Loss of 16q in high grade breast cancer is associated with estrogen receptor status: Evidence for progression in tumors with a luminal phenotype?

Abstract

Loss of the long arm of chromosome 16 (16q) is observed in the vast majority of low grade/grade I (GI) invasive ductal carcinomas of no special type (IDC-NSTs), whereas this event is uncommonly seen in high grade/grade III (GIII) IDC-NSTs. Together with data on the pathology and genetics of breast cancer recurrences, this has led to the proposal that GI and GIII breast cancers evolve through distinct genetic pathways and that progression from GI to GIII is an unlikely biological phenomenon. We compared the genomic profiles of GIII-IDC-NSTs with 16q whole arm loss (16qWL) according to estrogen receptor (ER) status. 16qWL was found in 36.5% of cases and was significantly associated with ER expression and luminal phenotype. ER+ GIII-IDC-NSTs with 16qWL displayed significantly higher levels of genomic instability than ER+ IDC-NSTs without 16qWL. Furthermore, ER+ and ER- IDC-NSTs stratified according to the presence of 16qWL harbored distinct patterns of genetic aberrations. Interestingly, ER+/16qWL tumors displayed genetic features usually found in tumors with homologous DNA repair defects and significantly more frequently harbored heterozygous loss of BRCA2 than the remaining ER+ cancers. Our results demonstrate that approximately one third of GIII tumors harbor 16qWL, confirming that progression from low to high grade breast cancer is not found in the majority of breast cancers. 16qWL was significantly more prevalent in ER+/luminal GIII-IDC-NSTs. Given that GI breast cancers harbor a luminal phenotype, our results suggest that if progression from GI to GIII breast cancer does happen, it may preferentially occur in breast cancers of luminal phenotype.

PPM1D gene amplification and overexpression in breast cancer: a qRT-PCR and chromogenic in situ hybridization study

“…This observation suggests that cases harbouring PPM1D gene amplification may display a 'firestorm' pattern (ie, tumours whose genome is characterized by multiple, clustered high-level amplifications). 9,41,42 Re-analysis of the data from Natrajan et al 9 revealed that all cases harbouring PPM1D gene amplification (n ¼ 8) displayed a 'firestorm' profile (Supplementary Figure 1). 9 Taken together, it is plausible that amplification of 17q23.2 may stem from a global pattern of genetic instability that favours the acquisition of multiple, high-level gene amplifications throughout the genome.…”

The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade

“…Furthermore, these prognostic signatures highlighted the fact that ER-positive cancers are a spectrum of lesions ranging from those with very low proliferation (as defined by microarrays) and good outcome to those with high microarray-defined proliferation and poor outcome. On the other hand, ER-negative cancers seem to constitute a collection of distinct entities, underpinned by distinct molecular aberrations [88,139,140], whose prognosis is possibly governed by biological phenomena other than proliferation. Recent studies have revealed that ER-negative cancers with high expression of immune response genes may have an outcome better than other ERnegative cancers [111,141,142], suggesting that distinct prognostic signatures for specific subgroups of breast cancer may be necessary to accurately define their outcome.…”

An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers

“…DNA was extracted as previously described [12]. DNA concentration was measured with Picogreen Ò according to the manufacturer's instructions (Invitrogen, Paisley, UK).…”

“…We microdissected and analysed a series of 48 GIII invasive ductal carcinomas of no special type (IDC-NSTs) with high resolution microarray-based comparative genomic hybridisation (aCGH) and mRNA expression arrays. Our study focused on GIII IDC-NSTs only to avoid bias introduced by distinct patterns of genetic aberrations between grade I and III cancers [12] and between invasive ductal carcinomas and special types [14][15][16].…”