Features of Patients With Hereditary Mixed Polyposis Syndrome Caused by Duplication of GREM1 and Implications for Screening and Surveillance.

Hereditary mixed polyposis syndrome is a rare colon cancer predisposition syndrome caused by a duplication of a noncoding sequence near the gremlin 1, DAN family BMP antagonist gene (GREM1) originally described in Ashkenazi Jews. Few families with GREM1 duplications have been described, so there are many questions about detection and management. We report 4 extended families with the duplication near GREM1 previously found in Ashkenazi Jews; 3 families were identified at cancer genetic clinics in Israel and 1 family was identified in a cohort of patients with familial colorectal cancer. Their clinical features include extracolonic tumors, onset of polyps in adolescence, and rapid progression of some polyps to advanced adenomas. One family met diagnostic criteria for Lynch syndrome. Expansion of the hereditary mixed polyposis syndrome phenotype can inform surveillance strategies for carriers of GREM1 duplications.

Two BRCA1/2 founder mutations in Jews of Sephardic origin.

Founder mutations in BRCA1/2 genes have been detected in several Jewish communities in Israel, including in Ashkenazi Jews and Jews who immigrated to Israel from Iraq, Yemen, Iran and Afghanistan. We analyzed DNA samples of patients of Sephardic origin (descendents of Jews from the Iberian Peninsula) with breast cancer (BC) and/or ovarian cancer (OC) and additional family history of these cancers. In this study we identified 2 mutations: p.A1708E in BRCA1 and c.67 + 1G > A (IVS2 + 1G > A) in BRCA2, each in 3 unrelated patients. The frequency of the two mutations was 26-31% among Sephardic high risk families and about 3% among the full cohort of 177 patients of this origin who were tested in our center. Based on haplotype analysis we concluded that these mutations are most probably founder mutations in Sephardic Jews. We recommend testing the two mutations in women of Sephardic origin who apply for BRCA testing because of personal and/or family history of BC and/or OC. Furthermore, we suggest adding them to the 5 mutations included in "The Jewish panel" of BRCA1/2 mutations that are being tested in Israel.

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC.

Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome.

Increased risk for atherosclerosis of various macrophage scavenger receptor 1 alleles.

AIMS: Macrophage scavenger receptor 1 (MSR1) mediates the uptake of modified low density lipoprotein (LDL)-cholesterol. The significance of MSR1 in atherosclerosis development in animal models is uncertain. In this study we sought to determine the significance of MSR1 polymorphisms in its encoding gene in susceptibility to atherosclerosis. METHODS: We genotyped three polymorphic sites in the MSR1 gene including a 3-bp "TTA" insertion-deletion in intron 7 (rs3036811, Indel 7), an intron 5 SNP (rs33959637, IVS5-59), and a missense coding single nucleotide polymorphism (SNP) in exon 6 (rs3747531, P275A) in 136 nondiabetic Ashkenazi men under age 55 years (mean = 47.3 +/- 4.8 years) undergoing coronary angiography. Assessment of coronary disease was done by the number of segments with stenosis greater than 20% (coronary artery narrowing greater than 20% [CAGE > 20%]), greater than 50% (CAGE > 50%), and total number of diseased vessels. Linear regression modeling was used to define associations between atherosclerotic burden and MSR1 SNPs and haplotypes. RESULTS: Significant associations were noted between IVS5-59 and number of diseased vessels (p = 0.009) and CAGE > 20% (p = 0.017), which remained significant upon controlling for age, cholesterol level, hypertension, and smoking. CONCLUSION: This study demonstrates an association between MSR1 polymorphisms and atherosclerosis, suggesting that atherosclerotic risk associated with classic risk factors may be modified by MSR1 polymorphisms. These findings point to a significant role of MSR1 in atherosclerosis.

Apolipoprotein E genotyping: accurate, simple, high throughput method using ABI Prism SNaPshot Multiplex System.

Apolipoprotein E (apo E) is an essential constituent of several plasma lipoproteins, and plays an important role in lipoprotein metabolism. The apo E gene exhibits two common functional polymorphisms, producing 3 isoforms known to be associated with the risks of developing cardiovascular disease and susceptibility to Alzheimer's disease. Numerous different methods have been established for determining the three apo E isoforms, yet there are disadvantages and ambiguities associated with all of them. We used a method adapted for multiplex automated primer extension analysis by improving a commercially available protocol (SNaPshot) and simultaneously typing apo E single nucleotide polymorphisms (SNPs) encoding for isoforms at codon 112 and 158. This protocol relies on the extension with fluorescent dideoxyNTPs of a primer that ends one nucleotide 5' of a given SNP (minisequencing). Improvement of the method is achieved by incorporating into the minisequencing reaction two pooled primers corresponding to both apo E SNPs followed by analysis on an ABI PRISM 310 DNA sequencer. We found full concordance with genotypes determined using universal heteroduplex. This method is readily available for many laboratories and is a simple, unequivocal easy to use technique suitable for large amount of clinical samples that may provide a significant improvement over previously reported methods for apo E genotyping.

One year experience with a low density lipoprotein apheresis system.

BACKGROUND: Low density lipoprotein apheresis is used as a complementary method for treating hypercholesterolemic patients who cannot reach target LDL-cholesterol levels on conventional dietary and drug treatment. The DALI system (direct absorption of lipoproteins) is the only extracorporeal LDL-removing system compatible with whole blood. OBJECTIVE: To describe our one year experience using the DALI system. METHODS: LDL apheresis was used in 13 patients due to inability to reach target LDL-C levels on conventional treatment. They included seven patients with familial hypercholesterolemia, three who had adverse reactions to statins, and three patients with ischemic heart disease who did not reach LDL-C target level on medical treatment. RESULTS: The average triglyceride, total cholesterol, high density lipoprotein-C and LDL-C levels before and after treatment in all patients were: 170 +/- 113 vs. 124 +/- 91, 269 +/- 74 vs. 132 +/- 48, 42 +/- 8 vs. 37 +/- 7.9, and 196 +/- 77 vs. 80 +/- 52 mg/dl, respectively. Comparing the results of a subgroup of seven patients who had previously been treated with plasma exchange, it is noteworthy that while the reduction in triglyceride, total cholesterol and LDL-C are comparable, the effect on HDL-C concentration was less apparent: from an average of 39.7 +/- 8.7 and 23 +/- 5.7 mg/dl before and after plasma exchange to an average of 43.9 +/- 8.1 and 38.4 +/- 7 mg/dl before and after LDL apheresis, respectively. Five patients developed treatment-related adverse events: three experienced allergic reactions manifested as shortness of breath, urticaria and facial flushing; one patient developed rhabdomyolysis, an adverse reaction that was not reported previously as a result of LDL apheresis; and one patient had myopathy with back pain. All untoward effects occurred during the first few treatment sessions. CONCLUSIONS: LDL apheresis using the DALI system is highly efficacious for the treatment of hypercholesterolemia. It is associated with a significant number of side effects occurring during the first treatment sessions. In patients not experiencing adverse effects in the early treatment period, it is well tolerated and can provide remarkable clinical benefit even after short-term therapy.