 | 30.6 | COSM763 |
23MS | TP53 | c.524G > A | p.R175H | 17 | 7578406 | 68.9 | COSM10648 |
30MS | PIK3CA | c.1633G > A | p.E545K | 3 | 178936091 | 56.2 | COSM763 |
31MS | PIK3CA | c.1633G > A | p.E545K | 3 | 178936091 | 10.6 | COSM763 |
32MS | PIK3CA | c.3140A > G | p.H1047R | 3 | 178952085 | 12.7 | COSM775 |
35MS | PIK3CA | c.1633G > A | p.E545K | 3 | 178936091 | 28.9 | COSM763 |
36MS | PIK3CA | c.3140A > T | p.H1047L | 3 | 178952085 | 44.9 | COSM776 |
40MS | PIK3CA | c.1624G > A | p.E542K | 3 | 178936082 | 25.5 | COSM760 |
41MS | TP53 | c.832C > T | p.P278S | 17 | 7577106 | 29.1 | COSM10939 |
43MS | TP53 | c.734G > T | p.G245V | 17 | 7577547 | 45.3 | COSM11196 |
44MS | TP53 | c.587G > C | p.R196P | 17 | 7578262 | 35.8 | COSM43814 |
47MS | PIK3CA | c.3140A > G | p.H1047R | 3 | 178952085 | 10.6 | COSM775 |
50MS | PIK3CA | c.3129G > A | p.M1043I | 3 | 178952074 | 33.4 | COSM29313 |
50MS | PIK3CA | c.3130A > C | p.N1044H | 3 | 178952075 | 33.4 | ----- |
52MS | PIK3CA | c.1637A > G | p.Q546R | 3 | 178936095 | 11.6 | COSM12459 |
56MS | PIK3CA | c.1624G > A | p.E542K | 3 | 178936082 | 16.9 | COSM760 |
65MS | PIK3CA | c.3140A > G | p.H1047R | 3 | 178952085 | 23.6 | COSM775 |
67MS | PIK3CA | c.3145G > C | p.G1049R | 3 | 178952090 | 82.4 | COSM12597 |
67MS | TP53 | c.842A > C | p.D281A | 17 | 7577096 | 44.6 | COSM11665 |
68MS | PIK3CA | c.3140A > G | p.H1047R | 3 | 178952085 | 15.9 | COSM775 |
79MS | PIK3CA | c.1637A > G | p.Q546R | 3 | 178936095 | 7.4 | COSM12459 |
80MS | PIK3CA | c.1633G > A | p.E545K | 3 | 178936091 | 29.5 | COSM763 |
Patient ID | Gene | HGVS | SafeSEQ VAF (%) | Protein | hg19 | COSMIC |
---|---|---|---|---|---|---|
7MS | PIK3CA | c.3140A > G | 0.14% | p.H1047R | 178952085 | COSM775 |
9MS | TP53 | c.637C > T | 0.91% | p.R213Ter | 7578212 | COSM10654 |
13MS | TP53 | c.398T > A | 20.56% | p.M133K | 7578532 | COSM11781 |
16MS | PIK3CA | c.3140A > T | 3.60% | p.H1047L | 178952085 | COSM776 |
16MS | TP53 | c.743G > T | 2.11% | p.R248L | 7577538 | COSM6549 |
30MS | PIK3CA | c.1651C > A | 0.17% | p.L551I | 178936109 | ---- |
30MS | PIK3CA | c.1633G > A | 0.05% | p.E545K | 178936091 | COSM763 |
10MS | TP53 | c.641A > G | 3.88% | p.H214R | 7578208 | COSM43687c |
10MS | TP53 | c.748C > T | 0.09% | p.P250S | 7577533 | COSM43695c |
31MS | TP53 | c.659A > G | 0.16% | p.Y220C | 7578190 | COSM10758c |
40MS | PIK3CA | c.1624G > A | 0.20% | p.E542K | 178936082 | COSM760 |
44MS | TP53 | c.587G > C | 1.03% | p.R196P | 7578262 | COSM43814 |
67MS | PIK3CA | c.3145G > C | 0.39% | p.G1049R | 178952090 | COSM12597 |
Patient ID | Diagnostic Mammography | Markers | Type | Gene | HGVS | SafeSEQ VAF (%) | Protein | Tumor VAF (%) | COSMIC | Chr |
---|---|---|---|---|---|---|---|---|---|---|
13MS | IDC, grade 3 | ER+/HER2+ | Luminal B | TP53 | c.398T > A | 20.56 | p.M133K | 75.2 | COSM11781 | 17 |
16MS | IDC, grade 3 | ER+/HER2+ | Luminal B | PIK3CA | c.3140A > T | 3.60 | p.H1047L | 28.2 | COSM776 | 3 |
16MS | IDC, grade 3 | ER+/HER2+ | Luminal B | TP53 | c.743G > T | 2.11 | p.R248L | 43.1 | COSM6549 | 17 |
44MS | IDC, grade 3 | ER+/HER2+ | Luminal B | TP53 | c.587G > C | 1.03 | p.R196P | 35.8 | COSM43814 | 17 |
9MS | IDC, grade 3 | ER-/PR-/HER2- | Triple negative | TP53 | c.637C > T | 0.91 | p.R213Ter | 46.9 | COSM10654 | 17 |
67MS | IDC, grade 2 | ER+/HER2− | Luminal A | PIK3CA | c.3145G > C | 0.39 | p.G1049R | 82.4 | COSM12597 | 3 |
7MS | IDC, grade 2 | ER+/HER2− | Luminal A | PIK3CA | c.3140A > G | 0.14 | p.H1047R | 31 | COSM775 | 3 |
30MS | IDC, grade 2 | ER+/HER2− | Luminal A | PIK3CA | c.1633G > A | 0.05 | p.E545K | 56.2 | COSM763 | 3 |
40MS | IDC, grade 1 | ER+/HER2+ | Luminal B | PIK3CA | c.1624G > A | 0.20 | p.E542K | 25.5 | COSM760 | 3 |
Characteristics | Total | ctDNA-Positive b | * p Value |
---|---|---|---|
n | n (%) | ||
Diagnostic age (years) | 0.040 | ||
<36 | 9 | 7 (77.8) | |
36–50 | 10 | 4 (40) | |
>66 | 10 | 2 (20) | |
Tumor size | 0.033 | ||
<2 cm | 15 | 2 (13.3) | |
2 to 5 cm | 13 | 10 (76.9) | |
>5 cm | 1 | 1 (10) | |
Tumor grade | 0.041 | ||
I | 5 | 1 (20) | |
II | 16 | 6 (37.5) | |
III | 7 | 6 (85.7) | |
Unknown | 1 | 0 (0) | |
Axilar lymph node | <0.001 | ||
Positive | 9 | 9 (100) | |
Negative | 20 | 4 (20) | |
Progesterone receptor | 0.615 | ||
Positive | 12 | 5 (41.7) | |
Negative | 17 | 8 (47) | |
Estrogen receptor | 0.571 | ||
Positive | 25 | 12 (48) | |
Negative | 4 | 1 (25) | |
HER2 status | 0.655 | ||
Positive | 1 | 1 (10) | |
Negative | 28 | 12 (42.8) | |
IHC subtype | 0.033 | ||
Luminal A tumor | 14 | 7 (50) | |
Luminal B tumor | 11 | 5 (45.4) | |
HER2-positive tumor | 1 | 0 (0) | |
Triple-negative | 3 | 1 (33.3) | |
BIRADS category | 0.004 | ||
4 | 14 | 1 (7.1) | |
5c | 15 | 12 (80) | |
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Share and Cite
Jimenez Rodriguez, B.; Diaz Córdoba, G.; Garrido Aranda, A.; Álvarez, M.; Vicioso, L.; Llácer Pérez, C.; Hernando, C.; Bermejo, B.; Julve Parreño, A.; Lluch, A.; et al. Detection of TP53 and PIK3CA Mutations in Circulating Tumor DNA Using Next-Generation Sequencing in the Screening Process for Early Breast Cancer Diagnosis. J. Clin. Med. 2019, 8, 1183. https://doi.org/10.3390/jcm8081183
Jimenez Rodriguez B, Diaz Córdoba G, Garrido Aranda A, Álvarez M, Vicioso L, Llácer Pérez C, Hernando C, Bermejo B, Julve Parreño A, Lluch A, et al. Detection of TP53 and PIK3CA Mutations in Circulating Tumor DNA Using Next-Generation Sequencing in the Screening Process for Early Breast Cancer Diagnosis. Journal of Clinical Medicine. 2019; 8(8):1183. https://doi.org/10.3390/jcm8081183
Chicago/Turabian StyleJimenez Rodriguez, Begona, Gema Diaz Córdoba, Alicia Garrido Aranda, Martina Álvarez, Luis Vicioso, Casilda Llácer Pérez, Cristina Hernando, Begoña Bermejo, Ana Julve Parreño, Ana Lluch, and et al. 2019. "Detection of TP53 and PIK3CA Mutations in Circulating Tumor DNA Using Next-Generation Sequencing in the Screening Process for Early Breast Cancer Diagnosis" Journal of Clinical Medicine 8, no. 8: 1183. https://doi.org/10.3390/jcm8081183
APA StyleJimenez Rodriguez, B., Diaz Córdoba, G., Garrido Aranda, A., Álvarez, M., Vicioso, L., Llácer Pérez, C., Hernando, C., Bermejo, B., Julve Parreño, A., Lluch, A., Ryder, M. B., Jones, F. S., Fredebohm, J., Holtrup, F., Queipo-Ortuño, M. I., & Alba, E. (2019). Detection of TP53 and PIK3CA Mutations in Circulating Tumor DNA Using Next-Generation Sequencing in the Screening Process for Early Breast Cancer Diagnosis. Journal of Clinical Medicine, 8(8), 1183. https://doi.org/10.3390/jcm8081183