Abstract
Loss of heterozygosity (LOH) in loci of the 17q21 and 13q12‐13 regions can collaborate in the inactivation of BRCA1, BRCA2, and possibly other genes implicated in the pathogenesis of breast carcinomas. We investigate allelic losses in microsatellites of the BRCA1 and BRCA2 regions, and their correlations with seven pathologic parameters in 140 breast carcinomas. Those cases showing LOH in the region of the RB gene, 13q14, were excluded from the study. The LOH analysis was performed by amplifying DNA by PCR, using four markers of the 17q21 region (D17S856, D17S855, D17S1323, and D17S1327) and four markers of the 13q12‐13 region (D13S290, D13S260, D13S310, and D13S267). LOH in the BRCA1 region was found in 47% of tumors, correlating significantly with estrogen receptor content (p = 0.025), progesterone receptors (p = 0.004), higher grade (p = 0.0008), peritumoral vessel invasion (p = 0.001), and lymph node metastases (p = 0.002). When we excluded the cases with LOH in the BRCA2 region and those not informative for it, the significance disappeared. In the BRCA2 region, a rate of LOH of 51% was found; it correlated significantly with estrogen receptor content (p = 0.002), progesterone receptors (p =0.03), peritumoral vessel invasion (p = 0.005), higher grade (p =0.002), and lymph node metastases (p = 0.001). When cases with BRCA1 losses and those not informative were excluded, again the significance disappeared. Concomitant losses in the BRCA1 and BRCA2 regions were found in 32% of cases, correlating significantly with lymph node metastases (p = 0.0002), estrogen receptor content (p = 0.003), progesterone receptors (p = 0.001), histologic grade (p =0.01), and peritumoral vessel invasion (p = 0.0004). These results suggest that concomitant losses in both regions could have a functional effect, influencing the presence of a poor tumor pathophenotype in breast carcinomas.
Similar content being viewed by others
References
Weinberg RA:Tumor suppressor genes. Science 254: 1138–1146, 1991
Radford DM, Phillips NJ, Fair KL, Ritter HH, Holt M, Donis-Keller H: Allelic loss and progression of breast cancer. Cancer Res 55: 5180–5183, 1995
Skirnisdottir S, Eiriksdottir G, Baldursson T, Barkardottir RB, Egilsson V, Ingvarsson S: High frequency of allelic imbalance at chromosome region 16q22-23 in human breast cancer: Correlation with high PgR and low S phase. Int J Cancer 64: 112–116, 1995
Deng G, Lu Y, Flotnikov G, Thor AD, Smith HS: Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274: 2057–2059, 1996
Patel U, Grundfest-Broniatowski S, Gupta M, Banerjee S: Microsatellite instabilities at five chromosomes in primary breast tumors. Oncogene 9: 3695–3700, 1994
Chen L-C, Neubauer A, Kurisu W, Waldman FM, Ljung B-M, Goodson W III, Goldman ES, Moore D II, Balazs M, Liu E, Mayall BH, Smith HS: Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer. Proc Natl Acad Sci USA 88: 3847–3851, 1991
Zenklusen JC, Bieche I, Lidereau R, Conti CJ: (C-A)n microsatellite repeat D7S522 is the most commonly deleted region in human primary breast cancer. Proc Natl Acad Sci USA 91: 12155–12158, 1994
Friedman LS, Ostermeyer EA, Lynch ED, Szabo CI, Anderson LA, Dowd P, Lee MK, Rowell SE, Boyd F, King M-C: The search for BRCA1. Cancer Res 54: 6374–6382, 1994
Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King M-C: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250: 1684–1689, 1990
Wooster R, Neuhausen SL, 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 CJ, Menko FH, Daly PA, Ormiston W, McManus R, Pye C, Lewis CM, Cannon-Albright LA, Peto J, Ponder BAJ, Skolnick MH, Easton DF, Goldgar DE, Stratton MR: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265:2088–2090, 1994
Szabo CI, King M-C: Inherited breast and ovarian cancer. Hum Mol Genet 4: 1811–1817, 1995
Kellsell DP, Spurr NK, Barnes DM, Gusterson B, Bishop DT: Combined loss of BRCA1/BRCA2 in grade 3 breast carcinomas. Lancet 347: 1554–1555, 1996
Beckmann MW, Picard F, An HX, van Roeyen CRC, Dominik SI, Mosny DS, Schnurch HG, Bender HG, Niederacher D: Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer. Br J Cancer 73: 1220–1226, 1996
van der Berg J, Johannsson O, Hakansson S, Olsson H, Borg A: Allelic loss at chromosome 13q12-q13 is associated with poor prognosis in familial and sporadic breast cancer. Br J Cancer 74: 1615–1619, 1996
Cleton-Jansen A-M, Collins N, Lakhani SR, Weissenbach J, Devilee P, Cornelisse CJ, Stratton MR: Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13. Br J Cancer 72: 1241–1244, 1995
Paulson TG, Wright FA, Parker BA, Russack V, Wahl GM: Microsatellite instability correlates with reduced survival and poor disease prognosis in breast cancer. Cancer Res 56: 4021–4026, 1996
Marcus JN, Watson P, Page DL, Narod SA, Lenoir GM, Tonin P, Linder-Stephenson L, Salerno G, Conway TA, Lynch HT: Hereditary breast cancer. Pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 77: 697–709, 1996
Porter DE, Dixon M, Smyth E, Steel CM: Breast cancer survival in BRCA1 carriers. Lancet 341: 184–185, 1993
Rubin SC, Benjamin I, Behbakht K, Takahashi H, Morgan MA, Livolsi VA, Berchuck A, Muto MG, Garber JE, Weber BL, Lynch HT, Boyd J: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 335: 1413–1416, 1996
Garcia-Patiño E, Gomendio B, Provencio M, Silva JM, Garcia JM, España P, Bonilla F: Germ-line BRCA1 mutations inwomenwith sporadic breast cancer: Clinical correlations. J Clin Oncol 16: 115–120, 1998
Oto M, Miyake S, Yuasa Y: Optimization of nonradioisotopic single strand conformation polymorphism analysis with a conventional minislab gel electrophoresis apparatus. Ann Biochem 213: 19–22, 1993
Borg A, Zhang QX, Alm P, Olsson H, Sellberg G: The retinoblastoma gene in breast cancer: allele loss is not correlated with loss of gene protein expression. Cancer Res 52: 2991–2994, 1992
Tsukamoto K, Ito N, Yoshimoto M, Iwase T, Tada T, Kasumi F, Nakamura Y, Emi M: Two distinct commonly deleted regions on chromosome 13q suggest involvement of BRCA2 and retinoblastoma genes in sporadic breast carcinomas. Cancer 78: 1929–1934, 1996
Lancaster JM, Wooster R, Mangion J, Phelan CM, Cochran C, Gumbs C, Seal S, Barfoof R, Collins N, Bignell G, Patel S, Hamoudi R, Larsson C, Wiseman RW, Berchuck A, Iglehart JD, Marks JR, Ashworth A, Stratton MR, Futreal PA: BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13: 238–240, 1996
Teng DH-F, Bogden R, Mitchell J, Baumgard M, Bell R, Berry S, Davis T, Ha PC, Kehrer R, Jammulapati S, Chen Q, Offit K, Skolnick MH, Tavtigian SV, Jhanwar S, Swedlund B, Wong AKC, Kamb A: Low incidence of BRCA2 mutations in breast carcinoma and other cancers. Nat Genet 13: 241–244, 1996
Miki Y, Katagiri T, Kasumi F, Yoshimoto T, Nakamura Y: Mutation analysis in the BRCA2 gene in primary breast cancers. Nat Genet 13: 245–247, 1996
Stratton JF, Gayther SA, Russell P, Dearden J, Gore M, Blake P, Easton D, Ponder BAJ: Contribution of BRCA1 mutations to ovarian cancer. N Engl J Med 336: 1125–1130, 1997
Marcus JN, Page DL, Watson P, Narod SA, Lenoir GM, Lynch HT: BRCA1 and BRCA2 hereditary breast carcinoma phenotypes. Cancer 80: 543–556, 1997
Harris JR, Morrow M, Norton L: Malignant tumors of the breast. In: DeVita VT, Hellman S, Rosenberg SA (eds), Cancer Principles and Practice of Oncology. Lippincott-Noreu, Philadelphia, 5th Edition, Vol 2, 1997, pp 1557–1616
Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM: Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88: 265–275, 1997
Sharan SK, Morimatsu M, Albrecht U, Lim D-S, Regel E, Dinh C, Sands A, Eichele G, Hasty P, Bradley A: Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking BRCA2. Nature 386: 804–810, 1997
Vaughn JP, Cirisano FD, Huper G, Berchuck A, Futreal PA, Marks JR, Iglehart JD: Cell cycle control of BRCA2. Cancer Res 56: 4590–4594, 1996
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Silva, J.M., Gonzalez, R., Provencio, M. et al. Loss of heterozygosity in BRCA1 and BRCA2 markers and high‐grade malignancy in breast cancer. Breast Cancer Res Treat 53, 9–17 (1999). https://doi.org/10.1023/A:1006082117266
Issue Date:
DOI: https://doi.org/10.1023/A:1006082117266