Landscape of Germline Mutations in DNA Repair Genes for Breast Cancer in Latin America: Opportunities for PARP-Like Inhibitors and Immunotherapy
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. The Scope of Germline Mutations in Breast Cancer in LA Countries
3.2. Genes reported for HBC in LA countries
3.3. BRCA1 and BRCA2 Genes in LA countries
3.4. Non-BRCA Genes Reported in Breast Cancer in LA Countries
4. Biallelic Cases, Double Heterozygosity and Young Women in LA Countries
5. Therapy Recommendation for DNA Repair Related Genes
6. Conclusions
7. Take Home Messages
- BRCA1/2 are the most analyzed and studied genes in LA countries, few studies report non-BRCA gene status in breast cancer.
- In addition to BRCA1/2, non-BRCA genes provide information about the DNA repair capacity status.
- Targeted therapy such as immunotherapy and mainly PARP inhibitors are focused on DNA repair gene status for better response.
- Studies focusing on non-BRCA genes are needed in LA countries.
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Country | Total Retrieved Papers 1 | Germline Data 2 | BRCA1/2 Papers | Non-BRCA Papers | Total Papers | References | |
---|---|---|---|---|---|---|---|
1 | Brazil | 3290 | ✔ | 13 | 19 | 32 | [34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65] |
2 | Chile | 455 | ✔ | 7 | 7 | 14 | [66,67,68,69,70,71,72,73,74,75,76,77,78,79] |
3 | Mexico | 2014 | ✔ | 8 | 4 | 12 | [80,81,82,83,84,85,86,87,88,89,90,91] |
4 | Colombia | 274 | ✔ | 5 | 1 | 6 | [92,93,94,95,96,97] |
5 | Argentina | 893 | ✔ | 4 | 4 | [98,99,100,101] | |
6 | Peru | 161 | ✔ | 2 | 1 | 3 | [102,103,104] |
7 | Puerto Rico | 253 | ✔ | 2 | 1 | 3 | [105,106,107] |
8 | Uruguay | 126 | ✔ | 3 | 3 | [108,109,110] | |
9 | Costa Rica | 56 | ✔ | 2 | 2 | [111,112] | |
10 | Cuba | 142 | ✔ | 1 | 1 | [113] | |
11 | Venezuela | 76 | ✔ | 1 | 1 | [114] | |
12 | Ecuador | 42 | |||||
13 | Paraguay | 31 | |||||
14 | Panama | 23 | |||||
15 | Dominican Republic | 18 | |||||
16 | El Salvador | 16 | |||||
17 | Bolivia | 13 | |||||
18 | Guatemala | 8 | |||||
19 | Nicaragua | 7 | |||||
20 | Honduras | 2 | |||||
21 | Belize | 1 | |||||
Total | 7901 | 11 | 48 | 33 | 81 |
Gene | Number of Variants | Argentina | Brazil | Chile | Colombia | Costa Rica | Cuba | Mexico | Peru | Puerto Rico | Uruguay | Venezuela |
---|---|---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | 363 | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
BRCA1 | 329 | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ | ✔ |
ATM | 17 | ✔ | ✔ | ✔ | ✔ | |||||||
TP53 | 11 | ✔ | ✔ | ✔ | ||||||||
CHEK2 | 8 | ✔ | ✔ | ✔ | ✔ | |||||||
BARD1 | 6 | ✔ | ✔ | ✔ | ✔ | ✔ | ||||||
MLH1 | 6 | ✔ | ✔ | ✔ | ||||||||
PALB2 | 6 | ✔ | ✔ | |||||||||
BRIP1 | 5 | ✔ | ✔ | |||||||||
MSH2 | 4 | ✔ | ✔ | |||||||||
MSH6 | 4 | ✔ | ✔ | |||||||||
NBN | 4 | ✔ | ✔ | |||||||||
PMS2 | 4 | ✔ | ||||||||||
APC | 3 | ✔ | ||||||||||
ATR | 3 | ✔ | ✔ | |||||||||
BLM | 3 | ✔ | ||||||||||
RAD51C | 3 | ✔ | ✔ | ✔ | ||||||||
CDKN2A | 2 | ✔ | ||||||||||
ERCC1 | 2 | ✔ | ✔ | |||||||||
ERCC2 | 2 | ✔ | ✔ | ✔ | ||||||||
ERCC3 | 2 | ✔ | ||||||||||
FANCB | 2 | ✔ | ||||||||||
FANCI | 2 | ✔ | ||||||||||
LIG4 | 2 | ✔ | ||||||||||
MUTYH | 2 | ✔ | ||||||||||
RAD51B | 2 | ✔ | ✔ | |||||||||
RAD51D | 2 | ✔ | ✔ | |||||||||
XRCC1 | 2 | ✔ | ✔ | |||||||||
CDH1 | 1 | ✔ | ||||||||||
FANCC | 1 | ✔ | ||||||||||
FANCF | 1 | ✔ | ||||||||||
FANCL | 1 | ✔ | ||||||||||
FANCM | 1 | ✔ | ||||||||||
MSH3 | 1 | ✔ | ||||||||||
NF1 | 1 | ✔ | ||||||||||
POLH | 1 | ✔ | ||||||||||
POLQ | 1 | ✔ | ||||||||||
PTEN | 1 | ✔ | ||||||||||
RAD50 | 1 | ✔ | ||||||||||
RAD51 | 1 | ✔ | ✔ | |||||||||
RECQL4 | 1 | ✔ | ||||||||||
SMAD4 | 1 | ✔ | ||||||||||
WRN | 1 | ✔ | ||||||||||
XPC | 1 | ✔ | ||||||||||
XRCC3 | 1 | ✔ | ✔ |
Gene | rs | Exon | Argentina | Brazil | Chile | Colombia | Costa Rica | Cuba | Mexico | Peru | Puerto Rico | Uruguay | Venezuela |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
BRCA1 VARIANT | |||||||||||||
c.68_69delAG | rs386833395 | 2 | (4) | (4) | (2) | (1) | (1) | (1) | |||||
c.181T>G | rs28897672 | 5 | (1) | (4) | (1) | ||||||||
c.211A>G | rs80357382 | 5 | (2) | (3) | (1) | (3) | (1) | (1) | |||||
c.3113A>G | rs16941 | 11 | (1) | (3) | (2) | (1) | |||||||
c.3548A>G | rs16942 | 11 | (1) | (3) | (1) | (1) | |||||||
c.1067A>G | rs1799950 | 11 | 2 | (3) | (1) | ||||||||
c.3119G>A | rs4986852 | 11 | (1) | (3) | (1) | (1) | (1) | ||||||
c.2612C>T | rs799917 | 11 | (1) | (3) | (1) | ||||||||
c.3331_3334delCAAG | rs80357701 | 11 | (9) | (3) | (6) | ||||||||
c.4308C>T | rs1060915 | 13 | (1) | (2) | (1) | ||||||||
c.4837A>G | rs1799966 | 16 | (1) | (3) | (1) | (1) | |||||||
c.5123C>A | rs28897696 | 18 | (1) | (2) | (8) | (3) | |||||||
c.5266dupC | rs397507247 | 20 | (4) | (16) | (1) | (1) | |||||||
BRCA2 VARIANT | |||||||||||||
c.865A>C | rs766173 | 10 | (1) | (2) | (1) | (1) | |||||||
c.2971A>G | rs1799944 | 11 | (1) | (2) | (2) | (1) | (1) | ||||||
c.5744C>T | rs4987117 | 11 | (1) | (2) | (2) | (1) | (1) | ||||||
c.2808_2811del | rs80359351 | 11 | (3) | (5) | (2) | (1) | (2) | (1) | (1) | ||||
c.5351dupA | rs80359507 | 11 | (1) | (2) | (2) | ||||||||
c.5946delT | rs80359550 | 11 | (5) | (4) | (1) | (4) | (1) | ||||||
c.7469T>C | rs11571707 | 15 | (2) | (4) | (1) | (1) | (1) | (1) | (1) | ||||
c.10234A>G | rs1801426 | 27 | (1) | (3) | (2) | (1) |
Gene | Mutation | Cases | Brazil | Colombia | Mexico | Peru | Puerto Rico | Uruguay | References |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | exon 1-2 deletion | 3 | ✔ | ✔ | [60,63,106] | ||||
BRCA1 | exon 3 deletion | 2 | ✔ | [60,63] | |||||
BRCA1 | exon 4-6 deletion | 2 | ✔ | [60,63] | |||||
BRCA1 | exon 5-7 deletion | 2 | ✔ | [53,60] | |||||
BRCA1 | exon 8 deletion | 2 | ✔ | [60,63] | |||||
BRCA1 | exon 8-13 deletion | 1 | ✔ | [104] | |||||
BRCA1 | exon 9-11 deletion | 1 | ✔ | [80] | |||||
BRCA1 | exon 9-12 deletion | 25 | ✔ | [80,81,84,88] | |||||
BRCA1 | exon 9-19 deletion | 2 | ✔ | [41,60] | |||||
BRCA1 | exon 12 deletion | 1 | ✔ | [80] | |||||
BRCA1 | exon 14 deletion | 1 | ✔ | [109] | |||||
BRCA1 | exon 14-16 deletion | 1 | ✔ | [60] | |||||
BRCA1 | exon 16-17 deletion | 2 | ✔ | [60,65] | |||||
BRCA1 | exon 18-19 deletion | 2 | ✔ | ✔ | [60,104] | ||||
BRCA1 | exon 19 deletion | 1 | ✔ | [60] | |||||
BRCA1 | exon 21-23 deletion | 1 | ✔ | [60] | |||||
BRCA1 | exon 24 duplication | 1 | ✔ | [65] | |||||
BRCA1 | 6-KB DUP EX13 | 7 | ✔ | [51] | |||||
BRCA2 | exon 1 deletion | 3 | ✔ | [80] | |||||
BRCA2 | exon 1-14 deletion | 2 | ✔ | [94] | |||||
BRCA2 | exon 2 deletion | 1 | ✔ | [60] | |||||
BRCA2 | exon 11 deletion | 1 | ✔ | [80] | |||||
BRCA2 | exon 13 deletion | 1 | ✔ | [60] | |||||
BRCA2 | exon 14 deletion | 1 | ✔ | [60] | |||||
BRCA2 | exon 15-16 deletion | 1 | ✔ | [92] | |||||
BRCA2 | exon 17 deletion | 1 | ✔ | [80] | |||||
BRCA2 | exon 22-24 deletion | 2 | ✔ | [80] | |||||
BRCA2 | exon 23 deletion | 2 | ✔ | [80] | |||||
BRCA2 | exon 25 deletion | 1 | ✔ | [60] | |||||
BRCA2 | exon 26 deletion | 1 | ✔ | [80] | |||||
BRCA2 | g.26826_30318del | 2 | ✔ | [35,64] |
Gene | rs | Variant | COSMIC | CLINVAR | Brazil | Chile | Colombia | Mexico | Peru | Uruguay |
---|---|---|---|---|---|---|---|---|---|---|
ATM | NA | c.634delT | ✔ | x | ||||||
ATM | NA | c.5648_5655del | x | |||||||
ATM | rs145119475 | c.4060C>A | ✔ | x | ||||||
ATM | rs1800056 | c.2572T>C | ✔ | ✔ | x | |||||
ATM | rs1801516 | c.5557G>A | ✔ | ✔ | x | x | ||||
ATM | rs1801673 | c.5558A>T | ✔ | ✔ | x | |||||
ATM | rs200381392 | c.1703G>T | ✔ | x | ||||||
ATM | rs202173660 | c.1444A>C | ✔ | ✔ | x | |||||
ATM | rs2234997 | c.378T>A | ✔ | ✔ | x | |||||
ATM | rs2235006 | c.1744T>C | ✔ | x | ||||||
ATM | rs4986761 | c.2119T>C | ✔ | ✔ | x | |||||
ATM | rs587782153 | c.5039C>T | ✔ | ✔ | x | |||||
ATM | rs758962678 | c.241A>G | ✔ | x | ||||||
ATM | rs759965045 | c.7702_7703del | ✔ | x | ||||||
ATM | rs771887195 | c.43del | ✔ | x | ||||||
ATM | rs786203421 | c.7000_7003delTACA | ✔ | x | ||||||
ATM | rs786204433 | c.5644C>T | ✔ | ✔ | x | |||||
TP53 | rs1042522 | c.215C>G | ✔ | ✔ | x | |||||
TP53 | rs11540652 | c.743G>A | ✔ | ✔ | x | |||||
TP53 | rs121912664 | c.1010G>A | ✔ | ✔ | x | |||||
TP53 | rs121913344 | c.916C>T | ✔ | ✔ | x | |||||
TP53 | rs144386518 | c.173C>G | ✔ | ✔ | x | |||||
TP53 | rs1800370 | c.108G>A | ✔ | ✔ | x | |||||
TP53 | rs1800371 | c.139C>T | ✔ | ✔ | x | |||||
TP53 | rs28934576 | c.818G>A | ✔ | ✔ | x | |||||
TP53 | rs55863639 | c.375G>A | ✔ | ✔ | x | |||||
TP53 | rs587782144 | c.473G>A | ✔ | ✔ | x | |||||
TP53 | rs587782620 | c.427G>A | ✔ | ✔ | x | |||||
CHEK2 | NA | c.1015C>T | x | |||||||
CHEK2 | NA | c.1151delT | x | |||||||
CHEK2 | NA | c.705A>C | x | |||||||
CHEK2 | NA | c.852G>T | x | |||||||
CHEK2 | rs1555926890? | c.506T>C | x | |||||||
CHEK2 | rs555607708 | c.1100delC | ✔ | x | x | |||||
CHEK2 | rs587781652 | c.485A>G | ✔ | x | ||||||
CHEK2 | rs864622149 | c.846+1G>C | ✔ | x | ||||||
BARD1 | NA | c.2215dupT | x | |||||||
BARD1 | rs143914387 | c.33G>T | x | |||||||
BARD1 | rs28997576 | c.1670G>C | x | |||||||
BARD1 | rs587781948 | c.1921C>T | x | |||||||
BARD1 | rs758972589 | c.334C>T | ✔ | ✔ | x | |||||
BARD1 | rs777937955 | c.1622C>A | x | |||||||
MLH1 | NA | c.1966C>T | x | |||||||
MLH1 | NA | c.413A>G | x | |||||||
MLH1 | NA | c.791G>A | x | |||||||
MLH1 | rs148317871 | c.2213G>A | ✔ | x | ||||||
MLH1 | rs63751615 | c.676C>T | ✔ | x | ||||||
MLH1 | del_exon8 | NA | NA | x | ||||||
PALB2 | NA | c.1861C>A | x | |||||||
PALB2 | NA | c.483C>G | x | |||||||
PALB2 | rs150390726 | c.23C>T | ✔ | x | ||||||
PALB2 | rs152451 | c.1676A>G | ✔ | x | ||||||
PALB2 | rs180177100 | c.1240C>T | ✔ | ✔ | x | |||||
PALB2 | rs45551636 | c.2993C>T | x | |||||||
BRIP1 | rs202072866 | c.415T>G | ✔ | ✔ | x | |||||
BRIP1 | rs28997569 | c.790C>T | ✔ | x | ||||||
BRIP1 | rs371185409 | c.3079G>A | ✔ | x | ||||||
BRIP1 | rs45589637 | c.2220G>T | ✔ | x | ||||||
BRIP1 | rs759031349 | c.689C>T | ✔ | x |
Patient ID | Gene 1 | Gene 2 | Age Onset | Country | Family History | Subtype | Reference |
---|---|---|---|---|---|---|---|
NA | BRCA1: c.1674del (pathogenic) | MSH6: c.2419G>A (uncertain significance) | NA | Colombia | YES | NA | [92] |
NA | BRCA1: c.1674del (pathogenic) | PMS2: c.2395C>T (uncertain significance); RAD51C: c.492T>G (uncertain significance) | NA | Colombia | YES | NA | [92] |
15 | PALB2: c.1240C>T (pathogenic) | PMS2: c.241G>A (uncertain significance) | 36 | Colombia | YES | ER+, HER2-, invasive ductal carcinoma | [92] |
8 | BRCA2: c.5616-5620del (not reported) | SMAD4: c.677C>T (conflicting interpretations) | 35 | Colombia | YES | HR+, HER2- invasive ductal carcinoma | [92] |
NA | BRCA1: c.4357+1G>T (pathogenic) | BRCA2: c.6405_6409delCTTAA (pathogenic) | 38 | Brazil | NA | ipsilateral BC | [63] |
NA | BRCA1: LGR (deletion of exons 4–6) | BRCA2: c.9004G>A (conflicting interpretation) | 43 | Brazil | NA | NA | [63] |
NA | BRCA2: c.8878C>T (pathogenic), c.9699_9702delTATG (pathogenic) | 52 | Brazil | NA | NA | [63] | |
CM001 | BRCA1: c.1129_1135insA (not reported), c.4063_4065delAAT (conflicting interpretations) | 37 | Venezuela | YES | ER+, PR+ | [114] | |
CM055 | BRCA1: c.1129_1135insA (not reported), c.4063_4065delAAT (conflicting interpretations) | 48 | Venezuela | YES | ER-, PR- | [114] | |
CM031 | BRCA2: c.1282T>C (not reported), c.3479G>A (conflicting interpretations) | 49 | Venezuela | YES | NA | [114] | |
5 | BRCA2: c.865A>C (benign), c.2971A>G(benign), c.8851G>A (benign) | 33 | Mexico | NA | ductal | [87] | |
12 | BRCA1: c.2245G>T (uncertain significance) | BRCA2: p.Ile3412Val (benign) | 34 | Mexico | NA | ductal | [87] |
7 | BRCA1: c.442-34C>T (benign) | BRCA2: c.865A>C (benign), c.2971A>G (benign) | 34 | Mexico | NA | ductal | [87] |
17 | BRCA1: c.3548A>G (benign), c.442-34C>T (benign) | 30 | Mexico | YES | ER+, PR+, HER2- | [89] | |
A11 | BRCA1: c.4308T>C (benign), c.442-34C (not reported), c.5152+66G>A (benign), c.548-58delT (benign) | BRCA2: c.426+67A>C (not reported), c.426-89T>C (benign), c.7435+53C>T (benign) | 12 | Argentina | YES | TNBC, Secretory carcinoma | [101] |
A17 | BRCA1: c.4308T>C (benign), c.5152+66G>A (benign), c.548-58delT (benign) | 25 | Argentina | NO | PR+, ER+, HER2+, infiltrating ductal carcinoma | [101] | |
A18 | BRCA1: c.442-34T>C (not reported) | BRCA2: c.7469T>C (benign), c.681+56C>T (benign), c.7242A>G (benign) | 21 | Argentina | NO | ER+, PR+ HER2-, infiltrating lobular carcinoma | [101] |
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Share and Cite
Urbina-Jara, L.K.; Rojas-Martinez, A.; Martinez-Ledesma, E.; Aguilar, D.; Villarreal-Garza, C.; Ortiz-Lopez, R. Landscape of Germline Mutations in DNA Repair Genes for Breast Cancer in Latin America: Opportunities for PARP-Like Inhibitors and Immunotherapy. Genes 2019, 10, 786. https://doi.org/10.3390/genes10100786
Urbina-Jara LK, Rojas-Martinez A, Martinez-Ledesma E, Aguilar D, Villarreal-Garza C, Ortiz-Lopez R. Landscape of Germline Mutations in DNA Repair Genes for Breast Cancer in Latin America: Opportunities for PARP-Like Inhibitors and Immunotherapy. Genes. 2019; 10(10):786. https://doi.org/10.3390/genes10100786
Chicago/Turabian StyleUrbina-Jara, Laura Keren, Augusto Rojas-Martinez, Emmanuel Martinez-Ledesma, Dione Aguilar, Cynthia Villarreal-Garza, and Rocio Ortiz-Lopez. 2019. "Landscape of Germline Mutations in DNA Repair Genes for Breast Cancer in Latin America: Opportunities for PARP-Like Inhibitors and Immunotherapy" Genes 10, no. 10: 786. https://doi.org/10.3390/genes10100786