Mutations in Gene Are Associated with Predisposition to Breast Cancer

English version České info

In this study, we aimed to find novel breast cancer susceptibility genes by whole-exome sequencing in nine early-onset familial breast cancer patients without BRCA1/2 mutations. We found that two index cases carried a potentially deleterious mutation in the RECQL gene (RecQ helicase-like). We further screened the RECQL gene in an additional 439 unrelated familial breast cancer patients. In total, we found nine index cases carried a pathogenic mutation in the RECQL gene among the 448 BRCA-negative familial breast cancer patients. The RECQL is one of five RecQ helicase proteins (named RECQL, BLM, WRN, RECQL4 and RECQL5). RECQL is considered to be genome caretaker, and mutations in three of five RecQ genes, BLM, WRN and RECQ4 are associated with cancer predisposition and/or premature aging. Here, we are the first to report that mutations in the RECQL gene are associated with predisposition to breast cancer and this finding may have potential clinical implications and raise research questions about RECQL.

Vyšlo v časopise: Mutations in Gene Are Associated with Predisposition to Breast Cancer. PLoS Genet 11(5): e32767. doi:10.1371/journal.pgen.1005228
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005228

Souhrn

Zdroje

1. Narod SA (2002) Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2: 113–123. 12635174

2. Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, et al. (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31: 55–59. 11967536

3. Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, et al. (2006) ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38: 873–875. 16832357

4. Seal S, Thompson D, Renwick A, Elliott A, Kelly P, et al. (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38: 1239–1241. 17033622

5. Rahman N, Seal S, Thompson D, Kelly P, Renwick A, et al. (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39: 165–167. 17200668

6. Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, et al. (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42: 410–414. doi: 10.1038/ng.569 20400964

7. Pike AC, Shrestha B, Popuri V, Burgess-Brown N, Muzzolini L, et al. (2009) Structure of the human RECQ1 helicase reveals a putative strand-separation pin. Proc Natl Acad Sci U S A 106: 1039–1044. doi: 10.1073/pnas.0806908106 19151156

8. Lucic B, Zhang Y, King O, Mendoza-Maldonado R, Berti M, et al. (2011) A prominent beta-hairpin structure in the winged-helix domain of RECQ1 is required for DNA unwinding and oligomer formation. Nucleic Acids Res 39: 1703–1717. doi: 10.1093/nar/gkq1031 21059676

9. Mirzaei H, Schmidt KH (2012) Non-Bloom syndrome-associated partial and total loss-of-function variants of BLM helicase. Proc Natl Acad Sci U S A 109: 19357–19362. doi: 10.1073/pnas.1210304109 23129629

10. Liu JL, Rigolet P, Dou SX, Wang PY, Xi XG (2004) The zinc finger motif of Escherichia coli RecQ is implicated in both DNA binding and protein folding. J Biol Chem 279: 42794–42802. 15292213

11. Cui S, Arosio D, Doherty KM, Brosh RM Jr., Falaschi A, et al. (2004) Analysis of the unwinding activity of the dimeric RECQ1 helicase in the presence of human replication protein A. Nucleic Acids Res 32: 2158–2170. 15096578

12. Doherty KM, Sharma S, Uzdilla LA, Wilson TM, Cui S, et al. (2005) RECQ1 helicase interacts with human mismatch repair factors that regulate genetic recombination. J Biol Chem 280: 28085–28094. 15886194

13. Chu WK, Hickson ID (2009) RecQ helicases: multifunctional genome caretakers. Nat Rev Cancer 9: 644–654. doi: 10.1038/nrc2682 19657341

14. Thompson ER, Doyle MA, Ryland GL, Rowley SM, Choong DY, et al. (2012) Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet 8: e1002894. doi: 10.1371/journal.pgen.1002894 23028338

15. He YJ, Qiao ZY, Gao B, Zhang XH, Wen YY (2014) Association between RECQL5 genetic polymorphisms and susceptibility to breast cancer. Tumour Biol 35: 12201–12204. doi: 10.1007/s13277-014-2528-2 25394896

16. Wu Y, Brosh RM Jr. (2010) Distinct roles of RECQ1 in the maintenance of genomic stability. DNA Repair (Amst) 9: 315–324. doi: 10.1016/j.dnarep.2009.12.010 20061189

17. Sharma S, Stumpo DJ, Balajee AS, Bock CB, Lansdorp PM, et al. (2007) RECQL, a member of the RecQ family of DNA helicases, suppresses chromosomal instability. Mol Cell Biol 27: 1784–1794. 17158923

18. Sharma S, Brosh RM Jr. (2007) Human RECQ1 is a DNA damage responsive protein required for genotoxic stress resistance and suppression of sister chromatid exchanges. PLoS One 2: e1297. 18074021

19. Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25: 1754–1760. doi: 10.1093/bioinformatics/btp324 19451168

20. Li R, Li Y, Fang X, Yang H, Wang J, et al. (2009) SNP detection for massively parallel whole-genome resequencing. Genome Res 19: 1124–1132. doi: 10.1101/gr.088013.108 19420381

21. Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38: e164. doi: 10.1093/nar/gkq603 20601685