Molecular profiles of hereditary epithelial ovarian cancers and their implications for the biology of this disease

Amir A Jazaeri, Amir A Jazaeri

Abstract

BRCA1 and BRCA2 germline mutations account for the majority of hereditary ovarian cancers and comprise 10% of total cases. Ovarian cancers arising from these mutations exhibit both overlapping and distinct clinical and molecular features. The expression profiles of sporadic ovarian cancers show similarities to those of BRCA1 and BRCA2-related tumors suggesting that BRCA-related pathways may be involved in their development as well. The purpose of this review is to consider the available data on ovarian cancers in the context of other investigations of BRCA-related transcriptional alterations, and highlight areas for future research.

Figures

Figure 1
Figure 1
Overall expression differences between BRCA1‐linked, BRCA2‐linked, and sporadic ovarian epithelial cancers. (A) Unsupervised multidimensional scaling model based on the overall gene expression in BRCA1‐linked, BRCA2‐linked, and sporadic tumors. (B) The magnitude of differences in gene expression between various tumor groups as determined by the number of genes differentially expressed among the tumor groups when the uniform statistical cutoff P

Figure 2

BRCA1 and BRCA2‐discriminating genes also…

Figure 2

BRCA1 and BRCA2‐discriminating genes also segregate sporadic ovarian cancers into two groups. (A)…

Figure 2
BRCA1 and BRCA2‐discriminating genes also segregate sporadic ovarian cancers into two groups. (A) Hierarchical clustering of 110 non‐redundant genes with statistically significant differential expression between BRCA1‐linked (B1) and BRCA2‐linked (B2) tumors (modified F test, P
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    1. Antoniou, A.C. , Pharoah, P.D. , Narod, S. , Risch, H.A. , Eyfjord, J.E. , Hopper, J.L. , Olsson, H. , Johannsson, O. , Borg, A. , Pasini, B. , Radice, P. , Manoukian, S. , Eccles, D.M. , Tang, N. , Olah, E. , Anton-Culver, H. , Warner, E. , Lubinski, J. , Gronwald, J. , Gorski, B. , Tulinius, H. , Thorlacius, S. , Eerola, H. , Nevanlinna, H. , Syrjakoski, K. , Kallioniemi, O.P. , Thompson, D. , Evans, C. , Peto, J. , Lalloo, F. , Evans, D.G. , Easton, D.F. , 2005. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J. Med. Genet.. 42, 602–603. - PMC - PubMed
    1. Boyd, J. , Sonoda, Y. , Federici, M.G. , Bogomolniy, F. , Rhei, E. , Maresco, D.L. , Saigo, P.E. , Almadrones, L.A. , Barakat, R.R. , Brown, C.L. , Chi, D.S. , Curtin, J.P. , Poynor, E.A. , Hoskins, W.J. , 2000. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA. 283, 2260–2265. - PubMed
    1. Brown, L.A. , Irving, J. , Parker, R. , Kim, H. , Press, J.Z. , Longacre, T.A. , Chia, S. , Magliocco, A. , Makretsov, N. , Gilks, B. , Pollack, J. , Huntsman, D. , 2006. Amplification of EMSY, a novel oncogene on 11q13, in high grade ovarian surface epithelial carcinomas. Gynecol. Oncol. 100, 264–270. - PubMed
    1. Bryant, H.E. , Schultz, N. , Thomas, H.D. , Parker, K.M. , Flower, D. , Lopez, E. , Kyle, S. , Meuth, M. , Curtin, N.J. , Helleday, T. , 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 434, 913–917. - PubMed
    1. Buller, R.E. , Shahin, M.S. , Geisler, J.P. , Zogg, M. , De Young, B.R. , Davis, C.S. , 2002. Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin. Cancer Res.. 8, 1196–1202. - PubMed
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Figure 2
Figure 2
BRCA1 and BRCA2‐discriminating genes also segregate sporadic ovarian cancers into two groups. (A) Hierarchical clustering of 110 non‐redundant genes with statistically significant differential expression between BRCA1‐linked (B1) and BRCA2‐linked (B2) tumors (modified F test, P

References

    1. Antoniou, A.C. , Pharoah, P.D. , Narod, S. , Risch, H.A. , Eyfjord, J.E. , Hopper, J.L. , Olsson, H. , Johannsson, O. , Borg, A. , Pasini, B. , Radice, P. , Manoukian, S. , Eccles, D.M. , Tang, N. , Olah, E. , Anton-Culver, H. , Warner, E. , Lubinski, J. , Gronwald, J. , Gorski, B. , Tulinius, H. , Thorlacius, S. , Eerola, H. , Nevanlinna, H. , Syrjakoski, K. , Kallioniemi, O.P. , Thompson, D. , Evans, C. , Peto, J. , Lalloo, F. , Evans, D.G. , Easton, D.F. , 2005. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J. Med. Genet.. 42, 602–603.
    1. Boyd, J. , Sonoda, Y. , Federici, M.G. , Bogomolniy, F. , Rhei, E. , Maresco, D.L. , Saigo, P.E. , Almadrones, L.A. , Barakat, R.R. , Brown, C.L. , Chi, D.S. , Curtin, J.P. , Poynor, E.A. , Hoskins, W.J. , 2000. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA. 283, 2260–2265.
    1. Brown, L.A. , Irving, J. , Parker, R. , Kim, H. , Press, J.Z. , Longacre, T.A. , Chia, S. , Magliocco, A. , Makretsov, N. , Gilks, B. , Pollack, J. , Huntsman, D. , 2006. Amplification of EMSY, a novel oncogene on 11q13, in high grade ovarian surface epithelial carcinomas. Gynecol. Oncol. 100, 264–270.
    1. Bryant, H.E. , Schultz, N. , Thomas, H.D. , Parker, K.M. , Flower, D. , Lopez, E. , Kyle, S. , Meuth, M. , Curtin, N.J. , Helleday, T. , 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 434, 913–917.
    1. Buller, R.E. , Shahin, M.S. , Geisler, J.P. , Zogg, M. , De Young, B.R. , Davis, C.S. , 2002. Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin. Cancer Res.. 8, 1196–1202.
    1. Cass, I. , Baldwin, R.L. , Varkey, T. , Moslehi, R. , Narod, S.A. , Karlan, B.Y. , 2003. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer. 97, 2187–2195.
    1. Chan, K.Y. , Ozcelik, H. , Cheung, A.N. , Ngan, H.Y. , Khoo, U.S. , 2002. Epigenetic factors controlling the BRCA1 and BRCA2 genes in sporadic ovarian cancer. Cancer Res.. 62, 4151–4156.
    1. Chen, S. , Iversen, E.S. , Friebel, T. , Finkelstein, D. , Weber, B.L. , Eisen, A. , Peterson, L.E. , Schildkraut, J.M. , Isaacs, C. , Peshkin, B.N. , Corio, C. , Leondaridis, L. , Tomlinson, G. , Dutson, D. , Kerber, R. , Amos, C.I. , Strong, L.C. , Berry, D.A. , Euhus, D.M. , Parmigiani, G. , 2006. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J. Clin. Oncol. 24, 863–871.
    1. Evans, D.G. , Shenton, A. , Woodward, E. , Lalloo, F. , Howell, A. , Maher, E.R. , 2008. Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a Clinical Cancer Genetics service setting: risks of breast/ovarian cancer quoted should reflect the cancer burden in the family. BMC Cancer. 8, 155
    1. Gurtan, A.M. , D'Andrea, A.D. , 2006. Dedicated to the core: understanding the Fanconi anemia complex. DNA Repair (Amst.). 5, 1119–1125.
    1. Hedenfalk, I. , Duggan, D. , Chen, Y. , Radmacher, M. , Bittner, M. , Simon, R. , Meltzer, P. , Gusterson, B. , Esteller, M. , Kallioniemi, O.P. , Wilfond, B. , Borg, A. , Trent, J. , Raffeld, M. , Yakhini, Z. , Ben-Dor, A. , Dougherty, E. , Kononen, J. , Bubendorf, L. , Fehrle, W. , Pittaluga, S. , Gruvberger, S. , Loman, N. , Johannsson, O. , Olsson, H. , Sauter, G. , 2001. Gene-expression profiles in hereditary breast cancer. N. Engl. J. Med. 344, 539–548.
    1. Hedenfalk, I. , Ringner, M. , Ben-Dor, A. , Yakhini, Z. , Chen, Y. , Chebil, G. , Ach, R. , Loman, N. , Olsson, H. , Meltzer, P. , Borg, A. , Trent, J. , 2003. Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc. Natl. Acad. Sci. USA. 100, 2532–2537.
    1. Hilton, J.L. , Geisler, J.P. , Rathe, J.A. , Hattermann-Zogg, M.A. , DeYoung, B. , Buller, R.E. , 2002. Inactivation of BRCA1 and BRCA2 in ovarian cancer. J. Natl. Cancer Inst. 94, 1396–1406.
    1. Hughes-Davies, L. , Huntsman, D. , Ruas, M. , Fuks, F. , Bye, J. , Chin, S.F. , Milner, J. , Brown, L.A. , Hsu, F. , Gilks, B. , Nielsen, T. , Schulzer, M. , Chia, S. , Ragaz, J. , Cahn, A. , Linger, L. , Ozdag, H. , Cattaneo, E. , Jordanova, E.S. , Schuuring, E. , Yu, D.S. , Venkitaraman, A. , Ponder, B. , Doherty, A. , Aparicio, S. , Bentley, D. , Theillet, C. , Ponting, C.P. , Caldas, C. , Kouzarides, T. , 2003. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell. 115, 523–535.
    1. Jazaeri, A.A. , Yee, C.J. , Sotiriou, C. , Brantley, K.R. , Boyd, J. , Liu, E.T. , 2002. Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers 8. J. Natl. Cancer Inst. 94, 990–1000.
    1. Jeng, Y.M. , Cai-Ng, S. , Li, A. , Furuta, S. , Chew, H. , Chen, P.L. , Lee, E.Y. , Lee, W.H. , 2007. Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation. Oncogene. 26, 6160–6166.
    1. Kennedy, R.D. , D'Andrea, A.D. , 2005. The Fanconi anemia/BRCA pathway: new faces in the crowd. Genes Dev.. 19, 2925–2940.
    1. King, M.C. , Marks, J.H. , Mandell, J.B. , New York Breast Cancer Study Group2003. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 302, 643–646.
    1. Kote-Jarai, Z. , Williams, R.D. , Cattini, N. , Copeland, M. , Giddings, I. , Wooster, R. , tePoele, R.H. , Workman, P. , Gusterson, B. , Peacock, J. , Gui, G. , Campbell, C. , Eeles, R. , 2004. Gene expression profiling after radiation-induced DNA damage is strongly predictive of BRCA1 mutation carrier status. Clin. Cancer Res.. 10, 958–963.
    1. Levitus, M. , Waisfisz, Q. , Godthelp, B.C. , de Vries, Y. , Hussain, S. , Wiegant, W.W. , Elghalbzouri-Maghrani, E. , Steltenpool, J. , Rooimans, M.A. , Pals, G. , Arwert, F. , Mathew, C.G. , Zdzienicka, M.Z. , Hiom, K. , De Winter, J.P. , Joenje, H. , 2005. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat. Genet.. 37, 934–935.
    1. Levitus, M. , Joenje, H. , de Winter, J.P. , 2006. The Fanconi anemia pathway of genomic maintenance. Cell Oncol. 28, 3–29.
    1. Levran, O. , Attwooll, C. , Henry, R.T. , Milton, K.L. , Neveling, K. , Rio, P. , Batish, S.D. , Kalb, R. , Velleuer, E. , Barral, S. , Ott, J. , Petrini, J. , Schindler, D. , Hanenberg, H. , Auerbach, A.D. , 2005. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat. Genet.. 37, 931–933.
    1. Lim, S.L. , Smith, P. , Syed, N. , Coens, C. , Wong, H. , van der Burg, M. , Szlosarek, P. , Crook, T. , Green, J.A. , 2008. Promoter hypermethylation of FANCF and outcome in advanced ovarian cancer. Br. J. Cancer. 98, 1452–1456.
    1. Milne, R.L. , Osorio, A. , Cajal, T.R. , Vega, A. , Llort, G. , de la Hoya, M. , Diez, O. , Alonso, M.C. , Lazaro, C. , Blanco, I. , Sanchez-de-Abajo, A. , Caldes, T. , Blanco, A. , Grana, B. , Duran, M. , Velasco, E. , Chirivella, I. , Cardenosa, E.E. , Tejada, M.I. , Beristain, E. , Miramar, M.D. , Calvo, M.T. , Martinez, E. , Guillen, C. , Salazar, R. , San Roman, C. , Antoniou, A.C. , Urioste, M. , Benitez, J. , 2008. The average cumulative risks of breast and ovarian cancer for carriers of mutations in BRCA1 and BRCA2 attending genetic counseling units in Spain. Clin. Cancer Res.. 14, 2861–2869.
    1. Modugno, F. , Moslehi, R. , Ness, R.B. , Nelson, D.B. , Belle, S. , Kant, J.A. , Wheeler, J.E. , Wonderlick, A. , Fishman, D. , Karlan, B. , Risch, H. , Cramer, D.W. , Dube, M.P. , Narod, S.A. , 2003. Reproductive factors and ovarian cancer risk in Jewish BRCA1 and BRCA2 mutation carriers (United States). Cancer Causes Control. 14, 439–446.
    1. Pal, T. , Permuth-Wey, J. , Kapoor, R. , Cantor, A. , Sutphen, R. , 2007. Improved survival in BRCA2 carriers with ovarian cancer. Fam. Cancer. 6, 113–119.
    1. Pavelka, J.C. , Li, A.J. , Karlan, B.Y. , 2007. Hereditary ovarian cancer—assessing risk and prevention strategies. Obstet. Gynecol. Clin. North Am.. 34, 651–665. vii-viii
    1. Pharoah, P.D. , Easton, D.F. , Stockton, D.L. , Gayther, S. , Ponder, B.A. , 1999. Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group. Cancer Res.. 59, 868–871.
    1. Potapova, A. , Hoffman, A.M. , Godwin, A.K. , Al-Saleem, T. , Cairns, P. , 2008. Promoter hypermethylation of the PALB2 susceptibility gene in inherited and sporadic breast and ovarian cancer. Cancer Res.. 68, 998–1002.
    1. Press, J.Z. , De Luca, A. , Boyd, N. , Young, S. , Troussard, A. , Ridge, Y. , Kaurah, P. , Kalloger, S.E. , Blood, K.A. , Smith, M. , Spellman, P.T. , Wang, Y. , Miller, D.M. , Horsman, D. , Faham, M. , Gilks, C.B. , Gray, J. , Huntsman, D.G. , 2008. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer. 8, 17
    1. Quinn, J.E. , James, C.R. , Stewart, G.E. , Mulligan, J.M. , White, P. , Chang, G.K. , Mullan, P.B. , Johnston, P.G. , Wilson, R.H. , Harkin, D.P. , 2007. BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy. Clin. Cancer Res.. 13, 7413–7420.
    1. Rahman, N. , Seal, S. , Thompson, D. , Kelly, P. , Renwick, A. , Elliott, A. , Reid, S. , Spanova, K. , Barfoot, R. , Chagtai, T. , Jayatilake, H. , McGuffog, L. , Hanks, S. , Evans, D.G. , Eccles, D. , Breast Cancer Susceptibility Collaboration (UK), Easton D.F. , Stratton, M.R. , 2007. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet.. 39, 165–167.
    1. Ramus, S.J. , Fishman, A. , Pharoah, P.D. , Yarkoni, S. , Altaras, M. , Ponder, B.A. , 2001. Ovarian cancer survival in Ashkenazi Jewish patients with BRCA1 and BRCA2 mutations. Eur. J. Surg. Oncol. 27, 278–281.
    1. Risch, H.A. , McLaughlin, J.R. , Cole, D.E. , Rosen, B. , Bradley, L. , Kwan, E. , Jack, E. , Vesprini, D.J. , Kuperstein, G. , Abrahamson, J.L. , Fan, I. , Wong, B. , Narod, S.A. , 2001. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am. J. Hum. Genet.. 68, 700–710.
    1. Rubin, S.C. , Benjamin, I. , Behbakht, K. , Takahashi, H. , Morgan, M.A. , LiVolsi, V.A. , Berchuck, A. , Muto, M.G. , Garber, J.E. , Weber, B.L. , Lynch, H.T. , Boyd, J. , 1996. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N. Engl. J. Med. 335, 1413–1416.
    1. Sakai, W. , Swisher, E.M. , Karlan, B.Y. , Agarwal, M.K. , Higgins, J. , Friedman, C. , Villegas, E. , Jacquemont, C. , Farrugia, D.J. , Couch, F.J. , Urban, N. , Taniguchi, T. , 2008. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 451, 1116–1120.
    1. Sekine, M. , Nagata, H. , Tsuji, S. , Hirai, Y. , Fujimoto, S. , Hatae, M. , Kobayashi, I. , Fujii, T. , Nagata, I. , Ushijima, K. , Obata, K. , Suzuki, M. , Yoshinaga, M. , Umesaki, N. , Satoh, S. , Enomoto, T. , Motoyama, S. , Tanaka, K. , Japanese Familial Ovarian Cancer Study Group2001. Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population. Clin. Cancer Res.. 7, 3144–3150.
    1. Tan, D.S. , Rothermundt, C. , Thomas, K. , Bancroft, E. , Eeles, R. , Shanley, S. , Ardern-Jones, A. , Norman, A. , Kaye, S.B. , Gore, M.E. , 2008. “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J. Clin. Oncol. 25, (34) 5530–5536.
    1. Taniguchi, T. , Tischkowitz, M. , Ameziane, N. , Hodgson, S.V. , Mathew, C.G. , Joenje, H. , Mok, S.C. , D'Andrea, A.D. , 2003. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat. Med. 9, 568–574.
    1. Thrall, M. , Gallion, H.H. , Kryscio, R. , Kapali, M. , Armstrong, D.K. , DeLoia, J.A. , 2006. BRCA1 expression in a large series of sporadic ovarian carcinomas: a Gynecologic Oncology Group study. Int. J. Gynecol. Cancer. 16, (Suppl. 1) 166–171.
    1. Tischkowitz, M. , Xia, B. , Sabbaghian, N. , Reis-Filho, J.S. , Hamel, N. , Li, G. , van Beers, E.H. , Li, L. , Khalil, T. , Quenneville, L.A. , Omeroglu, A. , Poll, A. , Lepage, P. , Wong, N. , Nederlof, P.M. , Ashworth, A. , Tonin, P.N. , Narod, S.A. , Livingston, D.M. , Foulkes, W.D. , 2007. Analysis of PALB2/FANCN-associated breast cancer families. Proc. Natl. Acad. Sci. USA. 104, 6788–6793.
    1. Walker, L.C. , Waddell, N. , Ten Haaf, A. , Grimmond, S. , Spurdle, A.B. , kConFab Investigators2008. Use of expression data and the CGEMS genome-wide breast cancer association study to identify genes that may modify risk in BRCA1/2 mutation carriers. Breast Cancer Res. Treat. 112, 229–236.
    1. Wang, Z. , Li, M. , Lu, S. , Zhang, Y. , Wang, H. , 2006. Promoter hypermethylation of FANCF plays an important role in the occurrence of ovarian cancer through disrupting Fanconi anemia-BRCA pathway. Cancer Biol. Ther. 5, 256–260.
    1. Weberpals, J.I. , Clark-Knowles, K.V. , Vanderhyden, B.C. , 2008. Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway. J. Clin. Oncol. 26, 3259–3267.
    1. Xia, B. , Sheng, Q. , Nakanishi, K. , Ohashi, A. , Wu, J. , Christ, N. , Liu, X. , Jasin, M. , Couch, F.J. , Livingston, D.M. , 2006. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell. 22, 719–729.

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