Aberrations of Chromosomes 1 and 16 in Breast Cancer: A Framework for Cooperation of Transcriptionally Dysregulated Genes

Abstract

Derivative chromosome der(1;16), isochromosome 1q, and deleted 16q—producing arm-level 1q-gain and/or 16q-loss—are recurrent cytogenetic abnormalities in breast cancer, but their exact role in determining the malignant phenotype is still largely unknown. We exploited The Cancer Genome Atlas (TCGA) data to generate and analyze groups of breast invasive carcinomas, called 1,16-chromogroups, that are characterized by a pattern of arm-level somatic copy number aberrations congruent with known cytogenetic aberrations of chromosome 1 and 16. Substantial differences were found among 1,16-chromogroups in terms of other chromosomal aberrations, aneuploidy scores, transcriptomic data, single-point mutations, histotypes, and molecular subtypes. Breast cancers with a co-occurrence of 1q-gain and 16q-loss can be distinguished in a “low aneuploidy score” group, congruent to der(1;16), and a “high aneuploidy score” group, congruent to the co-occurrence of isochromosome 1q and deleted 16q. Another three groups are formed by cancers showing separately 1q-gain or 16q-loss or no aberrations of 1q and 16q. Transcriptome comparisons among the 1,16-chromogroups, integrated with functional pathway analysis, suggested the cooperation of overexpressed 1q genes and underexpressed 16q genes in the genesis of both ductal and lobular carcinomas, thus highlighting the putative role of genes encoding gamma-secretase subunits (APH1A, PSEN2, and NCSTN) and Wnt enhanceosome components (BCL9 and PYGO2) in 1q, and the glycoprotein E-cadherin (CDH1), the E3 ubiquitin-protein ligase WWP2, the deubiquitinating enzyme CYLD, and the transcription factor CBFB in 16q. The analysis of 1,16-chromogroups is a strategy with far-reaching implications for the selection of cancer cell models and novel experimental therapies.

Mutational and copy number analysis of numerous sorted circulating and disseminated tumour cells to interrogate subclonal evolution in advanced breast cancer.

“…Also similar to our data, co-occurrence of 1q-gain and 16q-loss is a frequent cytogenetic abnormality in breast cancer. Transcriptome and functional pathway analysis suggested cooperation of overexpressed 1q genes and underexpressed 16q genes in the genesis of both ductal and lobular carcinomas (45). These data support our findings of 1q, 8q, 11q, 16q and 17p alterations to be present in all samples including the primary tumour.…”

Luminal breast epithelial cells from wildtype andBRCAmutation carriers harbor copy number alterations commonly associated with breast cancer

“…These clones expanded over time and acquired additional mutations that eventually led to cancer development 32 ( Supplementary Figure 8 ). While 1q/16q CNAs were found to be the only CNAs for some low grade tumors, these alterations are also associated with high aneuploid tumors 38 . Due to limitations in the resolution of our sequencing data, we were unable to confirm whether 1q-gain/16q-loss clones in our dataset were a result of der(1;16).…”

Methyladenosine Modification in RNAs: From Regulatory Roles to Therapeutic Implications in Cancer

“…Fukumoto et al, found that m 6 A modification on FZD10 mRNA is correlated with the PARPi resistance via Wnt/β-catenin pathway [153]. Interestingly, PARP1 and Wnt/β-catenin pathways were found to be enriched in BRCA bearing the specific chromosomal aberrations (Chr1q gains and Chr16q losses) [154]. More studies are needed to investigate the possibility of methyladenosine modification modulating therapeutic resistance by regulating aberrations of chromosomes in cancers.…”