Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families
Abstract
:1. Introduction
2. Methods
2.1. Participants and Selection Criteria
2.2. Multi-Gene Panel Testing by NGS
2.3. Measures of Genomic Instability by HRD
2.4. Statistical Analysis
3. Result
3.1. Patients’ Characteristics of the Cohort
3.2. Clinicopathological Characteristics of RAD51C/D Mutations Carriers
3.3. RAD51C/D Mutations
3.4. Homologous Recombination Deficiency (HRD)
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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RAD51C/D+ | Negative | Total | p-Value | ||||
---|---|---|---|---|---|---|---|
N= | 18 | N= | 3710 | N= | 3728 | ||
Pathogenic Mutation | |||||||
RAD51C+ | 5 | 27.8% | |||||
RAD51D+ | 13 | 72.2% | |||||
Gender | |||||||
F | 18 | 100.0% | 3647 | 98.3% | 3665 | 98.3% | 1 |
M | 0 | 0.0% | 63 | 1.7% | 63 | 1.7% | |
Cancer Type | |||||||
Breast Cancer | 12 | 66.7% | 3135 | 84.5% | 3147 | 84.4% | 0.0761 |
Ovarian Cancers | 5 | 27.8% | 480 | 12.9% | 485 | 13.0% | |
Breast & Ovarian Cancer | 1 | 5.6% | 95 | 2.6% | 96 | 2.6% | |
Dx Age (Breast Cancer) | |||||||
Median (Range) | 41 (29–72) | 44 (18–95) | 44 (18–95) | 0.4050 | |||
<45 | 8 | 61.5% | 1716 | 53.1% | 1724 | 53.2% | 0.5903 |
≥45 | 5 | 38.5% | 1514 | 46.9% | 1519 | 46.8% | |
Dx Age (Ovarian Cancer) | |||||||
Median (Range) | 45.5 (36–61) | 48 (9–79) | 48 (9–79) | 0.8800 | |||
<45 | 3 | 50.0% | 199 | 34.6% | 202 | 34.8% | 0.4238 |
≥45 | 3 | 50.0% | 376 | 65.4% | 379 | 65.2% | |
Bilateral Breast Cancer | |||||||
Y | 5 | 38.5% | 572 | 17.7% | 577 | 17.8% | 0.0648 |
N | 8 | 61.5% | 2658 | 82.3% | 2666 | 82.2% | |
Family History (1st & 2nd Degree) | |||||||
Breast CA | 7 | 38.9% | 1310 | 35.3% | 1317 | 35.3% | 0.8064 |
Ovarian CA | 2 | 11.1% | 149 | 4.0% | 151 | 4.1% | 0.1636 |
Characteristics of Breast Cancer | N= | 18 | N= | 3779 | N= | 3797 | |
Histology | |||||||
Ductal | 17 | 94.4% | 2688 | 72.6% | 2705 | 72.7% | 0.1404 |
In-situ | 1 | 5.6% | 657 | 17.7% | 658 | 17.7% | |
Others | 0 | 0.0% | 359 | 9.7% | 359 | 9.6% | |
NS | 0 | 75 | 75 | ||||
Grade | |||||||
1 | 3 | 18.8% | 502 | 19.2% | 505 | 19.2% | 0.0059 |
2 | 2 | 12.5% | 1226 | 46.9% | 1228 | 46.7% | |
3 | 11 | 68.8% | 886 | 33.9% | 897 | 34.1% | |
Stage | |||||||
0 | 1 | 5.6% | 691 | 19.3% | 692 | 19.2% | 0.0508 |
1 | 5 | 27.8% | 1305 | 36.4% | 1310 | 36.3% | |
2 | 7 | 38.9% | 1056 | 29.4% | 1063 | 29.5% | |
3 | 2 | 11.1% | 408 | 11.4% | 410 | 11.4% | |
4 | 3 | 16.7% | 128 | 3.6% | 131 | 3.6% | |
NS | 0 | 191 | 191 | ||||
T | |||||||
T0 | 2 | 11.1% | 726 | 20.4% | 728 | 20.3% | 0.1819 |
T1 | 7 | 38.9% | 1700 | 47.7% | 1707 | 47.6% | |
T2 | 7 | 38.9% | 997 | 28.0% | 1004 | 28.0% | |
T3 | 1 | 5.6% | 95 | 2.7% | 96 | 2.7% | |
T4 | 1 | 5.6% | 48 | 1.3% | 49 | 1.4% | |
NS | 0 | 213 | 213 | ||||
N | |||||||
N0 | 11 | 64.7% | 2445 | 68.6% | 2456 | 68.5% | 0.2180 |
N1 | 4 | 23.5% | 728 | 20.4% | 732 | 20.4% | |
N2 | 0 | 0.0% | 260 | 7.3% | 260 | 7.3% | |
N3 | 2 | 11.8% | 133 | 3.7% | 135 | 3.8% | |
NS | 1 | 213 | 214 | ||||
ER | |||||||
Pos | 11 | 64.7% | 2583 | 75.4% | 2594 | 75.4% | 0.3945 |
Neg | 6 | 35.3% | 841 | 24.6% | 847 | 24.6% | |
NS | 1 | 355 | 356 | ||||
PR | |||||||
Pos | 8 | 50.0% | 2178 | 64.3% | 2186 | 64.3% | 0.2955 |
Neg | 8 | 50.0% | 1207 | 35.7% | 1215 | 35.7% | |
NS | 2 | 394 | 396 | ||||
Her2 | |||||||
Pos | 2 | 12.5% | 772 | 24.0% | 774 | 24.0% | 0.6037 |
Equivocal | 1 | 6.3% | 258 | 8.0% | 259 | 8.0% | |
Neg | 13 | 81.3% | 2180 | 67.9% | 2193 | 68.0% | |
NS | 2 | 569 | 571 | ||||
TNBC | |||||||
Yes | 5 | 31.3% | 401 | 13.9% | 406 | 14.0% | 0.0611 |
No | 11 | 68.8% | 2485 | 86.1% | 2496 | 86.0% | |
Characteristics of Ovarian Cancer | N= | 6 | N= | 575 | N= | 581 | |
Site of Cancer | |||||||
Ovarian | 5 | 83.3% | 503 | 88.1% | 508 | 88.0% | 0.2093 |
Fallopian Tube | 0 | 0.0% | 11 | 1.9% | 11 | 1.9% | |
Peritoneal | 0 | 0.0% | 29 | 5.1% | 29 | 5.0% | |
Uterus | 0 | 0.0% | 19 | 3.3% | 19 | 3.3% | |
Mixed | 1 | 16.7% | 9 | 1.6% | 10 | 1.7% | |
NS | 0 | 4 | |||||
Histology | |||||||
Epithelial | 5 | 100.0% | 513 | 96.1% | 518 | 96.1% | 1 |
Germ Cell | 0 | 0.0% | 7 | 1.3% | 7 | 1.3% | |
Stromal | 0 | 0.0% | 5 | 0.9% | 5 | 0.9% | |
Others | 0 | 0.0% | 1 | 0.2% | 1 | 0.2% | |
Mixed | 0 | 0.0% | 8 | 1.5% | 8 | 1.5% | |
NS | 1 | 41 | 42 | ||||
Epithelial Subtype | |||||||
Serous | 5 | 100% | 160 | 30.7% | 165 | 31.2% | 0.1008 |
Mucinous | 0 | 0% | 54 | 10.4% | 54 | 10.3% | |
Endometrioid | 0 | 0% | 175 | 33.6% | 175 | 33.3% | |
Clear cell | 0 | 0% | 102 | 19.6% | 102 | 19.4% | |
Mixed | 0 | 0% | 19 | 3.6% | 19 | 3.6% | |
Others | 0 | 0% | 11 | 2.1% | 11 | 2.1% | |
Grade | |||||||
0 | 0 | 0.0% | 12 | 2.3% | 12 | 2.3% | 0.3903 |
1 | 0 | 0.0% | 65 | 12.7% | 65 | 12.6% | |
2 | 0 | 0.0% | 139 | 27.1% | 139 | 26.9% | |
3 | 5 | 100.0% | 288 | 56.3% | 293 | 56.7% | |
Mixed | 0 | 0.0% | 8 | 1.6% | 8 | 1.5% | |
NS | 1 | 63 | 64 | ||||
Stage | |||||||
1 | 0 | 0.0% | 267 | 51.4% | 267 | 50.9% | 0.0117 |
2 | 1 | 16.7% | 69 | 13.3% | 70 | 13.3% | |
3 | 3 | 50.0% | 139 | 26.8% | 142 | 27.0% | |
4 | 2 | 33.3% | 44 | 8.5% | 46 | 8.8% | |
NS | 0 | 56 | 56 |
Gene | Mutation Variants | Probands | Dx | Personal Cancer | HRD Status * (LOH Score) | Breast Histology | Ovarian Histology | Breast Cancer Risk for FM # | Other Germline Mutations | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Histo | ER | PR | HER2 | Grade | Histo | Lifetime Risk from Age 20 | Risk at Ages 40 and 50 | |||||||
RAD51C | c.394dupA; p.Thr132Asnfs*23 | 001 | 43 | Breast | ^ QC failed | Ductal | Pos | Pos | Neg | -- | -- | 26.4% (M) | 4.8% (M) | BRCA2 VUS c.2405A > G; p.(Asn802Ser) |
002 | 61 | Ovarian | Pos (0.46) | -- | -- | -- | -- | High | Serous | 23.8% (M) | 4.1% (M) | -- | ||
003 | 47 | Breast | Pos (0.49) | Ductal | Pos | Pos | Pos | -- | -- | 32.1% (H) | 6.7% (M) | -- | ||
004 | 47 72 74 | Ovarian Breast Breast | Pos (0.35) | DCIS IDC | Pos Pos | NA Pos | NA Neg | High | Serous | 21.4% (M) | 2.4% (P) | (Somatic) BRCA1 heterozygous deletion exons 4–6 | ||
c.1000_1003delinsTTTCC; p.Glu334Phefs*14 | 005 | 44 | Ovarian | Pos (0.4) | -- | -- | -- | -- | High | Serous | 16.6% (P) | 2.4% (P) | BRCA1 VUS c.5068A > C; p.(Lys1690Gln) | |
RAD51D | c.270_271dupTA; p.Lys91Ilefs*13 | 006 | 41 50 | Breast Breast | ^ SNP frequency aberrant | Ductal Ductal | Neg Neg | Neg Neg | Neg Neg | -- | -- | 29.1% (M) | 5.8% (M) | -- |
007 | 33 | Breast | Pos (0.66) | Ductal | Neg | Neg | Neg | -- | -- | 25.2% (M) | 4.7% (M) | -- | ||
008 | 33 37 | Breast Breast | ^ SNP frequency aberrant | Ductal Ductal | Pos Pos | Pos Pos | Neg Pos | -- | -- | 32.8% (H) | 7% (M) | -- | ||
009 | 49 | Breast | ^ SNP frequency aberrant | Ductal | Neg | Neg | Neg | -- | -- | 23.5% (M) | 4.2% (M) | -- | ||
010 | 59 | Ovarian | ^ SNP frequency aberrant | -- | -- | -- | -- | High | Serous | 13.8% (P) | 1.8% (P) | BRCA1 VUS c.2347A > G; p.(Ile783Val)BARD1 VUS c.539A > G; p.(Tyr180Cys) | ||
011 | 30 | Breast | ^ Not Done | Ductal | Pos | Neg | Neg | -- | -- | 25.2% (M) | 4.7% (M) | -- | ||
012 | 36 | Ovarian | Neg (0.34) | -- | -- | -- | -- | High | Serous | 15.5% (P) | 2.2% (M) | -- | ||
013 | 58 | Breast | Neg (0.017) | Ductal | Pos | Pos | Neg | -- | -- | 21.2% (M) | 3.8% (M) | MSH2 VUS c.1121A > G; p.(Gln374Arg) RAD51D VUS c.932T > A; p.(Ile311Asn) | ||
014 | 29 | Breast | Pos (0.58) | Ductal | Neg | Neg | Neg | -- | -- | 32.2% (H) | 6.8% (M) | BRCA2 VUS c.2239G>A; p.(Glu747Lys) | ||
015 | 40 | Breast | Pos (0.48) | Ductal | Pos | Neg | Neg | -- | -- | 32% (H) | 6.7% (M) | -- | ||
016 | 56 64 | Breast Breast | Pos (0.67) | Ductal Ductal | Neg Pos | Neg Pos | Pos Neg | -- | -- | 31.8% (H) | 6.1% (M) | BRCA1 VUS c.5068A > C; p.(Lys1690Gln) | ||
c.556C > T; p.Arg186* | 017 | 43 | Ovarian | Neg (0.36) | -- | -- | -- | -- | High | Serous | 14.1% (P) | 1.7% (P) | BRCA2 VUS c.2744C > G; p.(Thr915Ser) | |
c.801delC; p.Trp268Glyfs*42 | 018 | 38 38 | Breast Breast | Neg (0.28) | Ductal DCIS | Pos -- | Pos -- | Neg -- | -- | -- | 25.4% (M) | 4.7% (M) | -- |
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Kwong, A.; Ho, C.Y.S.; Au, C.H.; Tey, S.K.; Ma, E.S.K. Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families. J. Pers. Med. 2024, 14, 866. https://doi.org/10.3390/jpm14080866
Kwong A, Ho CYS, Au CH, Tey SK, Ma ESK. Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families. Journal of Personalized Medicine. 2024; 14(8):866. https://doi.org/10.3390/jpm14080866
Chicago/Turabian StyleKwong, Ava, Cecilia Yuen Sze Ho, Chun Hang Au, Sze Keong Tey, and Edmond Shiu Kwan Ma. 2024. "Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families" Journal of Personalized Medicine 14, no. 8: 866. https://doi.org/10.3390/jpm14080866