УДК:  614.2+575.191-616.006

Автор статьи:  Акильжанова А.Р.

Место работы автора:  РГП Национальный центр биотехнологии Республики Казахстан

Название журнала:  Биотехнология. Теория и практика

Год выпуска:  2010

Номер журнала:  1

Страницы:  с.17-34

Ключевые слова:  BRCA1/2 гены, аллель, семейная предрасположенность, восприимчивость,пенетрантность

Резюме на казахском языке:  Соңғы жылдары сүт безі қатерлі ісігінің генетикалық тұрғыдан бейімділігі жайлы түсінігімізде елеулі ілгеріліктерге жеттік. Қазіргі таңда сүт безінің қатерлі ісігіне генетикалық бейімділіктудыратын факторлар үш топқа бөлінеді. Геномдық ассоциативтік зерттеу мен позициялық клондау әдістерінің нәтижесінде BRCA1 және BRCA2 гендері сүт безінің қатерлі ісігіне генетикалықбейімділік тудыратын факторлардың ішінде жоғарғы пенетрантты болып табылады. BRCA1 және BRCA2 гендерінің атқаратын қызметтерімен байланысты гендерін мутациялық скрининг жүргізубарысында жаңа төрт ген белгілі болды; CHEK2, ATM, BRIP1 және PALB2. Бұл гендерде мутация сирек кездеседі және де орташа пенетрантты болып саналады. Ассоциативтік зерттеу жұмыстарыаз пенетрантты болып табылатын, сүт безінің қатерлі ісігіне генетикалық бейімділік тудыратын жалпы сегіз вариант бар екендігін анықтады. Айтылған жаңалықтарға қарамастан, сүт безі қатерліісігінің мираспен берілетін формасын тудыратын факторлардың көп бөлігі белгісіз. Бұл шолуда біз сүт безінің қатерлі ісігіне генетикалық бейімділік тудыратын белгілі факторлары мен олардыанықтау үшін қолданылған әдістерді толықтай сипаттауды ұйғардық. BRCA1 және BRCA2 гендерінетолықтай тоқтала отырып, сүт безінің қатерлі ісігіне генетикалық бейімділік тудыратын маңыздыфактор ретінде клиникада пайдалану сұрағын қарастыдық.

Резюме на английском языке:  In recent years, our understanding of genetic predisposition to breast cancer has advanced significantly. Three classes of predisposition factors, categorized by their associated risks of breast cancer, are currently known. BRCA1 and BRCA2 are high-penetrance breast cancer predispositiongenes identified by genome-wide linkage analysis and positional cloning. Mutational screening of genes functionally related to BRCA1 and/or BRCA2 has revealed four genes, CHEK2, ATM, BRIP1, and PALB2; mutations in these genes are rare and confer an intermediate risk of breast cancer. Association studies have further identified eight common variants associated with low-penetrance breast cancer predisposition. Despite these discoveries, most of the familial risk of breast cancer remains unexplained. In this review, we describe the known genetic predisposition factors, expound on the methods by whichthey were identified, describe BRCA1 and BRCA2 genes in detail and consider how knowledge about breast cancer susceptibility can be translated into the clinical practice.

Список литературы:  
1. Broca P. 1866. Traitґe des Tumeurs. Paris: Asselin.
2. Le Dran H. 1757. Memoire avec un precis de plusieurs observations sur le cancer. Mem. Acad. R. Chir.
3. Hopper J.L., Carlin J.B. 1992. Familial aggregation of a disease consequent upon correlation between relatives in a risk factor measured on a continuous scale. Am. J. Epidem. 136:1138–47.
4. Lichtenstein P., Holm N.V., Verkasalo P.K., Iliadou A., Kaprio J., et al. 2000. Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 343:78–85.
5. Peto J., Mack T.M. 2000. High constant incidence in twins and other relatives of women with breast cancer. Nat. Genet. 26:411–14.
6. Bishop D.T., Cannon-Albright L., McLellan T., Gardner E.J., Skolnick M.H. 1988. Segregation and linkage analysis of nine Utah breast cancer pedigrees. Genet. Epidemiol. 5:151–69.
7. Claus E.B., Risch N., Thompson W.D. 1991. Genetic analysis of breast cancer in the cancer and steroid hormone study. Am. J. Hum. Genet. 48:232–42.
8. Iselius L., Slack J., Littler M., Morton N.E. 1991. Genetic epidemiology of breast cancer in Britain. Ann. Hum. Genet. 55:151–59.
9. Williams W.R., Anderson D.E. 1984. Genetic epidemiology of breast cancer: segregation analysis of 200 Danish pedigrees. Genet. Epidemiol. 1:7–20.
10. Antoniou A.C., Pharoah P.D., McMullan G., Day N.E., Ponder B.A., Easton D. 2001. Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Genet.Epidemiol. 21:1–18.
1
11. Antoniou, Pharoah P.D., McMullan G., Day N.E., Stratton M.R., et al. 2002. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br. J. Cancer 86:76–83.
12. Cui J., Antoniou A.C., Dite G.S., Southey M.C., Venter D.J., et al. 2001. After BRCA1 and BRCA2-what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer. Am. J. Hum. Genet. 68:420–31.
13. Parmigiani G., Berry D., Aguilar O. 1998. Determining carrier probabilities for breast cancersusceptibilitygenes BRCA1 and BRCA2. Am. J. Hum. Genet. 62:145–58.
14. Antoniou A.C., Pharoah P.P., Smith P., Easton D.F. 2004. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br. J. Cancer 91:1580–90.
15. Hall J.M., Lee M.K., Newman B., Morrow J.E., Anderson L.A., et al. 1990. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684–89.
16. Wooster R., Neuhausen S.L., Mangion J., Quirk Y., Ford D., et al. 1994. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science 265:2088–90.
17. Guilford P., Hopkins J., Harraway J., McLeod M., McLeod N., et al. 1998. E-cadherin germline mutations in familial gastric cancer. Nature 392:402–5.
18. Hemminki A., Markie D., Tomlinson I., Avizienyte E., Roth S., et al. 1998. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391:184–87.
19. Hemminki A., Tomlinson I., Markie D., Jarvinen H., Sistonen P., et al. 1997. Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nat. Genet. 15:87–90.
20. Jenne D.E., Reimann H., Nezu J., Friedel W., Loff S., et al. 1998. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat. Genet. 18:38–43.
2
21. Nelen, Padberg G.W., Peeters E.A., Lin A.Y., van den Helm B., et al. 1996. Localization of the gene for Cowden disease to chromosome 10q22–23. Nat. Genet. 13:114–16.
22. Nelen M.R., van Staveren W.C., Peeters E.A., Hassel M.B., Gorlin R.J., et al. 1997. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum. Mol. Genet. 6:1383–87.
23. Dunning A.M., Healey C.S., Pharoah P.D., Teare M.D., Ponder B.A., Easton D.F. 1999. A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol. Biomark. Prev. 8:843–44.
24. Pharoah P.D., Dunning A.M., Ponder B.A., Easton D.F. 2004. Association studies for finding cancersusceptibility genetic variants. Nat. Rev. Cancer 4:850–60.
25. Breast Cancer Assoc. Consort. 2006. Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J. Natl. Cancer Inst. 98:1382–96.
26. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P.A., Harshman K., et al. 1994. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71.
27. Wooster R., Bignell G., Lancaster J., Swift S., Seal S., et al. 1995. Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–92.
28. Antoniou A.C., Spurdle A.B., Sinilnikova O.M., Healey S., Pooley K.A., et al. 2008. Common breast cancerpredisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am. J. Hum. Genet. 82:937–48.
29. Bell D.W., Varley J.M., Szydlo T.E., Kang D.H., Wahrer D.C., et al. 1999. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286:2528–31.
30. Easton D.F., Deffenbaugh A.M., Pruss D., Frye C., Wenstrup R.J., et al. 2007. A systematic genetic assessment of 1433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancerpredisposition genes. Am. J. Hum. Genet. 81:873–83.
3
31. Sharan, Wims M., Bradley A. 1995. Murine Brca1: sequence and significance for human missense mutations. Hum. Mol. Genet. 4:2275–78.
32. Simard J., P. Tonin, F. Durocher, K. Morgan, J. Rommens, et al. 1994. Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat. Genet. 8:392–398.
33. Tavtigian S.V., Simard J., Rommens J., Couch F., Shattuck-Eidens D., et al.1996. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat. Genet. 12:333–37.
34. Fodor F.H., A. Weston, I.J. Bleiweiss, L.D. McCurdy, M.M. Walsh, et al.1998. Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am. J. Hum. Genet. 63:45–51.
35. FitzGerald M.G, D.J. MacDonald, M. Krainer, I. Hoover,E. O’Neil, et al. 1996. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early- onset breast cancer. N. Engl. J. Med. 334:143–149.
36. Warner E., W. Foulkes, P. Goodwin, W. Meschino, J. Blondal, C. et al. 1999. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J. Natl. Cancer. Inst. 91:1241–1247.
37. Satagopan J.M., K. Offit, W. Foulkes, M.E. Robson, S. Wacholder, et al. 2001. The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol. Biomarkers Prev. 10:467–473.
38. Neuhausen S., T. Gilewski, L. Norton, T. Tran, P. McGuire, J. Swensen, et al. 1996. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat. Genet. 13:126–128.
39. Offit K., T. Gilewski, P. McGuire, A. Schluger, H. Hampel, et al.1996. Germline BRCA1 185delAG mutations in Jewish women with breast cancer. Lancet 347:1643–1645.
40. Moslehi R., Chu W., Karlan B., Fishman D., Risch H., et al. 2000. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am. J. Hum. Genet. 66:1259–1272.
41. Abeliovich D., Kaduri L., Lerer I., Weinberg N., Amir G., et al. 1997. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am. J. Hum. Genet. 60:505–514.
42. Gudmundsson J., G. Johannesdottir, A. Arason, J.T. Bergthorsson, S. Ingvarsson, et al 1996. Frequent occurrence of BRCA2 linkage in Icelandic breast cancer families and segregation of a common BRCA2 haplotype. Am. J. Hum. Genet. 58:749–756.
43. Thorlacius S., G. Olafsdottir, L. Tryggvadottir, S. Neuhausen,J. G. Jonasson, et al. 1996. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat. Genet. 13:117–119.
44. Johannesdottir G., J. Gudmundsson, J.T. Bergthorsson, A. Arason, B.A. Agnarsson, et al.1996. High prevalence of the 999del5 mutation in Icelandic breast and ovarian cancer patients. Cancer Res. 56:3663–3665.
45. Thorlacius S., S. Sigurdsson, H. Bjarnadottir, G. Olafsdottir, J.G. Jonasson, et al. 1997 Study of a single BRCA2 mutation with high carrier frequency in a small population. Am. J. Hum. Genet. 60:1079–1084.
46. Easton D.F., Ford D., Bishop D.T. 1995. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am. J. Hum. Genet. 56:265–71.
47. Ford D., Easton D.F., Stratton M., Narod S., Goldgar D., et al. 1998. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am. J. Hum. Genet. 62:676–89.
48. Antoniou A., Pharoah P.D., Narod S., Risch H.A., Eyfjord J.E., et al. 2003. 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. 72:1117–30.
49. Ford D., D.F. Easton, M. Stratton, S. Narod, D. Goldgar, et al, and The Breast Cancer Linkage Consortium 1998. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am. J. Hum. Genet. 62:676–689.
50. Easton D.F., D. Ford, D.T. Bishop, and Breast Cancer Linkage Consortium (1995). Breast and ovarian cancer incidence in BRCA1-mutation carriers. Am. J. Hum. Genet. 56:265–271.
5
51. King, J.H. Marks, and J.B. Mandell. 2003. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302:643–646.
52. Gayther S.A., W. Warren, S. Mazoyer, P.A. Russell, P.A. Harrington, et al. 1995. Germline mutationsof the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype–phenotype correlation. Nat. Genet. 11:428–433.
53. Thompson D., and D. Easton 2002. Breast Cancer Linkage Consortium. Variation in BRCA1 cancerrisks by mutation position. Cancer Epidemiol. Biomarkers Prev. 11:329–336.
54. Thompson D., and D. Easton 2001. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am. J. Hum. Genet. 68:410–419.
55. Gayther S.A, J. Mangion, P. Russell, S. Seal, R. Barfoot, et al.1997. Variation of risks of breast andovarian cancer associated with different germline mutations of the BRCA2 gene. Nat. Genet. 15:103–105.
56. Breast Cancer Link. Consort. 1999. Cancer risks in BRCA2 mutation carriers. J. Natl. Cancer Inst.91:1310–16.
57. Thompson D., Easton D.F. 2002. Cancer incidence in BRCA1 mutation carriers. J. Natl. Cancer Inst. 94:1358–65.
58. Breast Cancer Link. Consort. 1997. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 349:1505–10.
59. Lakhani SR. 1999. The pathology of familial breast cancer: Morphological aspects. Breast Cancer Res. 1:31–35.
60. Lakhani S.R., van der Vijver M., Jacquemier J., Anderson T.J., Osin P.P., et al. 2002. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J. Clin. Oncol. 20:2310–18.
61. Jacquemier J., Padovani L., Rabayrol L., Lakhani S.R., Penault-Llorca F., et al. 2005. Typical medullary breast carcinomas have a basal/myoepithelial phenotype. J. Pathol. 207:260–68
62. Lakhani S.R., Reis-Filho J.S., Fulford L., Penault-Llorca F., van der Vijver M., et al. 2005. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin. Cancer Res. 11:5175–80.
63. 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. 39:165–67.
64. Cox A., Dunning A.M., Garcia-Closas M., Balasubramanian S., Reed M.W., et al. 2007. A common coding variant in CASP8 is associated with breast cancer risk. Nat. Genet. 39:352–58.
65. Hunter D.J., Kraft P., Jacobs K.B., Cox D.G., Yeager M., et al. 2007. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat. Genet. 39:870–74.
66. Stacey S.N., Manolescu A., Sulem P., Rafnar T., Gudmundsson J., et al. 2007. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat. Genet. 39:865–69.
67. Easton D.F., Pooley K.A., Dunning A.M., Pharoah P.D., Thompson D., et al. 2007. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–93.
68. Collab. Group Horm. Factors Breast Cancer. 1996. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 347:1713–27.
69. Collab. Group Horm. Factors Breast Cancer. 1997. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350:1047–59.
70. Collab. Group Horm. Factors Breast Cancer. 2001. Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 358:1389–99.
71. Andrieu N., Goldgar D.E., Easton D.F., Rookus M., Brohet R., et al. 2006. Pregnancies, breastfeeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS). J. Natl. Cancer Inst. 98:535–44.
72. Brohet R.M., Goldgar D.E., Easton D.F., Antoniou A.C., Andrieu N., et al. 2007. Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J. Clin. Oncol. 25:3831–36.
73. Chang-Claude J., Andrieu N., Rookus M., Brohet R., Antoniou A.C., et al. 2007. Age at menarche and menopause and breast cancer risk in the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol. Biomark. Prev. 16:740–46.
74. Antoniou A.C., Sinilnikova O.M., Simard J., Leone M., Dumont M., et al. 2007. RAD51 135G–>C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am. J. Hum. Genet. 81:1186–200.
75. Pharoah P.D., Antoniou A., Bobrow M., Zimmern R.L., Easton D.F., Ponder BA. 2002. Polygenic susceptibility to breast cancer and implications for prevention. Nat. Genet. 31:33–36.
76. Farmer H., McCabe N., Lord C.J., Tutt A.N., Johnson D.A., et al. 2005. Targeting the DNA repairdefect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–21.
77. McCabe N., Turner N.C., Lord C.J., Kluzek K., Bialkowska A., et al. 2006. Deficiency in the repairof DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymeraseinhibition. Cancer Res. 66:8109–15.

Электронный вариант:  скачать

---

В последние годы в нашем понимании генетической предрасположенности к раку молочной железыбыл достигнут значительный прогресс. В настоящее время известно три класса факторов генетическойпредрасположенности, классифицированных по риску развития рака молочной железы. Гены BRCA1 иBRCA2 являются генами предрасположенности к развитию рака молочной железы высокой пенетрантности,определенные с помощью геномных ассоциативных исследований и позиционного клонирования. Скринингмутаций в генах, функционально связанных с BRCA1 и/или BRCA2, выявил четыре гена, CHEK2, ATM,BRIP1 и PALB2; мутации в этих генах редки и определяют промежуточный риск рака молочной железы. Ассоциативные исследования определили восемь общих вариантов, связанных с низко пенетрантнойпредрасположенностью к раку молочной железы. Несмотря на все эти открытия, большая часть семейногориска рака молочной железы остается невыясненной. В этом обзоре мы описываем известные генетическиефакторы предрасположенности, излагаем методы, с помощью которых они были выделены, более подробноостанавливаемся на генах BRCA1 и BRCA2, и рассматриваем вопросы о применении в клинике знаний огенетической предрасположенности к раку молочной железы.