A novel germline mutation of the PALB2 gene in a young Yakut breast cancer woman

Background. Breast cancer (BC) is the most common female malignancy worldwide. Partner And Localizer of BRCA2 gene (PALB2) is directly involved in DNA damage response. Germline mutation in PALB2 has been identified in breast cancer and familial pancreatic cancer cases, accounting for approximately 1–2% and 3–4%, respectively. The goal of this report was to describe new PALB2 mutation in a young Yakut breast cancer patient with family history of cancer. Material and Methods. Genomic DNA were isolated from blood samples and used to prepare libraries using a capture-based target enrichment kit, Hereditary Cancer Solution™ (SOP HiA GE NETICS , Switzerland), covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). Paired-end sequencing (2 × 150 bp) was conducted using NextSeq 500 system (Illumina, USA ). Results. Here we describe a case of a never-before-reported mutation in the PALB2 gene that led to the early onset breast cancer. We report the case of a 39-year-old breast cancer Yakut woman with a family history of pancreatic cancer. Bioinformatics analysis of the NGS data revealed the presence of the new PALB2 gene germinal frameshift deletion (NM_024675:exon1:c.47delA:p.K16fs). In accordance with dbPubMed ClinVar, new mutation is located in codon of the PALB2 gene, where the likely pathogenic donor splice site mutation (NM_024675.3:c.48+1delG) associated with hereditary cancer-predisposing syndrome has been earlier described. Conclusion. We found a new never-before-reported mutation in PALB2 gene, which probably associated with early onset breast cancer in Yakut indigenous women with a family history of pancreatic cancer.

1. Gifoni A.C.L.V.C., Gifoni M.A.C., Wotroba C.M., Palmero E.I., Costa E.L.V., Dos Santos W., Achatz M.I. Hereditary Breast Cancer in the Brazilian State of Ceará (The CHANCE Cohort): Higher-Than-Expected Prevalence of Recurrent Germline Pathogenic Variants. Front Oncol. 2022; 12. doi: 10.3389/fonc.2022.932957.

2. Plon S.E., Eccles D.M., Easton D., Foulkes W.D., Genuardi M., Greenblatt M.S., Hogervorst F.B., Hoogerbrugge N., Spurdle A.B., Tavtigian S.V.; IARC Unclassified Genetic Variants Working Group. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat. 2008; 29(11): 1282–91. doi: 10.1002/humu.20880.

3. Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., Grody W.W., Hegde M., Lyon E., Spector E., Voelkerding K., Rehm H.L.; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5): 405–24. doi: 10.1038/gim.2015.30.

4. Kononova S., Vinokurova D., Barashkov N.A., Semenova A., Sofronova S., Oksana S., Tatiana D., Struchkov V., Burtseva T., Romanova A., Fedorova S. The attitude of young people in the city of Yakutsk to DNA-testing. Int J Circumpolar Health. 2021; 80(1). doi: 10.1080/22423982.2021.1973697.

5. Kirillina M.P., Loskutova K.S., Lushnikova E.L., Nepomnyashchikh L.M. Expression of molecular biological markers in breast cancer under conditions of the Sakha Republic (Yakutia). Bull Exp Biol Med. 2014; 157(5): 623–7. doi: 10.1007/s10517-014-2630-x.

6. Pisareva L.F., Odintsova I.N., Ivanov P.M., Nikolaeva T.I. Breast cancer incidence among indigenous peoples and newcomers in Sakha republic (Yakutia). Siberian Journal of Oncology. 2007; (3): 69–72. (in Russian).

7. Eccles D.M. Hereditary cancer: guidelines in clinical practice. Breast and ovarian cancer genetics. Ann Oncol. 2004; 15(4): 133–8. doi: 10.1093/annonc/mdh917.

8. Slatko B.E., Gardner A.F., Ausubel F.M. Overview of Next-Generation Sequencing Technologies. Curr Protoc Mol Biol. 2018; 122(1): 59. doi: 10.1002/cpmb.59.

9. Van der Auwera G.A., Carneiro M.O., Hartl C., Poplin R., Del Angel G., Levy-Moonshine A., Jordan T., Shakir K., Roazen D., Thibault J., Banks E., Garimella, K.V., Altshuler D., Gabriel S., DePristo M.A. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline, Curr Protoc Bioinformatics. 2013; 43(1110): 11.10.1–11.10.33. doi: 10.1002/0471250953.bi1110s43.

10. DePristo M.A., Banks E., Poplin R., Garimella K.V., Maguire J.R., Hartl C., Philippakis A.A., del Angel G., Rivas M.A., Hanna M., McKenna A., Fennell T.J., Kernytsky A.M., Sivachenko A.Y., Cibulskis K., Gabriel S.B., Altshuler D., Daly M.J. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature genetics. 2011; 43(5): 491–8. doi: 10.1038/ng.806.

11. McKenna A., Hanna M., Banks E., Sivachenko A., Cibulskis K., Kernytsky A., Garimella K., Altshuler D., Gabriel S., Daly M., DePristo M.A. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9): 1297–303. doi: 10.1101/gr.107524.110.

12. Adzhubei I.A., Schmidt S., Peshkin L., Ramensky V.E., Gerasimova A., Bork P., Kondrashov A.S., Sunyaev S.R. A method and server for predicting damaging missense mutations. Nat Methods. 2010; 7(4): 248–9. doi: 10.1038/nmeth0410-248.

13. Schwarz J.M., Cooper D.N., Schuelke M., Seelow D. Mutation-Taster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014; 11(4): 361–2. doi: 10.1038/nmeth.2890.

14. Kumar P., Henikoff S., Ng P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009; 4(7): 1073–81. doi: 10.1038/nprot.2009.86.

15. Richards C.S., Bale S., Bellissimo D.B., Das S., Grody W.W., Hegde M.R., Lyon E., Ward B.E.; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med. 2008; 10(4): 294–300. doi: 10.1097/GIM.0b013e31816b5cae.

16. Hofstatter E.W., Domchek S.M., Miron A., Garber J., Wang M., Componeschi K., Boghossian L., Miron P.L., Nathanson K.L., Tung N. PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer. 2011; 10(2): 225–31. doi: 10.1007/s10689-011-9426-1.

17. Tischkowitz M.D., Sabbaghian N., Hamel N., Borgida A., Rosner C., Taherian N., Srivastava A., Holter S., Rothenmund H., Ghadirian P., Foulkes W.D., Gallinger S. Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer. Gastroenterology. 2009; 137(3): 1183–6. doi: 10.1053/j.gastro.2009.06.055.

18. Jones S., Hruban R.H., Kamiyama M., Borges M., Zhang X., Parsons D.W., Lin J.C., Palmisano E., Brune K., Jaffee E.M., Iacobuzio-Donahue C.A., Maitra A., Parmigiani G., Kern S.E., Velculescu V.E., Kinzler K.W., Vogelstein B., Eshleman J.R., Goggins M., Klein A.P. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009; 324(5924): 217. doi: 10.1126/science.1171202.

19. Slater E.P., Langer P., Niemczyk E., Strauch K., Butler J., Habbe N., Neoptolemos J.P., Greenhalf W., Bartsch D.K. PALB2 mutations in European familial pancreatic cancer families. Clin Genet. 2010; 78(5): 490–4. doi: 10.1111/j.1399-0004.2010.01425.x.

20. Hanenberg H., Andreassen P.R. PALB2 (partner and localizer of BRCA2). Atlas Genet Cytogenet Oncol Haematol. 2018; 22(12): 484–90. doi: 10.4267/2042/69016.

21. Practice Bulletin No 182: Hereditary Breast and Ovarian Cancer Syndrome. Obstet Gynecol. 2017; 130(3): 110–26. doi: 10.1097/AOG.0000000000002296.

22. Grellety T., Peyraud F., Sevenet N., Tredan O., Dohollou N., Barouk-Simonet E., Kind M., Longy M., Blay J.Y., Italiano A. Dramatic response to PARP inhibition in a PALB2-mutated breast cancer: moving beyond BRCA. Ann Oncol. 2020; 31(6): 822–3. doi: 10.1016/j.annonc.2020.03.283.