Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study
Abstract
:1. Introduction
2. Results
2.1. Patients Characteristics
2.2. Germline Variant Spectrum
2.3. Association between Deleterious Germline Variants and Clinicopathological Characteristics
2.3.1. Association between Deleterious Germline Variants and Age at the Initial Diagnosis of BC
2.3.2. Association between Deleterious Germline Variants and Family History of Cancer
2.3.3. Association between Deleterious Germline Variants and Molecular Subtype of BC
2.3.4. Association between Deleterious Germline Variants and Hereditary Risk
3. Discussion
4. Materials and Methods
4.1. Patients and Clinicopathological Factors
4.2. Hereditary High Risk Assessment
4.3. DNA Extraction
4.4. NGS Assay and Variant Classification
4.5. Statistical Analysis
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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Characteristics | No. | % |
---|---|---|
Gender | ||
Female | 695 | 99.3 |
Male | 5 | 0.7 |
Nationality | ||
Han | 696 | 99.4 |
Mongolian | 2 | 0.3 |
Uyghur | 2 | 0.3 |
Age at the initial diagnosis of BC | ||
<35 | 84 | 12.0 |
35–44 | 186 | 26.6 |
45–54 | 168 | 24.0 |
55–64 | 144 | 20.6 |
≥65 | 118 | 16.9 |
Family history 1 | ||
No | 487 | 69.6 |
Yes | 213 | 30.4 |
Personal history of cancer 2 | ||
No | 675 | 96.4 |
Yes | 25 | 3.6 |
Hereditary risk 3 | ||
Low | 304 | 43.4 |
High | 396 | 56.6 |
Laterality of BC | ||
Unilateral | 673 | 96.1 |
Bilateral | 27 | 3.9 |
Histology type | ||
DCIS | 59 | 8.4 |
Ductal | 534 | 76.3 |
Lobular | 19 | 2.7 |
Mixed | 57 | 8.1 |
Other 4 | 31 | 4.4 |
Histology grade | ||
I | 45 | 6.4 |
II | 390 | 55.7 |
III | 185 | 26.4 |
UNK | 80 | 11.4 |
Tumor stage | ||
Tis | 59 | 8.4 |
T1 | 327 | 46.7 |
T2 | 266 | 38.0 |
T3–T4 | 48 | 6.9 |
Nodal status | ||
Negative | 419 | 59.9 |
Positive | 281 | 40.1 |
TNM stage | ||
0 | 59 | 8.4 |
I | 222 | 31.7 |
II | 301 | 43.0 |
III | 93 | 13.3 |
IV | 25 | 3.6 |
Molecular subtype | ||
HR+Her2− | 399 | 57.0 |
HR+Her2+ | 70 | 10.0 |
HR−Her2+ | 67 | 9.6 |
HR−Her2− | 164 | 23.4 |
Ki-67 Index | ||
≤20% | 374 | 53.4 |
>20% | 326 | 46.6 |
Criteria of Hereditary High Risk | No. (%) | |
---|---|---|
C.1 | Diagnosed with breast cancer at age ≤ 45 years. | 288 (41.1) |
C.2 | Diagnosed with breast cancer at age 46–50 years with one of the following: | 12 (1.7) |
(1) A second breast cancer diagnosed at any age; | ||
(2) ≥1 close blood relative with BRCA-related cancer 1 at any age. | ||
C.3 | ≥1 close blood relative diagnosed with BRCA-related cancer 1 at age ≤ 50 years. | 54 (7.7) |
C.4 | ≥2 Non-close blood relatives diagnosed with BRCA-related 1 cancer at any age. | 9 (1.3) |
C.5 | Diagnosed at age ≤ 60 years with triple-negative breast cancer. | 120 (17.1) |
C.6 | Diagnosed at any age with male breast cancer. | 5 (0.7) |
C.7 | Diagnosed at any age with BRCA-related cancer 1. | 5 (0.7) |
Characteristics | No. | Panel-Gene Variants | HRR-Gene Variants | BRCA1/2 Variants | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Carrier n = 92 | Non-Carrier n = 608 | p | Carrier n = 89 | Non-Carrier n = 611 | p | Carrier n = 66 | Non-Carrier n = 634 | p | ||
Gender (%) | ||||||||||
Female | 695 | 91 (98.9) | 604 (99.3) | 1.000 | 88 (98.9) | 607 (99.3) | 1.000 | 66 (100.0) | 629 (99.2) | 1.000 |
Male | 5 | 1 (1.1) | 4 (0.7) | 1 (1.1) | 4 (0.7) | 0 (0.0) | 5 (0.8) | |||
Nationality (%) | ||||||||||
Han | 696 | 92 (100.0) | 604 (99.3) | NA | 89 (100.0) | 607 (99.3) | NA | 66 (100.0) | 630 (99.4) | NA |
Mongolian | 2 | 0 (0.0) | 2 (0.3) | 0 (0.0) | 2 (0.3) | 0 (0.0) | 2 (0.3) | |||
Uyghur | 2 | 0 (0.0) | 2 (0.3) | 0 (0.0) | 2 (0.3) | 0 (0.0) | 2(0.3) | |||
Age (%) | ||||||||||
<35 | 84 | 21 (22.8) | 63 (10.4) | <0.001 | 21 (23.6) | 63 (10.3) | <0.001 | 19 (28.8) | 65 (10.3) | <0.001 |
35–44 | 186 | 29 (31.5) | 157 (25.8) | 26 (29.2) | 160 (26.2) | 22 (33.3) | 164 (25.9) | |||
45–54 | 168 | 24 (26.1) | 144 (23.7) | 24 (27.0) | 144 (23.6) | 17 (25.8) | 151 (23.8) | |||
55–64 | 144 | 13 (14.1) | 131 (21.5) | 13 (14.6) | 131 (21.4) | 6 (9.1) | 138 (21.8) | |||
≥65 | 118 | 5 (5.4) | 113 (18.6) | 5 (5.6) | 113 (18.5) | 2 (3.0) | 116 (18.3) | |||
Family history 1 (%) | ||||||||||
No | 487 | 54 (58.7) | 433 (71.2) | 0.021 | 53 (59.6) | 434 (71.0) | 0.038 | 36 (54.5) | 451 (71.1) | 0.008 |
Yes | 213 | 38 (41.3) | 175 (28.8) | 36 (40.4) | 177 (29.0) | 30 (45.5) | 183 (28.9) | |||
Personal history of cancer 2 (%) | ||||||||||
No | 675 | 88 (95.7) | 587 (96.5) | 0.897 | 86 (96.6) | 589 (96.4) | 1.000 | 64 (97.0) | 611 (96.4) | 1.000 |
Yes | 25 | 4 (4.3) | 21 (3.5) | 3 (3.4) | 22 (3.6) | 2 (3.0) | 23 (3.6) | |||
Hereditary risk 3 (%) | ||||||||||
Low | 304 | 20 (21.7) | 284 (46.7) | <0.001 | 20 (22.5) | 284 (46.5) | <0.001 | 10 (15.2) | 294 (46.4) | <0.001 |
High | 396 | 72 (78.3) | 324 (53.3) | 69 (77.5) | 327 (53.5) | 56 (84.8) | 340 (53.6) | |||
Laterality (%) | ||||||||||
Unilateral | 673 | 88 (95.7) | 585 (96.2) | 0.896 | 86 (96.6) | 587 (96.1) | 0.899 | 64 (97.0) | 609 (96.1) | 0.877 |
Bilateral | 27 | 4 (4.3) | 23 (3.8) | 3 (3.4) | 24 (3.9) | 2 (3.0) | 25 (3.9) | |||
Histology type (%) | ||||||||||
DCIS | 59 | 4 (4.3) | 55 (9.0) | 0.589 | 4 (4.5) | 55 (9.0) | 0.637 | 4 (6.1) | 55 (8.7) | 0.773 |
Ductal | 534 | 74 (80.4) | 460 (75.7) | 71 (79.8) | 463 (75.8) | 51 (77.3) | 483 (76.2) | |||
Lobular | 19 | 3 (3.3) | 16 (2.6) | 3 (3.4) | 16 (2.6) | 3 (4.5) | 16 (2.5) | |||
Mixed | 57 | 8 (8.7) | 49 (8.1) | 8 (9.0) | 49 (8.0) | 6 (9.1) | 51 (8.0) | |||
Other 4 | 31 | 3 (3.3) | 28 (4.6) | 3 (3.4) | 28 (4.6) | 2 (3.0) | 29 (4.6) | |||
Histology grade (%) | ||||||||||
I | 45 | 2 (2.2) | 43 (7.1) | 0.115 | 2 (2.2) | 43 (7.0) | 0.144 | 1 (1.5) | 44 (6.9) | 0.131 |
II | 390 | 53 (57.6) | 337 (55.4) | 51 (57.3) | 339 (55.5) | 37 (56.1) | 353 (55.7) | |||
III | 185 | 30 (32.6) | 155 (25.5) | 29 (32.6) | 156 (25.5) | 23 (34.8) | 162 (25.6) | |||
UNK | 80 | 7 (7.6) | 73 (12.0) | 7 (7.9) | 73 (11.9) | 5 (7.6) | 75 (11.8) | |||
Tumor stage (%) | ||||||||||
Tis | 59 | 4 (4.3) | 55 (9.0) | 0.332 | 4 (4.5) | 55 (9.0) | 0.415 | 4 (6.1) | 55 (8.7) | 0.454 |
T1 | 327 | 41 (44.6) | 286 (47.0) | 40 (44.9) | 287 (47.0) | 27 (40.9) | 300 (47.3) | |||
T2 | 266 | 41 (44.6) | 225 (37.0) | 39 (43.8) | 227 (37.2) | 31 (47.0) | 235 (37.1) | |||
T3-T4 | 48 | 6 (6.5) | 42 (6.9) | 6 (6.7) | 42 (6.9) | 4 (6.1) | 44 (6.9) | |||
Nodal status (%) | ||||||||||
Negative | 419 | 47 (51.1) | 372 (61.2) | 0.084 | 46 (51.7) | 373 (61.0) | 0.092 | 33 (50.0) | 386 (60.9) | 0.133 |
Positive | 281 | 45 (48.9) | 236 (38.8) | 43 (48.3) | 238 (39.0) | 33 (50.0) | 248 (39.1) | |||
TNM stage (%) | ||||||||||
0 | 59 | 4 (4.3) | 55 (9.0) | 0.073 | 4 (4.5) | 55 (9.0) | 0.098 | 4 (6.1) | 55 (8.7) | 0.092 |
I | 222 | 25 (27.2) | 197 (32.4) | 24 (27.0) | 198 (32.4) | 15 (22.7) | 207 (32.6) | |||
II | 301 | 51 (55.4) | 250 (41.1) | 49 (55.1) | 252 (41.2) | 39 (59.1) | 262 (41.3) | |||
III | 93 | 11 (12.0) | 82 (13.5) | 11 (12.4) | 82 (13.4) | 7 (10.6) | 86 (13.6) | |||
IV | 25 | 1 (1.1) | 24 (3.9) | 1 (1.1) | 24 (3.9) | 1 (1.5) | 24 (3.8) | |||
Subtype (%) | ||||||||||
HR+Her2− | 399 | 46 (50.0) | 353 (58.1) | 0.001 | 46 (51.7) | 353 (57.8) | <0.001 | 33 (50.0) | 366 (57.7) | <0.001 |
HR+Her2+ | 70 | 6 (6.5) | 64 (10.5) | 6 (6.7) | 64 (10.5) | 4 (6.1) | 66 (10.4) | |||
HR−Her2+ | 67 | 4 (4.3) | 63 (10.4) | 2 (2.2) | 65 (10.6) | 1 (1.5) | 66 (10.4) | |||
HR−Her2− | 164 | 36 (39.1) | 128 (21.1) | 35 (39.3) | 129 (21.1) | 28 (42.4) | 136 (21.5) | |||
Ki-67 Index (%) | ||||||||||
≤20% | 374 | 31 (33.7) | 343 (56.4) | <0.001 | 31 (34.8) | 343 (56.1) | <0.001 | 20 (30.3) | 354 (55.8) | <0.001 |
>20% | 326 | 61 (66.3) | 265 (43.6) | 58 (65.2) | 268 (43.9) | 46 (69.7) | 280 (44.2) |
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Yang, L.; Xie, F.; Liu, C.; Zhao, J.; Hu, T.; Wu, J.; Zhao, X.; Wang, S. Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study. Int. J. Mol. Sci. 2022, 23, 11266. https://doi.org/10.3390/ijms231911266
Yang L, Xie F, Liu C, Zhao J, Hu T, Wu J, Zhao X, Wang S. Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study. International Journal of Molecular Sciences. 2022; 23(19):11266. https://doi.org/10.3390/ijms231911266
Chicago/Turabian StyleYang, Liu, Fei Xie, Chang Liu, Jin Zhao, Taobo Hu, Jinbo Wu, Xiaotao Zhao, and Shu Wang. 2022. "Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study" International Journal of Molecular Sciences 23, no. 19: 11266. https://doi.org/10.3390/ijms231911266
APA StyleYang, L., Xie, F., Liu, C., Zhao, J., Hu, T., Wu, J., Zhao, X., & Wang, S. (2022). Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study. International Journal of Molecular Sciences, 23(19), 11266. https://doi.org/10.3390/ijms231911266