Endometrial cancer and somatic G > T KRAS transversion in patients with constitutional MUTYH biallelic mutations

MUTYH-associated polyposis (MAP) is an autosomal recessive condition predisposing to colorectal cancer, caused by constitutional biallelic mutations in the base excision repair (BER) gene MUTYH. Colorectal tumours from MAP patients display an excess of somatic G>T mutations in the APC and KRAS genes due to defective BER function. To date, few extracolonic manifestations have been observed in MAP patients, and the clinical spectrum of this condition is not yet fully established. Recently, one patient with a diagnosis of endometrial cancer and biallelic MUTYH mutations has been described. We here report on two additional unrelated MAP patients with biallelic MUTYH germline mutations who developed endometrioid endometrial carcinoma. The endometrial tumours were evaluated for MEN, PIK3CA, KRAS, BRAF and CTNNB1 mutations. A G>T transversion at codon 12 of the KRAS gene was observed in one tumour. A single 1 bp frameshift deletion of PTEN was observed in the same sample. Overall, these findings suggest that endometrial carcinoma is a phenotypic manifestations of MAP and that inefficient repair of oxidative damage can be involved in its pathogenesis. (C) 2008 Elsevier Ireland Ltd. All rights reserved

HOMOZYGOUS DELETION IN STXBP2 CAUSATIVE OF FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS TYPE 5 (FHL-5)

Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening immunedeficiency, characterized by a hyperinflammatory syndrome. Familial forms are caused by mutations in genes associated with lymphocyte granule-mediated cytotoxicity. Four subtypes are defined by mutations in the following genes: PRF1 in FHL2, UNC13D in FHL3, STX11 in FHL4, and STXBP2 in FHL5. STXBP2 codes for Munc18-2 protein which is involved in regulation of SNARE-mediated membrane fusion events. FHL5 has been reported to account for up to 20% of cases with FHL in the German series. Since 2010, 47 different mutations of STXBP2 have been described, mainly missense/nonsense, frameshift and splicing. Here we describe a large deletion causative of FHL5. Methods: A female baby, aged 47 days, second child from related parents of Egyptian origin, developed a clinical syndrome fulfilling the Histiocyte Society diagnostic criteria for HLH and was directed to functional study and molecular analysis of FHL related genes. Results: Flowcytometry analysis showed normal perforin expression but almost undetectable degranulation capacity. Direct sequencing showed no mutations in UNC13D and STX11, while the analysis of STXBP2 gene showed no amplification of the last three exons. To test the hypothesis of an homozygous deletion, we used Syber Green RT-PCR, which revealed the loss of the genomic region. The deletion was confirmed by CGH-array. Western blot analysis documented the absence of expression of STXBP2 protein in this patient. Conclusion: Identification of biallelic mutations in children with a clinical diagnosis of HLH is of paramount clinical relevance as it confirms the diagnosis of FHL, thus giving the opportunity to bring the patient to early hematopoietic stem cell transplantation. The finding of a large homozygous deletion in STXBP2 gene extends the spectrum of possible causative mutations in FHL-5 and requires adaptation of the strategy of analysis to identify complex defects