Cytogenetic polyclonality in tumors of the breast

Heim, Sverre; Teixeira, Manuel R.; Dietrich, Claudia U.; Pandis, Nikos

doi:10.1016/s0165-4608(96)00322-6

Cited by 51 publications

(35 citation statements)

References 23 publications

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“…Hormone receptor loss is a known marker of aggressive disease, negative prognosis and limited treatment options. It has been suggested that the loss of hormone receptor expression is due to dedifferentiation of the metastatic tumor29 or the selection of cytogenetically unique clones that have an enhanced propensity to metastasize to distant sites 30, 31. Alternatively, the loss of hormone receptor expression in breast cancer patients may represent selection bias as a result of treatment 32.…”

Section: Discussionmentioning

confidence: 99%

Profiles of brain metastases: Prioritization of therapeutic targets

Ferguson

Zheng

Xiu

et al. 2018

Intl Journal of Cancer

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We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next‐generation sequencing with a targeted 47‐gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

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Section: Discussionmentioning

confidence: 99%

Profiles of brain metastases: Prioritization of therapeutic targets

Ferguson

Zheng

Xiu

et al. 2018

Intl Journal of Cancer

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“…Our LCM substudy indicated that primary tumors exhibit prominent microheterogeneity in PIK3CA mutation. Intratumoral genotypic and phenotypic heterogeneity in primary breast is well known, reflecting subclonal diversity (44)(45)(46).…”

Section: Mutational Events In the Tumor Pathogenesismentioning

confidence: 99%

PIK3CA Mutations May Be Discordant between Primary and Corresponding Metastatic Disease in Breast Cancer

Jensen

Laenkholm

Knoop

et al. 2011

Clinical Cancer Research

179

106

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Purpose: PIK3CA mutations are frequent in breast cancer and activate the PI3K/Akt pathway. Unexpectedly, PIK3CA mutation appears in general to be associated with better outcome. In a cohort of patients where both primary and metastatic lesions were available, the objective was to assess changes in PIK3CA mutations. We wished to discern whether selective pressures occur and the influence of PIK3CA mutation on time to recurrence.Experimental Design: Formalin-fixed paraffin-embedded tumor blocks were obtained from 104 patients with paired samples from primary tumors and corresponding asynchronous metastatic breast tumors. Samples were analyzed for PIK3CA mutations (exons 9 and 20) as well as immunohistochemical evaluation for PTEN, pAKT, Ki67, ER, and HER2.Results: PIK3CA mutation was detected in 45% of the primary tumors. Overall, there was a net gain in mutation in metastatic disease, to 53%; nonetheless, there were instances where metastases were wild type in patients with PIK3CA mutant primary tumors. Laser capture microdissection on a subset of cases revealed microheterogeneity for PIK3CA mutational status in the primary tumor. PIK3CA mutants overall showed a significantly longer time to first recurrence than wild type cases (P ¼ 0.03).Conclusion: PIK3CA mutations occur at high frequency in primary and metastatic breast cancer; these may not necessarily confer increased aggressiveness as mutants had a longer time to recurrence. Because PIK3CA status quite frequently changes between primary and metastatic disease, it emphasizes the necessity of assessing the PIK3CA status in the metastatic lesion for selection of PIK3CA inhibitor therapy. Clin Cancer Res; 17(4); 667-77. Ó2010 AACR.

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“…Hence, changes found in less prevalent clonal populations of tumour cells are less likely to be identified with these techniques. Given that there is evidence to suggest that most tumours are heterogeneous, [10][11][12] even with the increased resolution of aCGH, some genetic abnormalities that may drive tumour behaviour may go undetected, for example, when a given change is restricted to o10-20% of neoplastic cells.…”

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confidence: 99%

Unlocking pathology archives for molecular genetic studies: a reliable method to generate probes for chromogenic and fluorescent in situ hybridization

Lambros

Simpson

Jones

et al. 2006

Laboratory Investigation

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Chromogenic (CISH) and fluorescent (FISH) in situ hybridization have emerged as reliable techniques to identify amplifications and chromosomal translocations. CISH provides a spatial distribution of gene copy number changes in tumour tissue and allows a direct correlation between copy number changes and the morphological features of neoplastic cells. However, the limited number of commercially available gene probes has hindered the use of this technique. We have devised a protocol to generate probes for CISH that can be applied to formalin-fixed, paraffin-embedded tissue sections (FFPETS). Bacterial artificial chromosomes (BACs) containing fragments of human DNA which map to specific genomic regions of interest are amplified with /29 polymerase and random primer labelled with biotin. The genomic location of these can be readily confirmed by BAC end pair sequencing and FISH mapping on normal lymphocyte metaphase spreads. To demonstrate the reliability of the probes generated with this protocol, four strategies were employed: (i) probes mapping to cyclin D1 (CCND1) were generated and their performance was compared with that of a commercially available probe for the same gene in a series of 10 FFPETS of breast cancer samples of which five harboured CCND1 amplification; (ii) probes targeting cyclin-dependent kinase 4 were used to validate an amplification identified by microarray-based comparative genomic hybridization (aCGH) in a pleomorphic adenoma; (iii) probes targeting fibroblast growth factor receptor 1 and CCND1 were used to validate amplifications mapping to these regions, as defined by aCGH, in an invasive lobular breast carcinoma with FISH and CISH; and (iv) gene-specific probes for ETV6 and NTRK3 were used to demonstrate the presence of t(12;15)(p12;q25) translocation in a case of breast secretory carcinoma with dual colour FISH. In summary, this protocol enables the generation of probes mapping to any gene of interest that can be applied to FFPETS, allowing correlation of morphological features with gene copy number.

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Cytogenetic polyclonality in tumors of the breast

Cited by 51 publications

References 23 publications

Profiles of brain metastases: Prioritization of therapeutic targets

Profiles of brain metastases: Prioritization of therapeutic targets

PIK3CA Mutations May Be Discordant between Primary and Corresponding Metastatic Disease in Breast Cancer

Unlocking pathology archives for molecular genetic studies: a reliable method to generate probes for chromogenic and fluorescent in situ hybridization

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