Magnetic properties of Sr3NiIrO6 and Sr3CoIrO6: Magnetic hysteresis with coercive fields of up to 55 T

We report extraordinarily large magnetic hysteresis loops in the iridates Sr3NiIrO5 and Sr3CoIrO6. We find coercive magnetic fields of up to 55 T with switched magnetic moments ≈1??B per formula unit in Sr3NiIrO6 and coercive fields of up to 52 T with switched moments ≈3??B per formula unit in Sr3CoIrO6. We propose that the magnetic hysteresis involves the field-induced evolution of quasi-one-dimensional chains in a frustrated triangular configuration. The striking magnetic behavior is likely to be linked to the unusual spin-orbit-entangled local state of the Ir4+ ion and its potential for anisotropic exchange interactions.clos

Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy

Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also show that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorises patients into four immune clusters correlated with survival. The immune suppressed cluster is associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster is associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5, CD8A, and NKG7. The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials.Marjan M. Naeini, Felicity Newell, LaurenG. Aoude, Vanessa F. Bonazzi, Kalpana Patel, Guy Lampe, Lambros T. Koufariotis, Vanessa Lakis, Venkateswar Addala, Olga Kondrashova, Rebecca L. Johnston, Sowmya Sharma, Sandra Brosda, Oliver Holmes, Conrad Leonard, Scott Wood, Qinying Xu, Janine Thomas, Euan Walpole, G. Tao Mai, Stephen P. Ackland, Jarad Martin, Matthew Burge, Robert Finch, Christos S. Karapetis, Jenny Shannon, Louise Nott, Robert Bohmer, Kate Wilson, Elizabeth Barnes, John R. Zalcberg, B. Mark Smithers, John Simes, Timothy Price, Val Gebski, Katia Nones, David I. Watson, John V. Pearson, Andrew P. Barbour, Nicola Waddel

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases

Cereal Domestication and Evolution of Branching: Evidence for Soft Selection in the Tb1 Orthologue of Pearl Millet (Pennisetum glaucum [L.] R. Br.)

BACKGROUND: During the Neolithic revolution, early farmers altered plant development to domesticate crops. Similar traits were often selected independently in different wild species; yet the genetic basis of this parallel phenotypic evolution remains elusive. Plant architecture ranks among these target traits composing the domestication syndrome. We focused on the reduction of branching which occurred in several cereals, an adaptation known to rely on the major gene Teosinte-branched1 (Tb1) in maize. We investigate the role of the Tb1 orthologue (Pgtb1) in the domestication of pearl millet (Pennisetum glaucum), an African outcrossing cereal. METHODOLOGY/PRINCIPAL FINDINGS: Gene cloning, expression profiling, QTL mapping and molecular evolution analysis were combined in a comparative approach between pearl millet and maize. Our results in pearl millet support a role for PgTb1 in domestication despite important differences in the genetic basis of branching adaptation in that species compared to maize (e.g. weaker effects of PgTb1). Genetic maps suggest this pattern to be consistent in other cereals with reduced branching (e.g. sorghum, foxtail millet). Moreover, although the adaptive sites underlying domestication were not formerly identified, signatures of selection pointed to putative regulatory regions upstream of both Tb1 orthologues in maize and pearl millet. However, the signature of human selection in the pearl millet Tb1 is much weaker in pearl millet than in maize. CONCLUSIONS/SIGNIFICANCE: Our results suggest that some level of parallel evolution involved at least regions directly upstream of Tb1 for the domestication of pearl millet and maize. This was unanticipated given the multigenic basis of domestication traits and the divergence of wild progenitor species for over 30 million years prior to human selection. We also hypothesized that regular introgression of domestic pearl millet phenotypes by genes from the wild gene pool could explain why the selective sweep in pearl millet is softer than in maize

Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity

To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options.This work was supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (1093017, G.J.M., R.A.S., N.H., G.V.L., J.F.T.), an NHMRC project grant (APP1123217) and NHMRC Fellowship grants (R.A.S., N.K.H. - APP1139071, G.VL.). G.V.L is supported by an NHMRC Practitioner Fellowship and the University of Sydney Medical Foundation. R.A.S is supported by an NHMRC Practitioner Fellowship. J.S.W. is supported by a NHMRC early career fellowship (1111678). N.W. is supported by an NHMRC Senior Research Fellowship (1139071). N.K.H. is supported by an NHMRC Senior Principal Research Fellowship (1117663). P.M.F. was supported by the Deborah and John McMurtrie MIA Pathology Fellowship. T.J.D. was supported by the Jani Haenke Melanoma Pathology Fellowship. Support from Melanoma Institute Australia, the Royal Prince Alfred Hospital and New South Wales Health Pathology is also gratefully acknowledged

Comparison of immunohistochemistry with PCR for assessment of ER, PR, and Ki-67 and prediction of pathological complete response in breast cancer

Background: Proliferation may predict response to neoadjuvant therapy of breast cancer and is commonly assessed by manual scoring of slides stained by immunohistochemistry (IHC) for Ki-67 similar to ER and PgR. This method carries significant intra- and inter-observer variability. Automatic scoring of Ki-67 with digital image analysis (qIHC) or assessment of MKI67 gene expression with RT-qPCR may improve diagnostic accuracy. Methods: Ki-67 IHC visual assessment was compared to the IHC nuclear tool (AperioTM) on core biopsies from a randomized neoadjuvant clinical trial. Expression of ESR1, PGR and MKI67 by RT-qPCR was performed on RNA extracted from the same formalin-fixed paraffin-embedded tissue. Concordance between the three methods (vIHC, qIHC and RT-qPCR) was assessed for all 3 markers. The potential of Ki-67 IHC and RT-qPCR to predict pathological complete response (pCR) was evaluated using ROC analysis and non-parametric Mann-Whitney Test. Results: Correlation between methods (qIHC versus RT-qPCR) was high for ER and PgR (spearman´s r = 0.82, p < 0.0001 and r = 0.86, p < 0.0001, respectively) resulting in high levels of concordance using predefined cut-offs. When comparing qIHC of ER and PgR with RT-qPCR of ESR1 and PGR the overall agreement was 96.6 and 91.4%, respectively, while overall agreement of visual IHC with RT-qPCR was slightly lower for ER/ESR1 and PR/PGR (91.2 and 92.9%, respectively). In contrast, only a moderate correlation was observed between qIHC and RT-qPCR continuous data for Ki-67/MKI67 (Spearman’s r = 0.50, p = 0.0001). Up to now no predictive cut-off for Ki-67 assessment by IHC has been established to predict response to neoadjuvant chemotherapy. Setting the desired sensitivity at 100%, specificity for the prediction of pCR (ypT0ypN0) was significantly higher for mRNA than for protein (68.9% vs. 22.2%). Moreover, the proliferation levels in patients achieving a pCR versus not differed significantly using MKI67 RNA expression (Mann-Whitney p = 0.002), but not with qIHC of Ki-67 (Mann-Whitney p = 0.097) or vIHC of Ki-67 (p = 0.131). Conclusion: Digital image analysis can successfully be implemented for assessing ER, PR and Ki-67. IHC for ER and PR reveals high concordance with RT-qPCR. However, RT-qPCR displays a broader dynamic range and higher sensitivity than IHC. Moreover, correlation between Ki-67 qIHC and RT-qPCR is only moderate and RT-qPCR with MammaTyper® outperforms qIHC in predicting pCR. Both methods yield improvements to error-prone manual scoring of Ki-67. However, RT-qPCR was significantly more specific

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs