Complex landscapes of somatic rearrangement in human breast cancer genomes

Chondromyxoid fibroma (CMF) is an uncommon benign cartilaginous tumor of bone usually occurring during the second decade of life. CMF is associated with recurrent rearrangements of chromosome bands 6p23-25, 6q12-15, and 6q23-27. To delineate further the role and frequency of the involvement of three candidate regions (6q13, 6q23.3 and 6q24) in the pathogenesis of CMF, we studied a group of 43 cases using a molecular cytogenetic approach. Fluorescence in situ hybridization with probe sets bracketing the putative breakpoint regions was performed in 30 cases. The expression level of nearby candidate genes was studied by immunohistochemistry and quantitative RT-PCR in 24 and 23 cases, respectively. Whole-genome copy number screening was performed by array comparative genomic hybridization in 16 cases. Balanced and unbalanced rearrangements of 6q13 and 6q23.3 occurred in six and five cases, respectively, and a hemizygous deletion in 6q24 was found in five cases. Two known tumor suppressor genes map to the latter region: PLAGL1 and UTRN. However, neither of these two genes nor BCLAF1 and COL12A1, respectively located in 6q23.3 and 6q13, showed altered expression. Therefore, although rearrangements of chromosomal regions 6q13, 6q23.3, and 6q24 are common in CMF, the complexity of the changes precludes the use of a single fluorescence in situ hybridization probe set as an adjunct diagnostic tool. These data indicate that the genetic alterations in CMF are heterogeneous and are likely a result of a cryptic rearrangement beyond the resolution level of combined binary ratio fluorescence in situ hybridization or a point mutation.

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“…Such changes might be identifiable by recently developed technology such as massive sequencing. 27,28 …”

Section: Discussionmentioning

confidence: 99%

Heterogeneous and Complex Rearrangements of Chromosome Arm 6q in Chondromyxoid Fibroma

Romeo

Duim

Bridge

et al. 2010

The American Journal of Pathology

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“…APL pathophysiology and the basis for of targeted therapy to date are diseases driven by fusion proteins (23,24). In contrast, fusion proteins reported among innumerable other lesions in solid tumors are more likely to be associated with cancer progression (25,26).…”

Section: Can Targeted Therapies Really Work In Patients?mentioning

confidence: 99%

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

et al. 2011

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Many targeted therapies against cancer are aimed at inhibiting the enzymatic activity of kinases. Thus far, this approach has undoubtedly yielded significant clinical improvements, but has only rarely achieved cures. Other drugs, which selectively elicit proteasome-dependent degradation of oncoproteins, induce the loss of cancer cell self-renewal and promote cell differentiation and/or apoptosis. In acute promyelocytic leukemia, the cooperative degradation of PML/RARA by arsenic and retinoic acid cures most patients. In this condition and others, drug-induced proteolysis of oncoproteins is feasible and underlies improved clinical outcome. Several transcription factors, nuclear receptors, or fusion proteins driving cancer growth could be candidates for proteolysis-based drug-discovery programs. Summary: Some cancer therapies may degrade oncoproteins. Loss of the driver oncoprotein is associated with loss of cancer cell self-renewal. Leukemia- or sarcoma-associated fusion proteins are the best candidates for small-molecule screens aimed at initiating oncoprotein degradation. Cancer Discovery; 1(2). 117–27. ©2011 AACR.

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“…The mutational landscape of invasive breast carcinoma has been extensively documented in recent landmark studies. [1][2][3][4][5] However, little is known about the mutational profile of ductal carcinoma in situ (DCIS). Studies have addressed mutations of individual genes [6][7][8][9][10][11][12][13] but until very recently, assessment of a broad panel of genes in DCIS has not been performed, largely due the challenges in obtaining DNA from DCIS cases compatible with highly multiplexed methodologies.…”

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confidence: 99%

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

et al. 2017

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The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n = 20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P = 0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P = 0.005), including a significant positive association with amplification or gain of ERBB2 (Po 0.05). The association between TP53 mutation and ERBB2 amplification was confirmed in a wider DCIS cohort using p53 immunohistochemistry as a surrogate marker for TP53 mutations (P = 0.03). RUNX1 mutations and MAP2K4 copy number loss were novel findings in DCIS. Frequent copy number alterations included gains on 1q, 8q, 17q, and 20q and losses on 8p, 11q, 16q, and 17p. Patterns of genomic alterations observed in DCIS were similar to those previously reported for invasive breast cancers, with all DCIS having at least one bona fide breast cancer driver event. However, an increase in GATA3 mutations and fewer copy number changes were noted in DCIS compared with invasive carcinomas. The role of such alterations as prognostic and predictive biomarkers in DCIS is an avenue for further investigation.

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Complex landscapes of somatic rearrangement in human breast cancer genomes

Cited by 770 publications

References 39 publications

Heterogeneous and Complex Rearrangements of Chromosome Arm 6q in Chondromyxoid Fibroma

Heterogeneous and Complex Rearrangements of Chromosome Arm 6q in Chondromyxoid Fibroma

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

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