Improvement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group.

International audienceBACKGROUND: Knowledge about tumour gene mutation status is essential for the treatment of increasing numbers of cancer patients, and testing quality has a major impact on treatment response and cost. In 2012, 4,629 tests for BRAF p.V600 were performed in France, in patients with melanomas. METHODS: Two batches of unstained melanoma sections were sent, in May and November 2012, to the 46 laboratories supported by the French National Institute of Cancer (INCa). An external quality assessment (EQA) evaluated mutation status, response times and compliance with INCa recommendations. RESULTS: All the French laboratories involved in testing participated in the EQA. Fourteen different methods were used to detect BRAF mutations, most consisting of combinations of in-house techniques. False responses were noted in 25/520 cases (4.8%), 11 of which concerned confusion between p.V600E and p.V600K. Thus, 2.7% of responses would have led to inappropriate treatment. Within six months, mean response times decreased from 22 to 12 days (P<0.001), and the percentage of samples evaluated by a pathologist for tumour cell content increased, from 75.2% to 96.9% (P<0.001). CONCLUSION: Despite the use of non-certified methods, the false response rate was low. Nationwide EQA can improve the quality of molecular pathology tests on tumours

The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation

International audienceK idney transplantation is the only curative treatment for end-stage renal disease 1. The fact that the first successful kidney transplantation in man was between identical twins 2 , along with seminal work in animal models, hinted strongly that a single genetic locus does not govern the clinical outcome of a transplantation, no matter how relevant (such as the major histocompatibility complex (MHC), human leukocyte antigen (HLA)). Indeed, George Snell, in his landmark 1948 study 3 (as well as subsequent work by himself, and others), identified several dozen histocompatibility loci in the mouse 4 , although close to none has been identified to date in any species (including man). Fast forward to today, and, owing to the development and refinement of country-and continent-wide allocation processes, perioperative handling of the graft and patients, and selective immunosuppressive drugs that improve transplantation survival mainly by alleviating acute T cell-mediated rejection (TCMR), the number of kidney transplantations is continuously increasing worldwide. However, antibody-mediated rejection (ABMR) is recognized as a major cause of late transplantation failure, and its treatment remains challenging 5. In addition to the histological findings, a key feature of ABMR is the presence of donor-specific anti-HLA antibodies (DSA) 6. Nonetheless, in routine clinical care, cases meeting the histological criteria for ABMR but without detectable anti-HLA DSA could represent more than 50% of rejection events 7. These cases might be explained by the presence of pathogenic antibodies that are produced against other, non-HLA, histocompatibility antigens 8. MHC class I chain-related gene A (MICA; GenBank accession: NM_001177519), discovered almost 30 years ago 9 , encodes a polymorphic non-conventional MHC-encoded class I molecule 10. The MICA gene is located, within the HLA complex, 46 kb centromeric to the HLA-B locus 9. Close to 400 MICA alleles have been reported to date 10. The MICA glycoprotein (Uniprot accession: Q96QC4) is expressed on a restricted number of cell types, mainly epithelial and endothelial cells. MICA binds NKG2D, an activating receptor present on the surface of cytotoxic CD8 + αβ and γδ T lymphocytes as well as certain natural killer (NK) cells 10. Fifteen years ago Zou et al. 11 reported the first comprehensive study of the potential involvement of MICA in kidney transplant outcomes. That work, however, was focused only on anti-MICA antibodies and had no information on donor and recipient MICA (mis)matching, a situation that has persisted to date given that no study has analyzed simultaneously the sequence-based molecular MICA matching and the status of both anti-HLA and anti-MICA DSA in a large cohort for which information about all other relevant covariates was available and included in the final analysis (for review see refs. 12,13)