Different genetic pathways in the evolution of invasive breast cancer are associated with distinct morphological subtypes

Buerger, Horst; Otterbach, Friedrich; Simon, Ronald; Schäfer, Karl‐Ludwig; Poremba, Christopher; Diallo, Raihanatou; Brinkschmidt, Christian; Dockhorn‐Dworniczak, Barbara; Boecker, Werner

doi:10.1002/(sici)1096-9896(199912)189:4<521::aid-path472>3.0.co;2-b

Cited by 224 publications

(187 citation statements)

References 15 publications

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“…This is expected, given that only breast carcinomas of histological grades 2 and 3 were present in the population and gains of 8q are rather frequent in grade 2 and 3 breast cancers (Buerger et al, 1999a, b;Roylance et al, 1999). The comparison between the genomic profiles obtained for ductal and lobular carcinomas were also in agreement with previous studies (Buerger et al, 1999b;Shelley Hwang et al, 2004;Reis-Filho et al, 2005a;Simpson et al, 2005;Stange et al, 2006): gain of 1q and deletions of 16q were the most prevalent changes in lobular carcinomas, whereas gain of 8q was significantly more frequent in grade 2 and 3 ductal carcinomas. However, we could define the smallest region of overlap of the deletions of 16q, which mapped to 16q21 -q22.1 and encompassed the region of the cadherin gene cluster, and the gain of 8q, which encompassed two regions 8q13.2 -q21.13 and 8q21.3 -qtel (Supplementary Table 3).…”

Section: Discussionsupporting

confidence: 91%

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

et al. 2006

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We analysed the molecular genetic profiles of breast cancer samples before and after neoadjuvant chemotherapy with combination doxorubicin and cyclophosphamide (AC). DNA was obtained from microdissected frozen breast core biopsies from 44 patients before chemotherapy. Additional samples were obtained before the second course of chemotherapy (D21) and after the completion of the treatment (surgical specimens) in 17 and 21 patients, respectively. Microarray-based comparative genome hybridisation was performed using a platform containing B5800 bacterial artificial chromosome clones (genome-wide resolution: 0.9 Mb). Analysis of the 44 pretreatment biopsies revealed that losses of 4p, 4q, 5q, 12q13.11 -12q13.12, 17p11.2 and 17q11.2; and gains of 1p, 2p, 7q, 9p, 11q, 19p and 19q were significantly associated with oestrogen receptor negativity. 16q21 -q22.1 losses were associated with lobular and 8q24 gains with ductal types. Losses of 5q33.3 -q4 and 18p11.31 and gains of 6p25.1 -p25.2 and Xp11.4 were associated with HER2 amplification. No correlations between DNA copy number changes and clinical response to AC were found. Microarray-based comparative genome hybridisation analysis of matched pretreatment and D21 biopsies failed to identify statistically significant differences, whereas a comparison between matched pretreatment and surgical samples revealed a statistically significant acquired copy number gain on 11p15.2 -11p15.5. The modest chemotherapy-driven genomic changes, despite profound loss of cell numbers, suggest that there is little therapeutic selection of resistant non-modal cell lineages.

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Section: Discussionsupporting

confidence: 91%

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

et al. 2006

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“…Loss of 8p was also observed at significantly lower fre- quency in other types of breast cancers, 16,17,19,22 therefore, it can be considered as a potential locus harbouring a breast cancer susceptibility gene. There are a number of candidate genes within the region lost on the short arm of chromosome 8.…”

Section: Discussionmentioning

confidence: 97%

“…For example, the results obtained on sporadic cases in our study, non-familial tumours reported by others, as well as BRCA2-associated breast cancers showed a correlation between 8p-losses and positive lymph node status as well as higher tumour grading. 17,19,24,25 This evidence suggests that tumour suppressor genes located in 8p are more likely to be associated with tumour progression rather than initiation in this type of breast cancer. In our set of BRCAX tumours the frequencies of chromosome 8p loss was similar in Grade II and Grade III tumours, but was observed more frequently in tumours with negative (6/9 vs. 4/9) lymph node status.…”

Section: Discussionmentioning

confidence: 98%

Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization

Gronwald

Jauch

Cybulski

et al. 2004

Intl Journal of Cancer

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Very little is known about the chromosomal regions harbouring genes involved in initiation and progression of BRCAX-associated breast cancers. We applied comparative genomic hybridization (CGH) to identify the most frequent genomic imbalances in 18 BRCAX hereditary breast cancers and compared them to chromosomal aberrations detected in a group of 27 sporadic breast cancers. The aberrations observed most frequently in BRCAX tumours were gains of 8q (83%), 19q (67%), 19p (61%), 20q (61%), 1q (56%), 17q (56%) and losses of 8p (56%), 11q (44%) and 13q (33% Breast cancer continues to be the leading cause of morbidity and mortality in women throughout much of the developed world. At least 10% of these tumours develop in families with strong aggregations of both breast or ovarian cancers showing an autosomal dominant transmission pattern. 1 The etiology and progression of breast malignancies is associated with a series of genomic alterations. Only germ-line mutations of 2 breast cancer susceptibility genes BRCA1 and BRCA2 have been identified in a significant number of families of patients with breast or ovarian cancer aggregation. 2,3 Mutations in these genes explain the cancer etiology of the majority of breast ovarian cancer families, but only a small proportion of cases with hereditary site-specific breast cancer. 4,5 The risk in women without detectable BRCA1/2 coding region mutations but with a positive family history remains significantly increased. 1 Available data suggest that for at least twothirds of hereditary breast cancers (other than BRCA1/2) autosomal dominant moderate or highly penetrant genes (defined as BRCAX) are likely to exist. 4,5 The involvement of genes predisposing for other family syndromes that show moderately increased breast cancer risk such as PTEN, ATM, TP53, CHEK2 do not contribute significantly to hereditary breast cancer incidence. 6 -9 The failure to identify a third breast cancer susceptibility gene in the list of low-penetrant genes described above strongly suggests that other breast cancer susceptibility genes involved in the initiation of these tumours still remain to be found.Chromosomal segments involved recurrently in gains and losses of primary tumours provide target regions for the search of oncogenes and tumour suppressor genes, respectively, which may be involved in tumour initiation and progression. Genetic analyses on BRCAX patients identified several chromosomal regions potentially harbouring other breast cancer susceptibility genes. They include 8p12-p21, 10 13q21, 11 and 2q32, 12 however, they were excluded or need to be evaluated with regards to population specificity. 13 There are no comprehensive molecular cytogenetic studies that report characteristic chromosomal imbalances involved in tumour progression in BRCAX patients.We applied CGH to identify the most frequent genomic imbalances in BRCAX hereditary breast cancers and compared them to abnormalities detected in a group of breast cancers that were derived from patients who had no evidence of a familial aggrega...

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“…In several studies, chromosome 1q and 16q imbalances have been investigated separately: chromosome 1q gains have been found at any stage, [18][19][20] whereas chromosome 16q losses have been mostly detected in low and intermediately differentiated carcinoma 3,4 or in invasive lobular carcinoma. 21 Altogether, these data supported the hypothesis that low/intermediate-and high-grade breast carcinoma develop according to distinct pathways: chromosome 16q loss was proposed as a marker of a distinct genetic pathway in breast carcinoma development.…”

Section: Discussionmentioning

confidence: 99%

“…3,4 Gains of the long arm of chromosome 1 and losses of chromosome 16q are often the result of unbalanced translocations between these two chromosomes: 1,6 less frequently, they are the result of other rearrangements. 2,5 Chromosome 1q gains and 16q losses are considered as early changes since they have been detected as the sole chromosome abnormalities in near-diploid breast carcinoma 1,6 and in well-differentiated samples with a few alterations.…”

mentioning

confidence: 99%

Simultaneous chromosome 1q gain and 16q loss is associated with steroid receptor presence and low proliferation in breast carcinoma

et al. 2004

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We applied comparative genomic hybridization (CGH) to 46 breast carcinoma samples, collected from 1993 to 1995, in order to detect chromosome 1q gains and 16q losses and to define whether samples showing both these alterations had distinct biopathologic features and different clinical outcome. A total of 22 samples (48%) had simultaneous chromosome 1q gain and 16q loss, which was always associated with other genetic changes. In total, 23 samples had various chromosome imbalances (including chromosome 1q gain independent of chromosome 16q loss and vice versa) and one sample did not show detectable alterations. Samples having chromosome 1q gain/16q loss were compared to the other samples with regard to neoplasm size, lymph-node status, histologic and nuclear grade, estrogen and progesterone receptor presence, Ki-67, pRB, Cyclin D1, Cyclin A, p53, p21 and p27 expression as detected by immunohistochemistry. The samples showing chromosome 1q gain/16q loss had high steroid hormone receptor expression (P ¼ 0.02), low cell growth fraction (Ki-67, P ¼ 0.03) and high p27 expression (Po0.001). No statistical correlation with disease-free survival and overall survival or response to hormonal therapy was found. We conclude that simultaneous chromosome 1q gain/16q loss is a frequent event in invasive breast cancer, which occurs in a subset of both intermediateand high-grade breast carcinomas. Although the final chromosome 1q and 16q imbalances might have originated from different chromosome alterations in low-and high-grade samples, the gene-dosage effect might be important in conferring peculiar biopathologic characteristics to this subset of samples. The cytogenetic and molecular mechanisms underlying these chromosome changes deserve further investigations.

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Different genetic pathways in the evolution of invasive breast cancer are associated with distinct morphological subtypes

Cited by 224 publications

References 15 publications

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization

Simultaneous chromosome 1q gain and 16q loss is associated with steroid receptor presence and low proliferation in breast carcinoma

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