20q13.2 Amplification in intraductal hyperplasia adjacent to in situ and invasive ductal carcinoma of the breast

Werner, Martin; Mattis, A.; Aubele, Michaela; Cummings, Margaret C.; Zitzelsberger, Horst; Hutzler, Peter; Höfler, Heinz

doi:10.1007/s004280050429

Cited by 52 publications

(35 citation statements)

References 8 publications

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“…Apart from ADH and ALH, which bear remarkable morphological and molecular resemblance to welldifferentiated DCIS and LCIS, respectively, the other non-obligate/premalignant lesions have proven more difficult to characterize and establish their actual position along the pathways [2,16,[60][61][62][63][64][65][66][67]. Interestingly, ADH and low-grade DCIS show identical immunoprofiles and low numbers of chromosomal abnormalities, comprising recurrent loss of 16q (see ref 2 and refs cited therein).…”

Section: Hyperplasias and Columnar Cell Changementioning

confidence: 99%

“…However, its role in the multi-step model of breast carcinogenesis has been questioned (for a review see ref 2 and refs cited therein) [2,5,15,16,[64][65][66][67]. The morphological features and immunoprofile of HUTs are in stark contrast with those of the accepted precursors, since they are composed of a mixed population of cell types with a variable proportion of ER, PgR-positive luminal cells and myoepithelial/basal marker-positive cells.…”

Section: Hyperplasias and Columnar Cell Changementioning

confidence: 99%

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Molecular evolution of breast cancer

Simpson

Reis‐Filho

Gale

et al. 2005

The Journal of Pathology

453

378

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Molecular analysis of invasive breast cancer and its precursors has furthered our understanding of breast cancer progression. In the past few years, new multi-step pathways of breast cancer progression have been delineated through genotypic-phenotypic correlations. Nuclear grade, more than any other pathological feature, is strongly associated with the number and pattern of molecular genetic abnormalities in breast cancer cells. Thus, there are two distinct major pathways to the evolution of low-and high-grade invasive carcinomas: whilst the former consistently show oestrogen receptor (ER) and progesterone receptor (PgR) positivity and 16q loss, the latter are usually ER/PgR-negative and show Her-2 overexpression/amplification and complex karyotypes. The boundaries between the evolutionary pathways of well-differentiated/low-grade ductal and lobular carcinomas have been blurred, with changes in E-cadherin expression being one of the few distinguishing features between the two. In addition, lesions long thought to be precursors of breast carcinomas, such as hyperplasia of usual type, are currently considered mere risk indicators, whilst columnar cell lesions are now implicated as non-obligate precursors of atypical ductal hyperplasia (ADH) and well-differentiated ductal carcinoma in situ (DCIS). However, only through the combination of comprehensive morphological analysis and cutting-edge molecular tools can this knowledge be translated into clinical practice and patient management.

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Section: Hyperplasias and Columnar Cell Changementioning

confidence: 99%

Section: Hyperplasias and Columnar Cell Changementioning

confidence: 99%

Molecular evolution of breast cancer

Simpson

Reis‐Filho

Gale

et al. 2005

The Journal of Pathology

453

378

View full text Add to dashboard Cite

show abstract

“…On the basis of molecular data, primarily loss of heterozygosity and comparative genomic hybridization studies, a number of authors have shown clonal chromosomal aberrations in usual ductal hyperplasia, though they occur at lower frequency, with fewer alterations per lesion, as compared with atypical ductal hyperplasia, ductal carcinoma in situ, and invasive carcinomas; other studies have shown identical chromosomal changes in usual ductal hyperplasia and accompanying invasive carcinoma. 37,[42][43][44][45][46][47][48] Investigation of activating point mutations in PIK3CA, AKT and other cell signaling pathways in usual ductal hyperplasia, and other breast precursor lesions such as atypical ductal hyperplasia and columnar cell change, should be instructive in further characterizing the divergent molecular and histologic pathways of breast cancer evolution.…”

mentioning

confidence: 99%

High prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast

et al. 2010

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Papillary lesions of the breast have an uncertain relationship to the histogenesis of breast carcinoma, and are thus diagnostically and managerially challenging. Molecular genetic studies have provided evidence that ductal carcinoma in situ and even atypical ductal hyperplasia are precursors of invasive carcinoma. However, papillary lesions have been seldom studied. We screened papillary breast neoplasms for activating point mutations in PIK3CA, AKT1, and RAS protein-family members, which are common in invasive ductal carcinomas. DNA extracts were prepared from sections of 89 papillary lesions, including 61 benign papillomas (28 without significant hyperplasia; 33 with moderate to florid hyperplasia), 11 papillomas with atypical ductal hyperplasia, 7 papillomas with carcinoma in situ, and 10 papillary carcinomas. Extracts were screened for PIK3CA and AKT1 mutations using mass spectrometry; cases that were negative were further screened for mutations in AKT2, BRAF, CDK, EGFR, ERBB2, KRAS, NRAS, and HRAS. Mutations were confirmed by sequencing or HPLC assay. A total of 55 of 89 papillary neoplasms harbored mutations (62%), predominantly in AKT1 (E17K, 27 cases) and PIK3CA (exon 20 4exon 9, 27 cases). Papillomas had more mutations in AKT1 (54%) than in PIK3CA (21%), whereas papillomas with hyperplasia had more PIK3CA (42%) than AKT1 (15%) mutations, as did papillomas with atypical ductal hyperplasia (PIK3CA 45%, AKT1 27%, and NRAS 9%). Among seven papillomas with carcinoma in situ, three had AKT1 mutations. The 10 papillary carcinomas showed an overall lower frequency of mutations, including 1 with an AKT1 mutation (in a tumor arising from a papilloma), 1 with an NRAS gene mutation (Q61H), and 2 with PIK3CA mutations (1 overlapping with the NRAS Q61H). These findings indicate that approximately two-thirds of papillomas are driven by mutations in the PI3CA/AKT pathway. Some papillary carcinomas may arise from these lesions, but others may have different molecular origins.

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“…However, the exact timing of the majority of molecular genetic events during carcinogenesis and their correlation with defined histopathological stages are largely unknown. (1)(2)(3)(4)(5)(6)(7). Invasive ductal carcinoma (IDC) of the breast is the result of a multistep process, beginning with ductal hyperplasia and followed by atypical ductal hyperplasia, ductal carcinoma in situ (DCIS), invasive ductal carcinoma and metastatic disease (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

Use of laser capture microdissection allows detection of loss of heterozygosity in chromosome 9p in breast cancer

2017

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Abstract. The present study was designed to determine whether loss of heterozygosity (LOH) in the p arm of chromosome 9 in invasive ductal carcinoma of the breast is detected during the neoplastic progression of the disease. Using laser capture microdissection (LCM) epithelial cells were isolated from 14 invasive ductal carcinoma cases (IDC), ductal carcinomas in situ (DCIS), normal mammary lobules, skin and/or lymph nodes of paraffin embedded tissue sections. LOH analysis of chromosome 9p was performed utilizing the microsatellite markers D9S199, D9S157, D9S171, D9S265 and D9S270. The highest frequency of LOH was observed in invasive ductal carcinomas, which reached a maximum at the 9p22-23 chromosomal location (D9S157). In addition, DCIS lesions presented a high frequency of LOH in 9p22-23 (D9S157), followed by 9p21 (D9S171), D9S199 and D9S265, which were similar in frequency to those observed in IDC. A novel finding was the intralesional heterogeneity in LOH within the same DCIS or IDC case. This is an indication that clones of cells that differ in genetic composition coexist in the same lesion. Notably, phenotypically normal breast tissues adjacent to IDC or DCIS exhibited LOH at D9S157 and/or D9S171. Together, these data indicate that LOH of chromosome arm 9p occurs very early in the progression of cancer and that different clones of cells co-exist within a single tumor. IntroductionHuman cancer arises through the accumulation of genetic alterations in multiple oncogenes and tumor suppressor genes. However, the exact timing of the majority of molecular genetic events during carcinogenesis and their correlation with defined histopathological stages are largely unknown. (1-7). Invasive ductal carcinoma (IDC) of the breast is the result of a multistep process, beginning with ductal hyperplasia and followed by atypical ductal hyperplasia, ductal carcinoma in situ (DCIS), invasive ductal carcinoma and metastatic disease (1-3). Previous studies in the literature (8-10) indicate that alterations in the p arm of chromosome 9 may be a common denominator in human cancer, and may have a role in the early stages of breast cancer, including ductal hyperplasia and DCIS (11)(12)(13)(14). Of interest is the finding that loss of heterozygosity (LOH) in the p arm of chromosome 9 may be involved in the pathogenesis of breast cancer (15)(16)(17)(18)(19).In the present study, laser capture microdissection (LCM) was used to analyze paraffin-embedded tissues of the normal breast, ductal hyperplasia, DCIS and IDC to obtain DNA from selected populations of cells for molecular genetic analysis (20)(21)(22). LCM was used in order to obtain cells with a high degree of purity in their phenotypes, without contamination of stromal, inflammatory or other cells that could interfere with final conclusions of molecular analysis. The isolated cells representing different stages of breast cancer progression were used for detecting LOH using five microsatellite markers: D9S199, D9S 157, D9S 171, D9S265 and D9S270. The present study was conducte...

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20q13.2 Amplification in intraductal hyperplasia adjacent to in situ and invasive ductal carcinoma of the breast

Cited by 52 publications

References 8 publications

Molecular evolution of breast cancer

Molecular evolution of breast cancer

High prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast

Use of laser capture microdissection allows detection of loss of heterozygosity in chromosome 9p in breast cancer

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