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The high frequency of homologous recombination deficiency (HRD) is the main rationale of testing platinum-based chemotherapy in triple-negative breast cancer (TNBC), however, the existing methods to identify HRD are controversial and there is a medical need for predictive biomarkers. We assess the in vivo response to platinum agents in 55 patient-derived xenografts (PDX) of TNBC to identify determinants of response. The HRD status, determined from whole genome sequencing, is highly predictive of platinum response. BRCA1 promoter methylation is not associated with response, in part due to residual BRCA1 gene expression and homologous recombination proficiency in different tumours showing mono-allelic methylation. Finally, in 2 cisplatin sensitive tumours we identify mutations in XRCC3 and ORC1 genes that are functionally validated in vitro. In conclusion, our results demonstrate that the genomic HRD is predictive of platinum response in a large cohort of TNBC PDX and identify alterations in XRCC3 and ORC1 genes driving cisplatin response.

A common alternative splicing signature is associated with SF3B1 mutations in malignancies from different cell lineages

Two related oncogenes, TCL1 and MTCP1, are overexpressed in certain T-cell prolymphocytic leukemias as a result of chromosomal rearrangements that involve the translocation of one T-cell receptor gene to either chromosome 14q32 or Xq28, respectively. The human oncoprotein p13 MTCP1 is coded by the MTCP1 gene and its primary sequence is highly and only homologous to that of p14 TCL1 , the product of TCL1. These two proteins likely represent the first members of a new family of oncogenic proteins. A previous model of the three-dimensional solution structure of p13 MTCP1 was determined recently using exclusively homonuclear proton two-dimensional NMR methods and, almost simultaneously, high-resolution crystal structures of p13 MTCP1 and p14 TCL1 appeared in the literature. In order to gain more insight into the details of the solution structure, we uniformly labeled p13 MTCP1 with nitrogen-15. The refined structure benefits from 520 additional NOEs, extracted from either 15N-edited 3D experiments or homonuclear 2D NOESY recorded at 800 MHz, and from a nearly complete set of φ angular restraints. Measurements of 15N spin relaxation times and heteronuclear 15N{1H}NOEs at two magnetic field strengths provided additional insights into the dynamics of the protein backbone. On the basis of these new results, a putative binding surface for this particular class of oncogenes is discussed.

MTCP1 (for Mature-T-Cell Proliferation) was the first gene unequivocally identified in the group of uncommon leukemias with a mature phenotype. The three-dimensional solution structure of the human p8 MTCP1 protein encoded by the MTCP1 oncogene has been previously determined by homonuclear proton two-dimensional NMR methods at 600 MHz: it consists of an original scaffold comprising three a-helices, associated with a new cysteine motif. Two of the helices are covalently paired by two disulfide bridges, forming an a-hairpin which resembles an antiparallel coiled-coil. The third helix is orientated roughly parallel to the plane defined by the a-antiparallel motif and appears less well defined. In order to gain more insight into the details of this new scaffold, we uniformly labeled with nitrogen-15 a mutant of this protein (C12A-p8 MTCP1 )i n which the unbound cysteine at position 12 has been replaced by an alanine residue, thus allowing reproducibly high yields of recombinant protein. The refined structure benefits from 211 additional NOEs, extracted from 15 N-edited 3D experiments, and from a nearly complete set of # angular restraints allowing the estimation of the helical content of the structured part of the protein. Moreover, measurements of 15 N spin relaxation times and heteronuclear 15 N{ 1 H}NOEs provided additional insights into the dynamics of the protein backbone. The analysis of the linear correlation between J(0) and J(&) was used to interpret relaxation parameters. It appears that the apparent relative disorder seen in helix III is not simply due to a lack of experimental constraints, but associated with substantial contributions of sub-nanosecond motions in this segment. Abbreviations: 2D (3D), two-dimensional (three-dimensional); NOE, nuclear Overhauser enhancement; 15 N{ 1 H}, heteronuclear 15 N nuclear Overhauser enhancement; NOESY, nuclear Overhauser enhancement spectroscopy; DQF-COSY, double-quantum-filtered scalar-correlated spectroscopy; z-TOCSY, z-filtered total correlation spectroscopy; HSQC, heteronuclear single quantum correlation; HMQC, heteronuclear multiple quantum correlation; RN(Nz )( R 1), heteronuclear 15 N longitudinal relaxation rate; R N(Nxy )( R 2), heteronuclear 15 N transverse relaxation rate; RN(Hz!Nz), cross-relaxation rate between 15 N and its attached amide proton; rmsd, root mean square deviation; PCR, polymerase chain reaction; DTT

The human oncoprotein p13 MTCP1 is coded by the MTCP1 gene, a gene involved in chromosomal translocations associated with T-cell prolymphocytic leukemia, a rare form of human leukemia with a mature T-cell phenotype. The primary sequence of p13 MTCP1 is highly and only homologous to that of p14 TCL1 , a product coded by the gene TCL1 which is also involved in T-cell prolymphocytic leukemia. These two proteins probably represent the first members of a new family of oncogenic proteins. We present the three-dimensional solution structure of the recombinant p13 MTCP1 determined by homonuclear proton two-dimensional NMR methods at 600 MHz. After proton resonance assignments, a total of 1253 distance restraints and 64 dihedral restraints were collected. The solution structure of p13 MTCP1 is presented as a set of 20 DYANA structures. The rmsd values with respect to the mean structure for the backbone and all heavy atoms for the conformer family are 1.07 ± 0.19 and 1.71 ± 0.17 A, when the structured core of the protein (residues 11–103) is considered. The solution structure of p13 MTCP1 consists of an orthogonal β-barrel, composed of eight antiparallel β-strands which present an original arrangement. The two β-pleated loops which emerge from this barrel might constitute the interaction surface with a potential molecular partner.

Correction to: British Journal of Cancer (2015) 113, 1249–1253; doi:10.1038/bjc.2015.269; published online 27 October 2015 Upon publication of the above paper in the British Journal of Cancer, the authors identified an error in the formatting of their names. First names and surnames had been inverted.

To delimit the 14q32.1 recurrent breakpoint of ataxia telangiectasia clones, we performed an in situ hybridization study with various probes located on the 14q32 band. We thus mapped this breakpoint between the D14S1 and Pi loci. Furthermore, an interstitial duplication including D14S1 and a part of the IgH locus was demonstrated on a t(14;14) clone.

Using in situ chromosomal hybridization we have mapped the gene for the T-cell receptor alpha-chain in three different non-malignant T-cell clones occurring in ataxia telangiectasia. The constant region was translocated in each of the three clones. The variable region remained in its original position in two cases and was deleted in one clone which lost the derivative chromosome 14. We have therefore demonstrated that the T-cell receptor alpha-gene is split in at least two of these translocations. To our knowledge, this is the first direct evidence of the involvement of a gene from the immunoglobulin superfamily in chromosomal rearrangements in ataxia telangiectasia.