Genetic Characterization of Hereditary Breast Cancer

General information

Running from January 1995 - April 1999
Supported by the Dutch Cancer Society (grant number RUL 95-1039)
Project-leaders: Dr. P. Devilee, Prof.dr. C.J. Cornelisse, Dr. J.G.M. Klijn (Daniel den Hoed Cancer Clinic, Rotterdam)
Personnel: Tamara Peelen (until 4/99), Margreethe van Vliet (until 12/98), Anne Petrij-Bosch (until 5/97)
Closest collaborators: Breast Cancer Linkage Consortium, Dr. H.F.A. Vasen (Foundation for the Detection of Hereditary Tumors), The Dutch National Working Party on Hereditary Breast Cancer
This page was last updated on December 3, 1997

Background and objectives

Several genes predisposing to breast cancer have been identified to date, i.e., BRCA1, BRCA2, TP53, and PTEN. Mutations in BRCA1 are predicted to account for most families with breast and ovarian cancer, while families with a case of male breast cancer are mainly attributed to BRCA2. The Li-Fraumeni syndrome is caused by mutations in TP53, while PTEN mutations cause Cowden syndrome. In a total set of approximately 170 breast cancer families, collected for research purposes, the main objective of this project is to establish the proportion attributable to each of these genes, using a combination of linkage and mutation analysis. In families that cannot be attributed to any of these genes, a linkage search will be initiated to localize new breast cancer predisposing genes.

Recent results

Protein truncation testing. After BRCA1 was identified, we have successfully applied the protein truncation test (PTT) to rapidly detect frameshifting and nonsense mutations, which comprise the majority of gene-defects in BRCA1 (Hogervorst et al., 1995). This test has proven to be very robust for exon 11, which comprises 61% of the BRCA1-coding region, and can be easily PCR-amplified from genomic DNA.

Genetic heterogeneity. Using mutation-screening for BRCA1, and linkage analysis for BRCA2, we showed that almost all high-risk breast cancer families (those containing at least 4 cases of breast cancer diagnosed under the age of 60, and any number of ovarian cancer cases) are caused by either of these genes (Peelen et al., 1996).

Founder mutations. In a national collaborative effort, together with a laboratory in Brussels (Belgium), we screened 666 breast cancer families for mutations in BRCA1, in order to establish the spectrum of mutations in this particular corner of Europe (Peelen et al., 1997). A number of mutations were found repeatedly, among which the 2804delAA was most conspicuous in that it was found in 19 families. Each of the mutations found more than 5 times was shown by haplotype analysis to have derived from a single common ancestor.

Large genomic BRCA1 deletions. In a number of families where linkage analysis had provided good evidence for the presence of a BRCA1 mutation, all mutation searches, including complete sequencing of all the coding regions and flanking introns, had remained negative. We then performed cDNA-analysis and found that exon 22 was missing in the transcripts of two families, that exon 13 was missing in the transcripts of two other families, and that exons 13-16 were missing in the transcripts of a fifth family. Southern blot analysis indicated the presence of large genomic deletions (Petrij -Bosch et al., 1997). After isolating and characterizing the deletion-junction fragment these deletions were found to be 510 bp around exon 22, 3.8 kb around exon 13, and approximately 14 kb around exons 13-16. These deletions are missed by virtually all PCR-based mutation-screening echnolog. Subsequently, haplotype analysis established he del22 and del13 mutations as major founder mutations in the Dutch population as well, comprising as much as 34% of the total mutation spectrum.

Publications

Cornelis, R., Vasen, H., Meijers-Heijboer, H., Ford, D., Van Vliet, M., Van Tilborg, A., Cleton, F., Klijn, J., Menko, F., Meera Khan, P., Cornelisse, C., Devilee, P. (1995) Age at diagnosis as an indicator of eligibility for BRCA1 DNA-testing in familial breast cancer. Hum. Genet. 95: 539-544.

Cornelis, R.S., Van Vliet, M., Van de Vijver, M.J., Vasen, H.F.A., Voute, P.A., Top, B., Meera Khan, P., Devilee, P., Cornelisse, C.J. (1997) Three germline mutations in the TP53 gene. Hum. Mutat. 9: 157-163.

Hogervorst, F., Cornelis, R., Bout, M., Van Vliet, M., Oosterwijk, J., Olmer, R., Bakker, B., Klijn, J., Vasen, H., Meijers-Heijboer, H., Menko, F., Cornelisse, C., Den Dunnen, J., Devilee, P., Van Ommen, G. (1995) Rapid detection of BRCA1 mutations by the Protein Truncation Test. Nature Genet. 10:208-212.

Peelen, T., Cornelis, R.C., Van Vliet, M., Petrij-Bosch, A., Cleton-Jansen, A.-M., Meijers-Heijboer, H., Klijn, J.G.M., Vasen, H.F.A., Cornelisse, C.J., Devilee, P. (1996) The majority of 22 Dutch high-risk breast cancer families are due to either BRCA1 or BRCA2. Eur. J. Hum. Genet. 4: 225-230.

Peelen, T., Van Vliet, M., Petrij-Bosch, A., Mieremet, R., Szabo, C., Van den Ouweland, A.M.W., Hogervorst, F., Brohet, R., Ligtenberg, M.J.L., Teugels, E., Van der Luijt, R., Van der Hout, A.H., Gille, J.J.P., Pals, G., Jedema, I., Olmer, R., Van Leeuwen, I., Newman, B., Plandsoen, M., Van der Est, M., Brink, G., Hageman, S., Arts, P.J.W., Bakker, M.M., Willems, H.W., Van der Looij, E., Neyns, B., Bonduelle, M., Jansen, R., Oosterwijk, J.C., Sijmons, R., Smeets, H.J.M., Van Asperen, C.J., Meijers-Heijboer, H., Klijn, J.G.M., De Greve, J., King, M.C., Menko, F.H., Brunner, H.G., Halley, D., Van Ommen, G.-J.B., Vasen, H.F.A., Cornelisse, C.J., Van 't Veer, L.J., De Knijff, P., Bakker, E., Devilee, P. (1997) A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am. J. Hum. Genet. 60: 1041-1049.

Petrij-Bosch, A., Peelen, T., Van Vliet, M., Van Eijk, R., Olmer, R., Drusedau, M., Hogervorst, F.B.L., Hageman, S., Arts, P.J.W., Ligtenberg, M.J.L., Meijers-Heijboer, H., Klijn, J.G.M., Vasen, H.F.A., Cornelisse, C.J., Van 't Veer, L.J., Bakker, E., Van Ommen, G.-J.B., Devilee, P. (1997) BRCA1 genomic deletions are major founder mutations in Dutch breast cancer families. Nature Genet. 17: 341-342


Contributions to publications by the Breast Cancer Linkage Consortium

Lakhani, S.R., Easton, D.F., Stratton, M.R., Storferisser, A., Anderson, T.J., Farid, L.M., Gusterson, B.A., Jaquemier, J., Sloane, J.P., Venter, D., Vandevijver, M.J., Bishop, D.T., Barkardottir, R.B., Bignon, Y.J., Cornelisse, C., Changclaude, J., Daly, P.A., Devilee, P., Egilsson, V., Ford, D., Goldgar, D., Haites, N., Hamann, U., Klijn, J.G.M., Lasset, C., Lenoir, G., McManus, R., Neuhausen, S., Ormiston, W., Ponder, B.A.J., Peto, J., Steel, C.M., Stoppalyonnet, D., Smyth, E., Sobol, H., Spurr, N.K., Scott, R.J., Scherneck, S., Streuwing, J.P., Vasen, H., Weber, B. (1997) Pathology of familial breast cancer: Differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 349: 1505-1510.
 

Phelan, C.M., Rebbeck, T.R., Weber, B.L., Devilee, P., Ruttledge, M.H., Lynch, H.T., Lenoir, G.M., Stratton, M.R., Easton, D.F., Ponder, B.A.J., Cannon-Albright, L., Larsson, C., Goldgar, D.E., Narod, S.A. (1996) Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. Nature Genet. 12: 309-311.
 

Cornelis, R., Neuhausen, S.L., Johansson, O., Arason, A., Kelsell, D., Ponder, B.A.J., Tonin, P., Hamann, U., Lindblom, A., Lalle, P., Longy, M., Olàh, E., Scherneck, S., Bignon, Y., Sobol, H., Chang-Claude, J., Larsson, C., Spurr, N., Borg, A., Barkardottir, R.B., Narod, S., Devilee, P., the Breast Cancer Linkage Consortium (1995) High allele loss rates at 17q12-q21 in breast and ovarian tumors from BRCA1-linked families. Genes Chrom.Cancer 13: 203-210.
 

Easton, D., Ford, D., Bishop, D., the Breast Cancer Linkage Consortium (1995) Breast and ovarian cancer incidence in BRCA1-mutation carriers. Am. J. Hum. Genet. 56: 265-271.
 

Narod, S., Ford, D., Devilee, P., Barkardottir, R., Lynch, H., Smith, S., Ponder, B., Weber, B., Garber, J., Birch, J., Cornelis, R., Kelsell, D., Spurr, N., Smyth, E., Haites, N., Sobol, H., Bignon, Y., Chang-Claude, J., Hamann, U., Lindblom, A., Borg, A., Piver, M., Gallion, H., Struewing, J., Whittemore, A., Tonin, P., Goldgar, D., Easton, D., the Breast Cancer Linkage Consortium (1995) An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Am. J. Hum. Genet. 56: 254-264.
 

Narod, S., Ford, D., Devilee, P., Barkardottir, R.B., Eyfjörd, J., Lenoir, G., Serova, O., Easton, D., Goldgar, D. (1995) Genetic heterogeneity of breast-ovarian cancer revisited. Am. J. Hum. Genet. 57: 957-958.
 

Ford, D., Easton, D., Bishop, D., Narod, S., Goldgar, D., the Breast Cancer Linkage Consortium (1994) Risks of cancer in BRCA1-mutation carriers. Lancet 343: 692-695.
 

Easton, D., Bishop, D., Ford, D., Crockford, G., the Breast Cancer Linkage Consortium (1993) Genetic linkage analysis in familial breast and ovarian cancer: Results from 214 families. Am. J. Hum. Genet. 52: 678-701.


Related publications facilitated by this project

Dudok de Wit, A.C., Tibben, A., Frets, P.G., Meijers-Heijboer, E.J., Devilee, P., Klijn, J.G.M., Oosterwijk, J.C., Niermeijer, M.F. (1997) BRCA1 in the family: A case description of the psychological implications. Am. J. Med. Genet. 71: 63-71.
 

Couch, F.J., Weber, B.L., Borresen, A.L., Brody, L., Casey, G., Devilee, P., Fitzgerald, M., Friend, S., Gayther, S., Goldgar, D., Murphy, P., Szabo, C., Weber, B., Wiseman, R., Anderson, T., Durocher, F., Ganguly, A., King, M.C., Lenoir, G., Narod, S., Olopade, O., Plummer, S., Ponder, B., Serova, O., Simard, J., Stratton, M., Warren, B. (1996) Mutations and polymorphisms in the familial early onset breast cancer (BRCA1) gene. Hum Mutat 8:8-18.
 

Dudok de Wit, A.C., Tibben, A., Frets, P.G., Meijers-Heijboer, E.J., Devilee, P., Niermeijer, M.F. (1996) Males at-risk for the BRCA1-gene, the psychological impact. Psycho-Oncology 5: 251-257.
 

Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., Patel, S., Rice, C., Biggs, P., Hashim, Y., Smith, A., Connor, F., Arason, A., Gudmundsson, J., Ficenec, D., Kelsell, D., Ford, D., Tonin, P., Bishop, D.T., Spurr, N.K., Ponder, B.A.J., Eeles, R., Peto, J., Devilee, P., Cornelisse, C.J., Lynch, H., Narod, S., Lenoir, G., Egilsson, V., Barkardottir, R.B., Easton, D.F., Bentley, D.R., Futreal, P.A., Ashworth, A., Stratton, M.R. (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378: 789-792.
 

Dudok de Wit, A., Meijers-Heijboer, E., Tibben, A., Frets, P., Klijn, J., Devilee, P., Niermeijer, M. (1994) Effect on a Dutch family of predictive DNA-testing for hereditary breast and ovarian cancer. Lancet 344: 197
 

Stratton, M., Ford, D., Neuhausen, S., Seal, S., Wooster, R., Friedman, L., King, M.-C., Egilsson, V., Devilee, P., McManus, R., Daly, P., Smyth, E., Ponder, B., Peto, J., Cannon-Albright, L., Easton, D., Goldgar, D. (1994) Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nature Genet. 7: 103-107.
 

Wooster, R., Neuhausen, S., Mangion, J., Quirk, Y., Ford, D., Collins, N., Nguyen, K., Seal, S., Tran, T., Averill, D., Fields, P., Marshall, G., Narod, S., Lenoir, G., Lynch, H., Feunteun, J., Devilee, P., Cornelisse, C., Menko, F., Daly, P., Ormiston, W., McManus, R., Pye, C., Lewis, C., Cannon-Albright, L., Peto, J., Ponder, B., Skolnick, M., Easton, D., Goldgar, D., Stratton, M. (1994) Localization of a breast cancer susceptibility gene BRCA2 to chromosome 13q12. Science 265: 2088-2090.