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mutations in KDR , FLT4 (OMIM gene 136352), DUSP5 (OMIM gene 603069), GNAQ (OMIM gene 600998), GNA11 (OMIM gene 39313) or GNA14 (OMIM gene 604397) or by germline mutations in ANTXR1 (OMIM gene 606410) or KDR (OMIM gene 191306) ( 5 , 6 , 7 , 8 ). Verrucous venous malformation (OMIM disease not available) is sporadic and is caused by somatic mutations in MAP3K3 (OMIM gene 602539) ( 9 ). Pyogenic granuloma (OMIM disease not available) is sporadic and is caused by somatic mutations in BRAF , NRAS or KRAS ( 10 ) Venous malformations Multiple cutaneous


Lymphatic malformations (LMs) show phenotypic variability, as well as clinical and genetic heterogeneity. Inheritance is autosomal dominant, recessive or X-linked and major genes involved in predisposition for LMs are continuously being discovered. The literature also indicates that somatic mutations play an important role in the development of LMs. In fact, activating somatic mutations in PIK3CA have been reported in lymphatic endothelial cells obtained from patients with different kinds of LM. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.


Inherited genetic factors play an important role in breast cancer susceptibility. The BRCA1 and BRCA2 mutations are the most well-known genetic factors associated with increased risk of breast cancer. E-selectin is a cell surface glycoprotein and its serum levels are known to increase in various cancers. The present retrospective study aimed to evaluate whether E-selectin S128R polymorphism (NG_012124.1: g.7161A>C, NM_000450.2: c.445A>C, NP_000441.2: p.Ser149Arg), which is known to have a role in cancer risk, is associated with breast cancer susceptibility in BRCA 1/2 mutation non carriers with breast cancer. The study included 90 patients with breast cancer and 270 healthy controls. All breast cancer patients were screened for BRCA 1/2 mutations and confirmed to be BRCA 1/2 mutation non carriers before inclusion in the study. Genotyping for the E-selectin S128R polymorphism was performed using real-time polymerase chain reaction (PCR) analysis. The frequencies of the AA, AC and CC genotypes were 70.0, 25.5 and 4.5%, respectively, in the patient group and 79.25, 19.25 and 1.5%, respectively, in the controls. The frequencies of A and C alleles were 84.8 and 15.2% in the patient group, respectively, and 88.9 and 11.1%, respectively, in the controls. No significant differences were determined in the genotype and allele frequencies of the E-selectin S128R polymorphism between the patient and control groups (p = 0.095). The S128R (A/C) polymorphism was not found to be associated with an increased risk of breast cancer [odds ratio (OR) = 0.69; 95% confidence interval (95% CI): 0.43-1.10; p = 0.1248). There was no association between the S128R polymorphism and breast cancer susceptibility in BRCA 1/2 mutation non carriers with breast cancer in the studied Turkish population. Further studies with larger sample sizes are needed to validate our findings.

atrophy. The CNS hemangioblastoma operation may have led to optic nerve atrophy and vision loss in Case 2. Retinal hemangioblastomas were at the equator of the eye in Case 2. Germline mutations as a result of single nucleotide changes that were detected in these cases (c.202T>C, p.Ser68Pro) are reported in only two other cases in the literature [ 10 ] but, in these cases, no systemic involvement except RH was detected. The other details of these cases have not been mentioned in the literature. Although these two cases had the same mutation, renal involvement was

yrs 12% within 5 yrs 40%-50% at 20 yrs Ovarian 1%-2% 24%-40% 11%-18% Male breast 0.1% 1%-2% 5%-10% Prostate 15% (N. European origin) 18% (African Americans) <30% <39% Pancreatic 0.50% 1%-3% 2%-7% There is an increasing evidence that subsequent generations of mutations carriers tend to develop malignancies at younger ages, supporting the existence of genetic anticipation in BRCA1/2 inheritance. Cancers tend to be diagnosed at ages 7–8 years younger in mutations – positive off-springs of pathogenic mutation carriers [ 9 , 10 ]. Germline mutations in specific gene

two patients, BRCA2, FANCM and CHEK2 in one patient each) and one in nucleotide excision repair pathway (ERCC2) . Germline mutations in DRG genes have recently been described in individuals with hereditary CRC, though their contribution to a CRC risk is still unknown [ 14 , 28 , 29 , 30 ]. Recent data indicate that DRG defects are also relatively frequent somatic events in CRC, further supporting the notion that the inherited DRG variants are important in CRC carcinogenesis [ 29 , 30 ]. In line with this, some of these variants are described in other

Alterations of Copy Number of Methylation Pattern in Mismatch Repair Genes by Methylation Specific-Multiplex Ligation-Dependent Probe Amplification in Cases of Colon Cancer

Genetic alterations and changes in genomic DNA cytosine methylation patterns are associated with all types of cancer and are caused by germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1 (MutL homolog 1, 19 exons) and MSH2 (MutS homolog 2, 16 exons). Genomic DNA was extracted from tissue samples embedded in paraffin from 49 patients with adenocarcinoma and from 21 patients with carcinoma for the study group; genomic DNA was extracted from lymphocytes from 10 healthy donors for the control group. We used methylation specific multiplex ligation-dependent probe amplification (MS-ML-PA), which allows the detection of copy number changes and unusual methylation levels of 10 to 50 different sequences in one reaction by use of the methylationsensitive restriction enzyme HhaI and sequence-specific capillary electrophoresis for the study of 24 genes.

We found the mean methylation rates for MLH1 (97.14%), MSH2 (24.28%), MSH6 (MutS homolog 6) (67.14%), MSH3 (MutS homolog 3) (78.57%), MLH3 (MutL homolog 3) (75.71%), PMS2 (postmeiotic segregation increased 2) (65.71%), MGMT(O-6-methylguanine-DNA methyltransferase) (82.85%). We conclude that the mismatch repair (MMR) system is critical for the maintenance of genomic stability.


The most significant and well characterized genetic risk factors for breast and/or ovarian cancer are germline mutations in the BRCA1 and BRCA2 genes. The BRCA1 and BRCA2 gene mutations strikingly increase breast cancer risk, suggesting that polymorphisms in these genes are logical candidates in seeking to identify low penetrance susceptibility alleles. The aim of this study was to initiate a screen for BRCA1/2 gene mutations in order to identify the genetic variants in the Republic of Macedonia, and to evaluate the association of several single nucleotide polymorphisms (SNPs) in these genes with breast cancer risk. In this study, we included 100 patients with invasive breast cancer from the Republic of Macedonia, classified according to their family history and 100 controls. The methodology included direct sequencing, single nucleotide primer extension method and multiplex ligation probe amplification (MLPA) analysis, all followed by capillary electrophoresis (CE) on an ABI PRISM™ 3130 Genetic Analyzer. We identified a total of seven carriers of mutations in the BRCA1/2 genes. None of the tested polymorphisms was associated with sporadic breast cancer risk, however, polymorphism rs8176267 in BRCA1 and N372H in BRCA2 showed an association with breast cancer risk in patients with at least one family member with breast cancer.

mutation by radiation. Nature 2000; 405: 37. Strachan T, Read A. Human Molecular Genetics 2. Oxford: BIOS Scientific Publishers Ltd; 1999. Sadamoto S, Suzuki S, Kamiya K, Kominami R, Dohi K, Niwa O. Radiation induction of germline mutation at a hypervariable mouse minisatellite locus. Int J Radiat Biol 1994; 65: 549-57. Bois P, Stead JHD, Bakshi S, Williamson J, Neumann R, Moghadaszadeh B, et al. Isolation and characterization of mouse minisatellites. Genomics 1998; 50: 317-30. Sankaranarayanan K. Ionizing radiation and genetic risks X. The potential "disease

References Halford SE, Rowan AJ, Lipton L, Sieber OM, Pack K, Thomas HJ, Hodgson SV, Bodmer WF, Tomlinson IP. Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers. Am J Pathol 2003; 162(5): 1545-1548. Nielsen M, Franken PF, Reinards TH, Weiss MM, Wagner A, van der Klift H, Kloosterman S, Houwing-Duistermaat JJ, Aalfs CM, Ausems MG, Bröcker-Vriends AH, Gomez Garcia EB, Hoogerbrugge N, Menko FH, Sijmons RH, Verhoef S, Kuipers EJ, Morreau H, Breuning MH, Tops CM, Wijnen JT, Vasen HF, Fodde R