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And Radiotherapy Response in Breast Cancer www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 24), pp: 17078-17092 Research Paper Copy number changes at 8p11-12 predict adverse clinical outcome and chemo- and radiotherapy response in breast cancer Cathy B. Moelans1, Caroline M. G. van Maldegem2, Elsken van der Wall3 and Paul J. van Diest1 1Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands 2Department of Gynaecology, Albert Schweitzer Hospital, Dordrecht, The Netherlands 3Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands Correspondence to: Cathy B. Moelans, email: [email protected] Keywords: breast cancer; loss; prognostic; predictive; 8p Received: November 30, 2017 Accepted: March 12, 2018 Published: March 30, 2018 Copyright: Moelans et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Purpose: The short arm of chromosome 8 (8p) is a frequent target of loss of heterozygosity (LOH) in cancer, and 8p LOH is commonly associated with a more aggressive tumor phenotype. The 8p11-12 region is a recurrent breakpoint area characterized by a sharp decrease in gains/amplifications and increase in allelic loss towards 8pter. However, the clustering of genomic aberrations in this region, even in the absence of proximal amplifications or distal LOH, suggests that the 8p11-12 region could play a pivotal role in oncogenesis. Results: Loss in the FGFR1 and ZNF703-containing 8p11 region was seen in 25% of patients, correlated with lower mRNA expression levels and independently predicted poor survival, particularly in systemic treatment-naïve patients and even without adjacent 8p12 loss. Amplification of FGFR1 at 8p11 and loss of DUSP26 and UNC5D, located in the 8p12 breakpoint region, independently predicted worse event free survival. Gains in the 8p12 region encompassing WRN, NRG1, DUSP26 and UNC5D, seen in 20-30% of patients, were associated with higher mRNA expression and independently predicted chemotherapy sensitivity. Losses at 8p12 independently predicted radiotherapy resistance. Material and methods: Multiplex ligation-dependent probe amplification was used to investigate copy number aberrations at 8p11-12 in 234 female breast cancers. Alterations were correlated with clinicopathologic characteristics, survival and response to therapy. Results were validated using public METABRIC data Conclusion: Allelic loss and amplification in the 8p11-12 breakpoint region predict poor survival and chemo- and radiotherapy response. Assessment of 8p11-12 gene copy number status seems to augment existing prognostic and predictive tools. INTRODUCTION frequent in aggressive breast cancers with worse overall survival [10–14], in poorly differentiated and advanced The short arm of chromosome 8 (8p) is a frequent stages of hepatocellular carcinoma [15], in advanced target of loss of heterozygosity (LOH) in colorectal, clinical stages of colorectal carcinomas [16], in bladder hepatocellular, prostate, bladder, lung, ovarian as well cancers of high grade and stage [17], and in prostate as breast cancer [1–9]. Furthermore, LOH on 8p is more carcinomas with worse outcome [18, 19]. This suggests www.oncotarget.com 17078 Oncotarget that (synergistic) loss or inactivation of tumor suppressor of cases (versus 20% for ZNF703). This region contains genes on 8p plays a role in the progression of multiple two other genes, KCNU1 (36641842 bp from pter) and cancer types. UNC5D (35092975 bp from pter). A putative breakpoint To establish molecular drivers of 8p loss, several between ZNF703 and KCNU1 was observed in 155/2173 studies have tried to pinpoint one or more regions cases (7%) while putative breakpoints between KCNU1 of minimal deletion using either cell lines or human and UNC5D and between UNC5D and DUSP26 were breast cancers [5, 12, 13, 20, 21]. The results have been present in 204/2173 (9.4%) and 197/2173 (9.1%) cases. inconsistent, with regions at 8p12, 8p12-21, 8p22 and Breakpoints between DUSP26 and neighbouring gene 8p22-23.3 being reported. Recently, Cai et al. pinpointed RNF122 were however much less frequent (3/2173; 0.1%). a region commonly affected by 8p deletions using Between NRG1 and WRN, another weaker breakpoint was TCGA data, and subsequently examined the effect of a observed, with 36% and 39% loss, and 13% and 9% gain/ chromosome 8p 2-35 Mb targeted deletion, which was amplification of NRG1 and WRN, respectively. insufficient to transform MCF10A cells, but altered the fatty acid and ceramide metabolism leading to increased 8p11-12 copy number alterations by MLPA invasiveness and enhanced autophagy [14]. LOH of 8p is often but not always associated Table 1 shows the frequency of allelic loss, copy with amplification of the neighbouring 8p12-p11.23 number increase and high-level amplification observed region, containing FGFR1 and ZNF703. Concomitant in the investigated genes and genomic subregions and break and amplification are likely to result from the Table 2 shows the significant associations of these copy breakage-fusion-bridge mechanism [22]. However, number alterations with pathological characteristics. the clustering of breakpoints, even in the absence of Raw chromosome 8p MLPA and corresponding clinical/ proximal amplifications or distal deletions, suggests pathological data are provided in Supplementary Table that the 8p12 region is sensitive to breakages and could 4. Overall, regardless of the genomic sub-region, copy play a pivotal role in oncogenesis via inactivation of number increase on the short arm of chromosome 8 was one or several tumor suppressor genes, and/or activation associated with high grade (p=0.037) and high mitotic of one or more oncogenes. Adding to the complexity, activity (p=0.011). Copy number increase and high level the nature of specific driver genes and the type of copy amplification were most frequently observed in luminal number alteration in this breakpoint region may be B-like tumors (p=0.017 and p=0.003 respectively; 68% context dependent. Here, we explore METABRIC data demonstrated a copy number increase at 8p). The presence and confirm that 8p LOH is a frequent phenomenon in of an allelic loss on the short arm of chromosome 8 was poor-prognosis breast cancer, with a sharp increase in associated with ductal histology (p=0.027), PR negativity the frequency of copy number loss between ZNF703 (p=0.031), high grade (p=0.008) and high mitotic activity (20% loss, 26% gain/amplification) and WRN (39% loss, (p=0.003). Allelic loss at 8p was most frequent in non- 9% gain/amplification) at 8p12. Subsequently, we show luminal A-like (p=0.003; 32% in luminal A-like) tumors in a large series of breast cancer patients that allelic and tended to be more prevalent in luminal B-like loss and amplification in the 8p11-12 breakpoint region (p=0.053; 57%) and triple negative (p=0.065; 61%) predict poor survival and chemoradiotherapy response. tumors presenting at older age (p=0.057). Regardless of why cancer cells select for amplifications Copy number increase of at least 1 of the 4 genes in in some settings and copy number loss in others, these the 8p12 region (WRN, NRG1, DUSP26 and/or UNC5D) results should increase consideration of the prognostic was associated with HER2 negativity (p=0.014). Copy and predictive potential of copy number aberrations in number increase, especially high-level amplification of this region. at least 1 of the 3 genes in the 8p11 region (ZNF703, FGFR1 and/or FNTA) was predominantly seen in luminal RESULTS B-like tumors (p=0.016 and p=0.005, respectively) and tumors with high mitotic counts (p=0.039 and p=0.016, METABRIC breakpoint identification respectively). Allelic loss of at least 1 gene in the 8p12 region was more prevalent in luminal B-like tumors Supplementary Figure 1 depicts a heatmap of (p=0.040) and tumors diagnosed at older age (p=0.027). putative copy number calls on chromosome 8p observed Allelic loss of the 8p11 genomic subregion was associated in METABRIC (n=2173 informative cases). In 94% of with ER and PR negativity (p=0.015 and p=0.011, cases, the copy number status of FGFR1 and ZNF703 respectively), high mitotic activity (p=0.034), a non- was similar. However, a very strong putative breakpoint luminal A-like subtype (p=0.013) and triple negativity was observed in a more distal region between ZNF703 (p=0.013; 45% demonstrated allelic loss at the 8p11 (37553269 bp from pter) and DUSP26 (33448851 bp from region). Supplementary Figure 2 depicts the frequencies pter), where DUSP26 was gained or amplified in 14% of of 8p regional copy number alterations in each molecular cases (versus 26% of cases for ZNF703) and lost in 34% breast cancer subtype. www.oncotarget.com 17079 Oncotarget Table 1: Frequency of allelic loss, copy number increase (gain or amplification) and amplification (cut-off 2.0) by MLPA Gene Ensembl Distance from Cut-off Cut-off Gain/ % Loss % Gain/ % Amp cytogenetic band pter (Mbp) Loss Amp Amp WRN 8p12 31.0 0.82 1.14 10 8 1 NRG1 8p12 31.6 0.81 1.17 9 10 1 DUSP26 8p12 33.6 0.80 1.31 16 10 1 UNC5D 8p12 35.2 0.78 1.43 13 12 3 ZNF703 8p11.23 37.7 0.71 1.37 9 31 15 FGFR1 8p11.23 38.4 0.82 1.16 12 19 7 FNTA 8p11.21 43.0 0.77 1.36 5 19 3 PRKDC 8q11.21 47.8 0.75 1.25 1 26 2 8p12 ≥1 of 4 genes - - - 36 31 4 8p12 only ≥1 of 4 genes - - - 6 9 0 transition ≥1 of 3 genes - - - 33 21 4 transition only ≥1 of 3 - - - 9 5 0 8p11 ≥1 of 3 genes - - - 26 42 16 8p11 only ≥1 of 3 genes - - - 7 8 5 8p11-12 ≥1 of 7 genes - - - 44 52 17 Cut-offs for loss and gain/amplification were determined per gene, based on the minimum and maximum ratio values of normal breast tissue.
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