CD1 Gene Polymorphisms and Phenotypic Variability in X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is characterized by marked phenotypic variation ranging from adrenomyeloneuropathy (AMN) to childhood cerebral ALD (CCALD). X-ALD is caused by mutations in the ABCD1 gene, but no genotype-phenotype correlation has been established so far and modifier gene variants are suspected to modulate phenotypes. Specific classes of lipids, enriched in very long-chain fatty acids that accumulate in plasma and tissues from X-ALD patients are suspected to be involved in the neuroinflammatory process of CCALD. CD1 proteins are lipid- antigen presenting molecules encoded by five CD1 genes in human (CD1A-E). Association studies with 23 tag SNPs covering the CD1 locus was performed in 52 patients with AMN and 87 patients with CCALD. The minor allele of rs973742 located 4-kb downstream from CD1D was significantly more frequent in AMN patients (χ2 = 7.6; P = 0.006). However, this association was no longer significant after Bonferroni correction for multiple testing. The other polymorphisms of the CD1 locus did not reveal significant association. Further analysis of other CD1D polymorphisms did not detect stronger association with X-ALD phenotypes. Although the association with rs973742 warrants further investigations, these results indicate that the genetic variants of CD1 genes do not contribute markedly to the phenotypic variance of X-ALD

A new genotoxicity assay based on p53 target gene induction

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Detecting inversions in routine molecular diagnosis in MMR genes

International audienceInversions, i.e. a change in orientation of a segment of DNA, are a recognized cause of human diseases which remain overlooked due to their balanced nature. Inversions can have severe or more subtle impacts on gene expression. We describe two families that exemplify these aspects and underline the need for inversion detection in routine diagnosis. The first family (F1) displayed a sibship with two constitutional mismatch repair deficiency patients and a family history of colon cancer in the paternal branch. The second family (F2) displayed a severe history of Lynch syndrome. These families were analyzed using a whole gene panel (WGP) strategy i.e. including colon cancer genes with their intronic and flanking genomic regions. In F1, a PMS2 inversion encompassing the promoter region to intron 1 and a PMS2 splice variant were found in the maternal and paternal branch, respectively. In F2, we described the first MSH6 inversion, involving the 5' part of MSH6 and the 3' part of the nearby gene ANXA4. Inversion detection mandates genomic sequencing, but makes a valuable contribution to the diagnostic rate. WGP is an attractive strategy as it maximizes the detection power on validated genes and keeps sufficient depth to detect de novo events

Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations.

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Blood functional assay for rapid clinical interpretation of germline TP53 variants

International audienceThe interpretation of germline TP53 variants is critical to ensure appropriate medical management of patients with cancer and follow-up of variant carriers. This interpretation remains complex and is becoming a growing challenge considering the exponential increase in TP53 tests. We developed a functional assay directly performed on patients' blood

Allelic analyses of the 23 tag SNPs genotyped in CCALD and AMN patients.

a<p>: The Fisher's exact test was used for SNP with a Minor Allele Frequency (MAF)<0.10.</p>b<p>: Permutation-based empirical <i>P</i> value were calculated for SNP showing a trend of association (<i>P</i> value<0.10).</p

Allelic analyses of <i>CD1D</i> and <i>CD1B</i> variants in the CCALD and AMN patients.

a<p>: The Fisher's exact test was used for SNP with a Minor Allele Frequency (MAF)<0.10.</p>b<p>: Permutation-based empirical <i>P</i> value were calculated for SNP showing a trend of association (<i>P</i> value<0.10).</p

Tagging of the <i>CD1 locus</i>.

<p>A) Allelic association results of the tag SNPs genotyped in CCALD and AMN patients: each black dot represents a tag SNP; -log₁₀<i>P</i> is plotted for each of the 21 tag SNPs; the five <i>CD1</i> genes are indicated by black boxes; B) LD between the corresponding tag SNPs: LD is represented by shades of grey as a function of r² values (black diamond for r²≥0.90, white diamond for r² = 0). Associated tag SNPs are marked with an asterisk.</p

Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome

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Further delineation of the NTHL1 associated syndrome: A report from the French Oncogenetic Consortium

International audienceAbstract Biallelic pathogenic variants in the NTHL1 (Nth like DNA glycosylase 1) gene cause a recently identified autosomal recessive hereditary cancer syndrome predisposing to adenomatous polyposis and colorectal cancer. Half of biallelic carriers also display multiple colonic or extra‐colonic primary tumors, mainly breast, endometrium, urothelium, and brain tumors. Published data designate NTHL1 as an important contributor to hereditary cancers but also underline the scarcity of available informations. Thanks to the French oncogenetic consortium (Groupe Génétique et Cancer), we collected NTHL1 variants from 7765 patients attending for hereditary colorectal cancer or polyposis (n = 3936) or other hereditary cancers (n = 3829). Here, we describe 10 patients with pathogenic biallelic NTHL1 germline variants, that is, the second largest NTHL1 series. All carriers were from the “colorectal cancer or polyposis” series. All nine biallelic carriers who underwent colonoscopy presented adenomatous polyps. For digestive cancers, average age at diagnosis was 56.2 and we reported colorectal, duodenal, caecal, and pancreatic cancers. Extra‐digestive malignancies included sarcoma, basal cell carcinoma, breast cancer, urothelial carcinoma, and melanoma. Although tumor risks remain to be precisely defined, these novel data support NTHL1 inclusion in diagnostic panel testing. Colonic surveillance should be conducted based on MUTYH recommendations while extra‐colonic surveillance has to be defined