Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organspecific cancer risks according to gene and gender and to determine survival after cancer. Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 followup years. Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Preparation of Colloidal Sols: A magnetite colloid was prepared in alkaline solution according to the procedure published by Massart [11]. An aqueous solution containing 2.3 g (8.5 mmol) FeCl 3 ×6H 2 O in 4 mL H 2 O and 1.69 g (4.3 mmol) Fe(NH 4 ) 2 (SO 4 ) 2 in 1 mL of 2 M HCl, was added to 50 mL of 1 M (CH 3 ) 4 NOH×5H 2 O. The resulting black suspension was stirred for 1 h at room temperature and then sonicated in an ultrasonic bath for 1 h. The colloid was then centrifuged at 20 000 g for 1 h. The supernatant was decanted and the slurry resuspended in 20 mL water by sonication before being passed through a 0.2 mm pore cellulose nitrate membrane.A titanium dioxide sol was prepared by hydrolysis of titanium tetraisopropoxide under a nitrogen atmosphere following the procedure described by O'Regan et al. [12]. 25 mL of titanium tetraisopropoxide was mixed with 4 mL of isopropanol in a dropping-funnel under a nitrogen atmosphere. This mixture was added slowly over a period of 5 min to 150 mL of vigorously stirred double-distilled, deionized water in a 250 mL three-neck flask equipped with heater, thermometer and stirrer. Ten minutes after the final alkoxide addition, 1 mL of 69 % HNO 3 was added. The white hydrolysis mixture was then stirred for 8 h at 80 C to remove the isopropanol, filtered through a 0.2 mm pore cellulose nitrate membrane, and sonicated for 1 h to produce a stable colloidal solution with a bluish-white coloration.Preparation of the Composites and Method of Calcination: Typically, a sample of the sliced copolymer gel (ca. 5 mm thick) was added to the colloidal sol and left for the desired period of time. The colloid-loaded gels were removed, washed with water and allowed to dry in air. Thermogravimetric analysis (TGA) measurements were made using a NETZSCH STA 409EP machine. Samples were heated under air in an alumina crucible to a final temperature of 800 C at a rate of 5 K/min. Large samples of the mineralized gels were calcined by heating to a temperature of 450 or 500 C in a Carbolite furnace (type ELF11/6) at a heating rate of 1 C min ±1 .

We present measurements of the electrical conductivity of metallic nanowires which have been fabricated by chemical deposition of a thin continuous palladium film onto single DNA molecules to install electrical functionality. The DNA molecules have been positioned between macroscopic Au electrodes and are metallized afterwards. Low-resistance electrical interfacing was obtained by pinning the nanowires at the electrodes with electron-beam-induced carbon lines. The investigated nanowires exhibit ohmic transport behavior at room temperature. Their specific conductivity is only one order of magnitude below that of bulk palladium, confirming that DNA is an ideal template for the production of electric wires, which can be utilized for the bottom-up construction of miniaturized electrical circuits.

A B S T R A C T PurposePatients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. Patients and MethodsData were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex-and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. ResultsThe cohort comprised 2,118 MMR gene mutation carriers (MLH1, n ϭ 806; MSH2, n ϭ 1,004; MSH6, n ϭ 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers. ConclusionThe sex-and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.

Summary BACKGROUND Lynch syndrome is caused by germline mutations in mismatch repair genes (MSH2, MLH1, MSH6 or PMS2), which lead to a high risk of predominantly colorectal and endometrial cancer. Recently, we found that also constitutional 3′ end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM expressing tissues. This results in a tissue specific MSH2-deficiency, which may evoke a different cancer risk and spectrum. To optimize the care for EPCAM deletion carriers we studied their cancer risk and spectrum. METHODS Clinical data of 194 carriers from 41 EPCAM families were systematically collected and compared to those of 431 carriers from 91 families with mutations in MLH1, MSH2, or MSH6. FINDINGS EPCAM deletion carriers exhibited a 75% [95%CI 65–85%] cumulative risk of colorectal cancer before the age of 70 years, with a mean age at diagnosis of 43 years, which is comparable to that of carriers of a combined EPCAM-MSH2 deletion (69% [95%CI 47-91%], p=0·8609) or of a mutation in MSH2 (77% [95%CI 64-90%], p=0·5892) or MLH1 (79% [95%CI 68-90%], p=0·5492) and higher than that of MSH6 mutation carriers (50% [95%CI 38-62%], p<0·0001). In contrast, women with EPCAM deletions (n=87) exhibited a 12% [95%CI 0-27%] cumulative risk of endometrial cancer, which is significantly lower than in carriers of a combined EPCAM-MSH2 deletion (55% [95%CI 20-90%], p<0·0001) or of a mutation in MSH2 (51% [95%CI 33-69%], p=0·0006) or MSH6 (34% [95%CI 20-48%], p=0·0309) and lower than in MLH1 (33% [95%CI 15-51%] p=0·1193) mutation carriers. This risk seems to be restricted to large deletions that extend close to the MSH2 gene promoter. Overall, a relatively high incidence of duodenal (n=3) and pancreatic (n=4) cancers was observed. INTERPRETATION EPCAM deletion carriers do have a high risk of colorectal cancer. Only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the impact of mosaic MSH2-deficiency on cancer risk and are indicative for a protocol revision for surveillance and preventive surgery in EPCAM deletion carriers.

Later age of disease onset and lower incidence of colorectal cancer may contribute to a lower proportion of identified MSH6 mutations in families suspected of HNPCC. However, in approximately half of these families, at least one patient developed colorectal or endometrial cancer in the fourth decade of life. Therefore, a surveillance program as stringent as that for families with MLH1 or MSH2 mutations is recommended.

Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of malignancy-related death and is the eighth most common cancer with the lowest overall 5-year relative survival rate. To identify new molecular markers and candidates for new therapeutic regimens, we investigated the gene expression profile of microdissected cells from 11 normal pancreatic ducts, 14 samples of PDAC, and 4 well-characterized pancreatic cancer cell lines using the Affymetrix U133 GeneChip set. RNA was extracted from microdissected samples and cell lines, amplified, and labeled using a repetitive in vitro transcription protocol. Differentially expressed genes were identified using the significance analysis of microarrays program. We found 616 differentially expressed genes. Within these, 140 were also identified in PDAC by others, such as Galectin-1, Galectin-3, and MT-SP2. We validated the differential expression of several genes (e.g., CENPF, MCM2, MCM7, RAMP, IRAK1, and PTTG1) in PDAC by immunohistochemistry and reverse transcription polymerase chain reaction. We present a whole genome expression study of microdissected tissues from PDAC, from microdissected normal ductal pancreatic cells and pancreatic cancer cell lines using high-density microarrays. Within the panel of genes, we identified novel differentially expressed genes, which have not been associated with the pathogenesis of PDAC before.