Top

Published in:

01-11-2007 | Breast Oncology

Correlation of Levels and Patterns of Genomic Instability With Histological Grading of DCIS

Authors: Rachel E. Ellsworth, PhD, Darrell L. Ellsworth, PhD, Brad Love, PhD, Heather L. Patney, BS, Laurel R. Hoffman, BS, Jennifer Kane, HT (ASCP), Jeffrey A. Hooke, MD, Craig D. Shriver, MD

Published in: Annals of Surgical Oncology | Issue 11/2007

Abstract

Background

Histological grading of ductal carcinoma-in-situ (DCIS) lesions separates DCIS into three subgroups (well-, moderately, or poorly differentiated). It is unclear, however, whether breast disease progresses along a histological continuum or whether each grade represents a separate disease. In this study, levels and patterns of allelic imbalance (AI) were examined in DCIS lesions to develop molecular models that can distinguish pathological classifications of DCIS.

Methods

Laser microdissected DNA samples were collected from DCIS lesions characterized by a single pathologist including well- (n = 18), moderately (n = 35), and poorly differentiated (n = 47) lesions. A panel of 52 microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer was used to assess patterns of AI.

Results

The overall frequency of AI increased significantly (P < .001) with increasing grade (well differentiated, 12%; moderately differentiated, 17%; poorly differentiated, 26%). Levels of AI were not significantly different between well- and moderately differentiated grades of disease but were significantly higher (P < .0001) in poorly differentiated compared with well- or moderately differentiated disease. No statistically significant differences in patterns of AI were detected between well- and moderately differentiated disease; however, AI occurred significantly more frequently (P < .05) in high-grade lesions at chromosomes 6q25–q27, 8q24, 9p21, 13q14, and 17p13.1, and significantly more frequently in low-grade lesions at chromosome 16q22.3–q24.3.

Conclusions

The inability to discriminate DCIS at the genetic level suggests that grades 1 and 2 DCIS may represent a single, non–high-grade form of DCIS, whereas poorly differentiated DCIS seems to be a genetically more advanced disease that may represent a discrete disease entity, characterized by a unique spectrum of genetic alterations.

Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7–33PubMed

Consensus Conference Committee. Consensus conference on the classification of ductal carcinoma in situ. Hum Pathol 1997;28:1221–5CrossRef

Tavassoli FA, Hoefler H, Rosai J, et al. Intraductal proliferative lesions. In: Tavassoli FA, Devilee P, eds. WHO Classification: Tumors of the Breast and Female Genital Organs. Lyon, France: IARC Press, 2003:63–80

Schwartz GF. The current treatment of ductal carcinoma in situ. Breast J 2001;7:308–10PubMedCrossRef

Skinner KA, Silverstein MJ. The management of ductal carcinoma in situ of the breast. Endocr Relat Cancer 2001;8:33–45PubMedCrossRef

Ho GH, Calvano JE, Bisogna M, et al. In microdissected ductal carcinoma in situ, HER-2/neu amplification, but not p53 mutation, is associated with high nuclear grade and comedo histology. Cancer 2000;89:2153–60PubMedCrossRef

Done SJ, Eskandarian S, Bull S, Redston M, Andrulis IL. p53 missense mutations in microdissected high-grade ductal carcinoma in situ of the breast. J Natl Cancer Inst 2001;93:700–4PubMedCrossRef

Simpson JL, Quan DE, O’Malley F, Odom-Maryon T, Clarke PE. Amplification of CCND1and expression of its protein product, cyclin D1, in ductal carcinoma in situ of the breast. Am J Pathol 1997;151:161–8PubMed

Allred DC, Mohsin SK, Fuqua SAW. Histological and biological evolution of human premalignant breast disease. Endocr Relat Cancer 2001;8:47–61PubMedCrossRef

10.

Fujii H, Szumel R, Marsh C, Zhou W, Gabrielson E. Genetic progression histologic grade and allelic loss in ductal carcinoma in situ of the breast. Cancer Res 1996;56:5260–5PubMed

11.

Vos CB, ter Haar NT, Rosenberg C, et al. Genetic alteration on chromosome 16 and 17 are important features of ductal carcinoma in situe of the breast and are associated with histologic type. Br J Cancer 1999;81:1410–8PubMedCrossRef

12.

Ellsworth DL, Shriver CD, Ellsworth RE, Deyarmin B, Somiari RI. Laser capture microdissection of paraffin-embedded tissues. Biotechniques 2003;34:42–6PubMed

13.

Ellsworth DL, Ellsworth RE, Love B, et al. Outer breast quadrants demonstrate increased levels of genomic instability. Ann Surg Oncol 2004;11:861–8PubMedCrossRef

14.

Ellsworth RE, Ellsworth DL, Lubert SM, Hooke J, Somiari RI, Shriver CD. High-throughput loss of heterozygosity mapping in 26 commonly deleted regions in breast cancer. Cancer Epidemiol Biomarkers Prev 2003;12:915–9PubMed

15.

Medintz IL, Lee C-CR, Wong WW, Pirkola K, Sidransky D, Mathies RA. Loss of heterozygosity assay for molecular detection of cancer using energy-transfer primers and capillary array electrophoresis. Genome Res 2000;10:1211–8PubMedCrossRef

16.

Ellsworth RE, Ellsworth DL, Neatrour DM, et al. Allelic imbalance in primary breast carcinomas and metastatic tumors of the axillary lymph nodes. Mol Cancer Res 2005;3:71–7PubMedCrossRef

17.

Ellsworth RE, Ellsworth DL, Deyarmin B, et al. Timing of critical genetic changes in human breast disease. Ann Surg Oncol 2005;12:1054–60PubMedCrossRef

18.

Hwang ES, DeVries S, Chew KL, et al. Patterns of chromosomal alterations in breast ductal carcinoma in situ. Clin Cancer Res 2004;10:5160–7PubMedCrossRef

19.

Buerger H, Otterbach F, Simon R, et al. Comparative genomic hybridization of ductal carcinoma in situ of the breast—evidence of multiple genetic pathways. J Pathol 1999;187:396402CrossRef

20.

O’Connell P, Pekkel V, Fuqua SAW, Osborne CK, Allred DC. Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J Natl Cancer Inst 1998;90:697–703PubMedCrossRef

21.

Ando Y, Iwase H, Ichihara S, et al. Loss of heterzygosity and microsatellite instability in ductal carcinoma in situ of the breast. Cancer Lett 2000;156:207–14PubMedCrossRef

22.

Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 1992;70:923–35PubMedCrossRef

23.

Chappell SA, Walsh T, Walker RA, Shaw JA. Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 recpetor gene correlates with poor differentiation in early breast carcinomas. Br J Cancer 1997;76:1558–61PubMed

24.

Aulmann S, Bentz M, Sinn HP. C-myc oncogene amplification in ductal carcinoma in situ of the breast. Breast Cancer Res Treat 2002;74:25–31PubMedCrossRef

25.

Bieche I, Lidreau R. Loss of heterozygosity at 13q14 correlates with RB1 gene underexpression in human breast cancer. Mol Carcinog 2000;29:151–8PubMedCrossRef

26.

Lukas J, Parry D, Aagaard L, et al. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 1995;375:503–6PubMedCrossRef

27.

Ellsworth RE, Hooke JA, Love B, et al. Correlation of levels and patterns of genomic instability with histological grading of invasive breast tumors. Breast Cancer Res Treat 2007 (in press)

28.

Sotiriou C, Wirapati P, Loi S, et al. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst 2006;98:262–72PubMedCrossRef

Title: Correlation of Levels and Patterns of Genomic Instability With Histological Grading of DCIS
Authors: Rachel E. Ellsworth, PhD
Darrell L. Ellsworth, PhD
Brad Love, PhD
Heather L. Patney, BS
Laurel R. Hoffman, BS
Jennifer Kane, HT (ASCP)
Jeffrey A. Hooke, MD
Craig D. Shriver, MD
Publication date: 01-11-2007
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 11/2007
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-007-9459-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Correlation of Levels and Patterns of Genomic Instability With Histological Grading of DCIS

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 11/2007

Clinical Implication of CXCL12 Expression in Gastric Cancer

Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Colorectal Carcinomatosis: If at First You Don't Succeed...

Altered E-Cadherin Expression and p120 Catenin Localization in Esophageal Squamous Cell Carcinoma

Utility of a Prognostic Nomogram Designed for Gastric Cancer in Predicting Outcome of Patients with R0 Resected Duodenal Adenocarcinoma

Ex vivo Search for Sentinel Node in Postmastectomy Specimens: Should We Use a Transverse Incision for Mastectomy?

Intra-operative Parathyroid Hormone Monitoring in Patients with Parathyroid Cancer