Наследственные патогенные варианты в гене PALB2

Ген PALB2 кодирует ключевой белок, участвующий в наиболее точном механизме репарации двунитевых разрывов ДНК – гомологичной рекомбинации. PALB2 действует как связующее звено между белками BRCA1 и BRCA2, обеспечивая формирование функционального BRCA-комплекса и стимулируя инвазию цепи белком RAD51. Герминальные патогенные варианты в гене PALB2 являются фактором предрасположенности к наследственному раку со средней и высокой пенетрантностью. Мутации значительно повышают риск развития рака молочной железы, являясь 3-м по распространенности геном риска после BRCA1 и BRCA2, с кумулятивным риском до 52,8 % к 80 годам. Кроме того, мутации PALB2 ассоциированы с повышенным риском рака яичников, поджелудочной и предстательной желез. Биаллельные мутации вызывают анемию Фанкони. Особое клиническое значение мутаций PALB2 заключается в их терапевтической предсказательной роли. Наличие герминальных патогенных вариантов в PALB2 является определяющим маркером чувствительности опухолей к PARP-ингибиторам, таким как олапариб, талазопариб и рукапариб, что подтверждается высокими показателями объективного ответа в клинических исследованиях при раке молочной, предстательной и поджелудочной желез.

Таким образом, комплексное генетическое тестирование, включающее PALB2, становится необходимым элементом современной онкологической практики для геноспецифической оценки риска, персонализации профилактических стратегий и оптимизации тактики лечения за счет применения таргетной терапии.

1. Ciccia A., Elledge S.J. The DNA damage response: making it safe to play with knives. Mol Cell 2010;40:179–204. DOI: 10.1016/j.molcel.2010.09.019

2. Chapman J.R., Taylor M.R.G., Boulton S.J. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell 2012;47:497–510. DOI: 10.1016/j.molcel.2012.07.029

3. Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 1995;378:789–92. DOI: 10.1038/378789a0

4. Xia B., Sheng Q., Nakanishi K. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell 2006;22:719–29. DOI: 10.1016/j.molcel.2006.05.022

5. Reid S., Schindler D., Hanenberg H. et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 2007;39:162–4. DOI: 10.1038/ng1947

6. Xia B., Dorsman J.C., Ameziane N. et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 2007;39:159–61. DOI: 10.1038/ng1942

7. Zhang F., Ma J., Wu J. et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol 2009;19:524–529. DOI: 10.1016/j.cub.2009.02.018

8. Wu S., Zhou J., Zhang K. et al. Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management. Front Oncol 2020;10:301. DOI: 10.3389/fonc.2020.00301

9. Anantha R.W., Simhadri S., Foo T.K. et al. Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance. Elife 2017:6:e21350. DOI: 10.7554/eLife.21350

10. Park J.Y., Singh T.R., Nassar N. et al. Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair. Oncogene 2014;33:4803–12. DOI: 10.1038/onc.2013.421

11. Bleuyard J.Y., Buisson R., Masson J.Y., Esashi F. ChAM, a novel motif that mediates PALB2 intrinsic chromatin binding and facilitates DNA repair. EMBO Rep 2012;13:135–41. DOI: 10.1038/embor.2011.243

12. Голотюк М.А., Бережной А.А., Казанцева Н.В. и др. Герминальные мутации в генах PALB2 и CHEK2 и наследственный рак. Уральский медицинский журнал 2023;22(3):126–36. DOI: 10.52420/2071-5943-2023-22-3-126-136

13. Richardson M.E., Bishop M.F.H., Holdren M.A. et al. Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline PALB2 sequence variants. Am J Hum Genet 2025;112:2266–80. DOI: 10.1016/j.ajhg.2025.08.020

14. Boonen R.A.C.M., Rodrigue A., Stoepker C. et al. Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2. Nat Commun 2019;10:5296. DOI: 10.1038/s41467-019-13194-2

15. Rahman N., Seal S., Thompson D. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 2007;39:165–7. DOI: 10.1038/ng1959

16. Tischkowitz M., Capanu M., Sabbaghian N. et al. Rare germline mutations in PALB2 and breast cancer risk: a population-based study. Hum Mutat 2012;33:674–80. DOI: 10.1002/humu.22022

17. Ding Y.C., Steele L., Kuan C.J. et al. Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. Breast Cancer Res Treat 2011;126:771–8. DOI: 10.1007/s10549-010-1195-2

18. Carter N.J., Marshall M.L., Susswein L.R. et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol 2018;151:481–8. DOI: 10.1016/j.ygyno.2018.09.030

19. Dudley B., Karloski E., Monzon F.A. et al. Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy. Cancer 2018;124:1691–700. DOI: 10.1002/cncr.31242

20. Waszak S.M., Northcott P.A., Buchhalter I. et al. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 2018;19:785–98. DOI: 10.1016/S1470-2045(18)30242-0

21. Casadei S., Norquist B.M., Walsh T. et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res 2011;71:2222–9. DOI: 10.1158/0008-5472.CAN-10-3958

22. Teo Z.L., Provenzano E., Dite G.S. et al. Tumour morphology predicts PALB2 germline mutation status. Br J Cancer 2013;109:154–63. DOI: 10.1038/bjc.2013.295

23. Casadei S., Gulsuner S., Shirts B.H. et al. Characterization of splice-altering mutations in inherited predisposition to cancer. Proc Natl Acad Sci USA 2019;116:26798–807. DOI: 10.1073/pnas.1915608116

24. Pauty J., Couturier A.M., Rodrigue A. et al. Cancer-causing mutations in the tumor suppressor PALB2 reveal a novel cancer mechanism using a hidden nuclear export signal in the WD40 repeat motif. Nucleic Acids Res 2017;45:2644–57. DOI: 10.1093/nar/gkx011

25. Dorling L., Carvalho S., Allen J. et al.; Breast Cancer Association Consortium. Breast cancer risk genes – association analysis in more than 113,000 women. N Engl J Med 2021;384:428–39. DOI: 10.1056/NEJMoa1913948

26. Darst B.F., Dadaev T., Saunders E. et al. Germline sequencing DNA repair genes in 5545 men with aggressive and nonaggressive prostate cancer. J Natl Cancer Inst 2021;113:616–25. DOI: 10.1093/jnci/djaa132

27. Zhen D.B., Rabe K.G., Gallinger S. et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med 2015;17:569–77. DOI: 10.1038/gim.2014.153

28. Erkko H., Xia B., Nikkilä J. et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 2007;446:316–9. DOI: 10.1038/nature05609

29. Erkko H., Dowty J.G., Nikkilä J. et al. Penetrance analysis of the PALB2 c.1592delT founder mutation. Clin Cancer Res 2008;14:4667–71. DOI: 10.1158/1078-0432.CCR-08-0210

30. Obermeier K., Sachsenweger J., Friedl T.W.P. et al. Heterozygous PALB2 c.1592delT mutation channels DNA double-strand break repair into error-prone pathways in breast cancer patients. Oncogene 2016;35:3796–806. DOI: 10.1038/onc.2015.448

31. Tischkowitz M., Xia B., Sabbaghian N. et al. Analysis of PALB2/ FANCN-associated breast cancer families. Proc Natl Acad Sci USA 2007;104:6788–93. DOI: 10.1073/pnas.0701724104

32. Nguyen-Dumont T., Hammet F., Mahmoodi M. et al. Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry. Breast Cancer Res Treat 2015;149:547–54. DOI: 10.1007/s10549-014-3260-8

33. Calabrese A., von Arx C., Tafuti A.A. et al. Prevention, diagnosis and clinical management of hereditary breast cancer beyond BRCA1/2 genes. Cancer Treat Rev 2024;129:102785. DOI: 10.1016/j.ctrv.2024.102785

34. Antoniou A., Pharoah P.D.P., Narod S. et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72:1117–30. DOI: 10.1086/375033

35. Southey M.C., Teo Z.L., Dowty J.G. et al. A PALB2 mutation associated with high risk of breast cancer. Breast Cancer Res 2010;12:R109. DOI: 10.1186/bcr2796

36. Antoniou A.C., Casadei S., Heikkinen T. et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014;371:497–506. DOI: 10.1056/NEJMoa1400382

37. Southey M.C., Goldgar D.E., Winqvist R. et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J Med Genet 2016;53:800–11. DOI: 10.1136/jmedgenet-2016-103839

38. Slavin T.P., Maxwell K.N., Lilyquist J. et al. The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer 2017;3:22. DOI: 10.1038/s41523-017-0024-8

39. Easton D.F., Pharoah P.D.P., Antoniou A.C. et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 2015;372:2243–57. DOI: 10.1056/NEJMsr1501341

40. Couch F.J., Shimelis H., Hu C. et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol 2017;3:1190–6. DOI: 10.1001/jamaoncol.2017.0424

41. Norquist B.M., Harrell M.I., Brady M.F. et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol 2016;2:482–90. DOI: 10.1001/jamaoncol.2015.5495

42. Yang X., Leslie G., Doroszuk A. et al. Cancer risks associated with germline pathogenic variants: an international study of 524 families. J Clin Oncol 2020;38:674–85. DOI: 10.1200/JCO.19.01907

43. Dillon K.M., Bekele R.T., Sztupinszki Z. et al. PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer. NPJ Precis Oncol 2022;6:49. DOI: 10.1038/s41698-022-00291-7

44. Dansonka-Mieszkowska A., Kluska A., Moes J. et al. A novel germline PALB2 deletion in Polish breast and ovarian cancer patients. BMC Med Genet 2010;11:20. DOI: 10.1186/1471-2350-11-20

45. Hu C., Hart S.N., Polley E.C. et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA 2018;319:2401–9. DOI: 10.1001/jama.2018.6228

46. Hansford S., Kaurah P., Li-Chang H. et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol 2015;1:23–32. DOI: 10.1001/jamaoncol.2014.168

47. AlDubayan S.H., Giannakis M., Moore N.D. et al. Inherited DNA-repair defects in colorectal cancer. Am J Hum Genet 2018;102:401–14. DOI: 10.1016/j.ajhg.2018.01.018

48. Toss A., Ponzoni O., Riccò B. et al. Management of PALB2-associated breast cancer: a literature review and case report. Clin Case Rep 2023;11:e7747. DOI: 10.1002/ccr3.7747

49. Isaac D., Karapetyan L., Tamkus D. Association of germline mutation and response to platinum-based chemotherapy in metastatic breast cancer: a case series. JCO Precis Oncol 2018;2:1–5. DOI: 10.1200/PO.17.00258

50. Wattenberg M.M., Asch D., Yu S. et al. Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. Br J Cancer 2020;122:333–9. DOI: 10.1038/s41416-019-0582-7

51. Emelyanova M., Pudova E., Khomich D. et al. Platinum-based chemotherapy for pancreatic cancer: impact of mutations in the homologous recombination repair and Fanconi anemia genes. Ther Adv Med Oncol 2022;14:17588359221083050. DOI: 10.1177/17588359221083050

52. Tung N.M., Robson M.E., Ventz S. et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol 2020;38:4274–82. DOI: 10.1200/JCO.20.02151

53. Gruber J.J., Afghahi A., Timms K. et al. A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes. Nat Cancer 2022;3:1181–91. DOI: 10.1038/s43018-022-00439-1

54. Illuzzi G., Staniszewska A.D., Gill S.J. et al. Preclinical characterization of AZD5305, A next-generation, highly selective PARP1 inhibitor and trapper. Clin Cancer Res 2022;28:4724–36. DOI: 10.1158/1078-0432.CCR-22-0301

55. Abida W., Campbell D., Patnaik A. et al. Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase II TRITON2 study. Clin Cancer Res 2020;26: 2487–96. DOI: 10.1158/1078-0432.CCR-20-0394

56. Reiss K.A., Mick R., O’Hara M.H. et al. Phase II study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic variant Variant in BRCA1, BRCA2, or PALB2. J Clin Oncol 2021;39:2497–505. DOI: 10.1200/JCO.21.00003

57. Tung N.M., Boughey J.C., Pierce L.J. et al. Management of hereditary breast cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline. J Clin Oncol 2020;38:2080–106. DOI: 10.1200/JCO.20.00299

58. Tischkowitz M., Balmaña J., Foulkes W.Det al. Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2021;23:1416–23. DOI: 10.1038/s41436-021-01151-8