A Recurrent Chromosome Breakpoint in Breast Cancer at the NRG1 / Neuregulin 1 / Heregulin Gene

American Association for Cancer Research (AACR) - Tập 64 Số 19 - Trang 6840-6844 - 2004
Huai-En Huang1, Suet‐Feung Chin1, Christophe Ginestier2, Valérie‐Jeanne Bardou2, José Adélaı̈de2, N. Gopalakrishna Iyer1, María J. García1, Jessica C. Pole1, Grace Callagy1, Stephen M. Hewitt3, William J. Gullick4, Jocelyne Jacquemier2, Carlos Caldas1, Max Chaffanet2, Daniel Birnbaum2, Paul A. Edwards1
11Cancer Genomics Program, Hutchison-MRC Research Centre, Departments of Pathology and Oncology, University of Cambridge, Cambridge, United Kingdom;
22Molecular Oncology and Medical Oncology Departments, Marseille Cancer Research Institute, Institut National de la Santé et de la Recherche Médicale and Institut Paoli-Calmettes, Marseille, France;
33Tissue Array Research Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Advanced Technology Center, Bethesda, Maryland; and
44Department of Biosciences, University of Kent, Canterbury, Kent, United Kingdom

Tóm tắt

Abstract Most studies of genomic rearrangements in common cancers have focused on regional gains and losses, but some rearrangements may break within specific genes. We previously reported that five breast cancer cell lines have chromosome translocations that break in the NRG1 gene and that could cause abnormal NRG1 expression. NRG1 encodes the Neuregulins 1 (formerly the Heregulins), ligands for members of the ErbB/epidermal growth factor-receptor family, which includes ErbB2/HER2. We have now screened for breaks at NRG1 in paraffin sections of breast tumors. Tissue microarrays were screened by fluorescence in situ hybridization, with hybridization probes proximal and distal to the expected breakpoints. This screen detects breaks but does not distinguish between translocation or deletion breakpoints. The screen was validated with array-comparative genomic hybridization on a custom 8p12 high-density genomic array to detect a lower copy number of the sequences that were lost distal to the breaks. We also precisely mapped the breaks in five tumors with different hybridization probes. Breaks in NRG1 were detected in 6% (19 of 323) of breast cancers and in some lung and ovarian cancers. In an unselected series of 213 cases with follow-up, breast cancers where the break was detected tended to be high-grade (65% grade III compared with 28% of negative cases). They were, like breast tumors in general, mainly ErbB2 low (11 of 13 were low) and estrogen receptor positive (11 of 13 positive).

Từ khóa


Tài liệu tham khảo

Adelaide J, Huang HE, Murati A, et al A recurrent chromosome translocation breakpoint in breast and pancreatic cancer cell lines targets the neuregulin/NRG1 gene. Genes Chromosomes Cancer 2003;37:333-45.

Richter J, Wagner U, Kononen J, et al High-throughput tissue microarray analysis of cyclin E gene amplification and overexpression in urinary bladder cancer. Am J Pathol 2000;157:787-94.

Ginestier C, Charafe-Jauffret E, Bertucci F, et al Distinct and complementary information provided by use of tissue and DNA microarrays in the study of breast tumor markers. Am J Pathol 2002;161:1223-33.

Courtay-Cahen C, Morris JS, Edwards PA Chromosome translocations in breast cancer with breakpoints at 8p12. Genomics 2000;66:15-25.

Chin SF, Daigo Y, Huang HE, et al A simple and reliable pretreatment protocol facilitates fluorescent in situ hybridisation on tissue microarrays of paraffin wax embedded tumor samples. Mol Pathol 2003;56:275-9.

Isola J, DeVries S, Chu L, Ghazvini S, Waldman F Analysis of changes in DNA sequence copy number by comparative genomic hybridization in archival paraffin-embedded tumor samples. Am J Pathol 1994;145:1301-8.

Fiegler H, Carr P, Douglas EJ, et al DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 2003;36:361-74.

Srinivasan R, Benton E, McCormick F, Thomas H, Gullick WJ Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 growth factor receptors and their ligands, neuregulin-1 alpha, neuregulin-1 beta, and betacellulin, in normal endometrium and endometrial cancer. Clin Cancer Res 1999;5:2877-83.

Kononen J, Bubendorf L, Kallioniemi A, et al Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 1998;4:844-7.

Raj EH, Skinner A, Mahji U, et al Neuregulin 1-alpha expression in locally advanced breast cancer. Breast 2001;10:41-5.

Liu X, Baker E, Eyre HJ, Sutherland GR, Zhou M Gamma-heregulin: a fusion gene of DOC-4 and neuregulin-1 derived from a chromosome translocation. Oncogene 1999;18:7110-4.

Wang XZ, Jolicoeur EM, Conte N, et al gamma-heregulin is the product of a chromosomal translocation fusing the DOC4 and HGL/NRG1 genes in the MDA-MB-175 breast cancer cell line. Oncogene 1999;18:5718-21.

Schaefer G, Fitzpatrick VD, Sliwkowski MX Gamma-heregulin: a novel heregulin isoform that is an autocrine growth factor for the human breast cancer cell line, MDA-MB-175. Oncogene 1997;15:1385-94.

Falls DL Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 2003;284:14-30.

Stern DF ErbBs in mammary development. Exp Cell Res 2003;284:89-98.

Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 1988;54:105-15.

Bradbury JM, Arno J, Edwards PA Induction of epithelial abnormalities that resemble human breast lesions by the expression of the neu/erbB-2 oncogene in reconstituted mouse mammary gland. Oncogene 1993;8:1551-8.

Tognon C, Knezevich SR, Huntsman D, et al Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2002;2:367-76.

Tonon G, Modi S, Wu L, et al t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 2003;33:208-13.

Look AT Oncogenic transcription factors in the human acute leukemias. Science (Wash DC) 1997;278:1059-64.

Thông tin
Thông tin xuất bản

American Association for Cancer Research (AACR)

Tập 64 Số 19

6840-6844

Thông tin tác giả