<i>TP53</i> alterations in primary and secondary Sézary syndrome: A diagnostic tool for the assessment of malignancy in patients with erythroderma

<div><p>Recent massive parallel sequencing data have evidenced the genetic diversity and complexity of Sézary syndrome mutational landscape with <i>TP53</i> alterations being the most prevalent genetic abnormality. We analyzed a cohort of 35 patients with SS and a control group of 8 patients with chronic inflammatory dermatoses. <i>TP53</i> status was analyzed at different clinical stages especially in 9 patients with a past-history of mycosis fungoides (MF), coined secondary SS. <i>TP53</i> mutations were only detected in 10 patients with either primary or secondary SS (29%) corresponding to point mutations, small insertions and deletions which were unique in each case. Interestingly, <i>TP53</i> mutations were both detected in sequential unselected blood mononuclear cells and in skin specimens. Cytogenetic analysis of blood specimens of 32 patients with SS showed a <i>TP53</i> deletion in 27 cases (84%). Altogether 29 out of 35 cases exhibited <i>TP53</i> mutation and/or deletion (83%). No difference in prognosis was observed according to <i>TP53</i> status while patients with secondary SS had a worse prognosis than patients with primary SS. Interestingly, patients with <i>TP53</i> alterations displayed a younger age and the presence of <i>TP53</i> alteration at initial diagnosis stage supports a pivotal oncogenic role for <i>TP53</i> mutation in SS as well as in erythrodermic MF making <i>TP53</i> assessment an ancillary method for the diagnosis of patients with erythroderma as patients with inflammatory dermatoses did not display <i>TP53</i> alteration.</p></div

Schematic representation of somatic mutations identified in <i>TP53</i> by targeted deep sequencing (n = 35).

<p>Mutation sites were marked and amino acid changes were indicated. Colors and shapes indicated the kind of mutation and the presence in the COSMIC database.</p

Clinical and biological features of patients with primary Sézary Syndrome (SS) or with past-history of Mycosis Fungoides (MF) at secondary SS stage.

<p>Clinical and biological features of patients with primary Sézary Syndrome (SS) or with past-history of Mycosis Fungoides (MF) at secondary SS stage.</p

Clinical data and somatic alterations of <i>TP53</i> gene in Sézary syndrome.

<p>Age at diagnosis (years), Clinical status means survival time in months after diagnosis of Sézary syndrome until the death or last clinical status, ⱡ data determined by fluorescence <i>in situ</i> hybridization, ¥ data determined by quantitative fluorescence <i>in situ</i> hybridization.</p

Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study

Nearly one-half of BRCA1 and BRCA2 sequence variations are variants of uncertain significance (VUSs) and are candidates for splice alterations for example, by disrupting/creating splice sites. As out-of-frame splicing defects lead to a marked reduction of the level of the mutant mRNA cleared through nonsense-mediated mRNA decay, a cDNA-based test was developed to show the resulting allelic imbalance (AI). Fifty-four VUSs identified in 53 hereditary breast/ovarian cancer (HBOC) patients without BRCA1/2 mutation were included in the study. Two frequent exonic single-nucleotide polymorphisms on both BRCA1 and BRCA2 were investigated by using a semiquantitative single-nucleotide primer extension approach and the cDNA allelic ratios obtained were corrected using genomic DNA ratios from the same sample. A total of five samples showed AI. Subsequent transcript analyses ruled out the implication of VUS on AI and identified a deletion encompassing BRCA2 exons 12 and 13 in one sample. No sequence abnormality was found in the remaining four samples, suggesting implication of cis- or trans-acting factors in allelic expression regulation that might be disease causative in these HBOC patients. Overall, this study showed that AI screening is a simple way to detect deleterious splicing defects and that a major role for VUSs and deep intronic mutations in splicing anomalies is unlikely in BRCA1/2 genes. Methods to analyze gene expression and identify regulatory elements in BRCA1/2 are now needed to complement standard approaches to mutational analysis