Familial colorectal cancer: eleven years of data from a registry program in Switzerland

Deleterious germ-line variants involving the DNA mismatch repair (MMR) genes have been identified as the cause of the hereditary nonpolyposis colorectal cancer syndrome known as the Lynch syndrome, but in numerous familial clusters of colon cancer, the cause remains obscure. We analyzed data for 235 German-speaking Swiss families with nonpolyposis forms of colorectal cancer (one of the largest and most ethnically homogeneous cohorts of its kind) to identify the phenotypic features of forms that cannot be explained by MMR deficiency. Based on the results of microsatellite instability analysis and immunostaining of proband tumor samples, the kindreds were classified as MMR-proficient (n=134, 57%) or MMR-deficient (n=101, 43%). In 81 of the latter kindreds, deleterious germ-line MMR-gene variants have already been found (62 different variants, including 13 that have not been previously reported), confirming the diagnosis of Lynch syndrome. Compared with MMR-deficient kindreds, the 134 who were MMR proficient were less likely to meet the Amsterdam Criteria II regarding autosomal dominant transmission. They also had primary cancers with later onset and colon-segment distribution patterns resembling those of sporadic colorectal cancers, and they had lower frequencies of metachronous colorectal cancers and extracolonic cancers in general. Although the predisposition to colorectal cancer in these kindreds is probably etiologically heterogeneous, we were unable to identify distinct phenotypic subgroups solely on the basis of the clinical data collected in this study. Further insight, however, is expected to emerge from the molecular characterization of their tumor

Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal, dominantly inherited, colorectal cancer (CRC) predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1 and MSH2. Thus far, only limited data exist on the occurrence of genetic anticipation in HNPCC, i.e. the earlier age at diagnosis of CRC in successive generations. Performing nonparametric distribution-free statistical analyses, we investigated 55 parent-child pairs who had been diagnosed with CRC and who came from 21 Swiss HNPCC families with characterised MMR germline mutation (15 in MLH1 and 6 in MSH2). The overall median age at diagnosis was 43years, with an interquartile range (IQR) of 14 and incidence ages ranging from 18 to 62years. Descendants of HNPCC patients (median age at diagnosis 39years, IQR=12) were found to be diagnosed with CRC significantly earlier than their parents (47years, IQR=10), with the median of the paired age difference amounting to 8years (IQR=15; P<0.0001). Birth cohort effects could be excluded, since the same, statistically significant, age difference was also observed in the oldest offspring birth cohort (birth year <1916; P=0.01). Genetic anticipation appeared to be more pronounced when the disease allele was transmitted through the father than through the mother (median age difference 11 vs. 4years, respectively; both P<0.01). If confirmed in larger, ideally prospective studies, these results may have important implications for genetic counselling and clinical management of HNPCC familie

Evidence for breast cancer as an integral part of Lynch syndrome

Lynch syndrome, an autosomal dominant cancer predisposition caused by mutations in DNA mismatch repair (MMR) genes, mainly mainly mutL homolog 1, OMIM 120436 (MLH1) and mutS homolog 2, OMIM 609309 (MSH2), encompasses a tumor spectrum including primarily gastrointestinal, endometrial, and ovarian cancer. This study aimed at clarifying the heavily debated issue of breast cancer being part of Lynch syndrome. Detailed clinical data on cancer occurrence in Swiss female MLH1/MSH2 mutation carriers were gathered, all available breast cancer specimens assessed for molecular evidence for MMR deficiency (i.e., microsatellite instability (MSI), MMR protein expression, and somatic (epi)genetic MMR gene alterations) and compiled with the scarce molecular data available from the literature. Seventy unrelated Swiss Lynch syndrome families were investigated comprising 632 female family members at risk of which 92 were genetically verified mutation carriers (52 MLH1 and 40 MSH2). On contrast to endometrial and ovarian cancer, which occurred significantly more often and at younger age in MLH1/MSH2 mutation carriers (median 50.5 and 49.0 years; P < 0.00001), overall cumulative breast cancer incidence closely mirrored the one in the Swiss population (56.5 years). Six (85.7%) of seven breast cancer specimens available for molecular investigations displayed the hallmarks of MMR deficiency. Combined with data from the literature, MSI was present in 26 (70.3%) of 37 and altered MMR protein expression in 16 (72.7%) of 22 breast cancer specimens from MLH1/MSH2 mutation carriers. These findings, thus, provide strong molecular evidence for a pivotal role of MMR deficiency in breast cancer development in Lynch syndrome

Report of an international survey of molecular genetic testing laboratories

Objective: To collect data on the practices of molecular genetic testing (MGT) laboratories for the development of national and international policies for quality assurance (QA). Methods: A web-based survey of MGT laboratory directors (n = 827; response rate 63%) in 18 countries on 3 continents. QA and reporting indices were developed and calculated for each responding laboratory. Results: Laboratory setting varied among and within countries, as did qualifications of the directors. Respondents in every country indicated that their laboratory receives specimens from outside their national borders (64%, n = 529). Pair-wise comparisons of the QA index revealed a significant association with the director having formal training in molecular genetics (p < 0.005), affiliation with a genetics unit (p = 0.003), accreditation of the laboratory (p < 0.005) and participation in proficiency testing (p < 0.005). Research labs had a lower mean report score compared to all other settings (p < 0.05) as did laboratories accessioning <150 samples per year. Conclusion: MGT is provided under widely varying conditions and regulatory frameworks. The data provided here may be a useful guide for policy action at both governmental and professional levels

Imaging patterns of Pneumocystis jirovecii pneumonia in HIV-positive and renal transplant patients - a multicentre study.

To investigate differences in chest computed tomography (CT) and chest radiographs (CXRs) of Pneumocystis jirovecii pneumonia (PJP) between renal transplant recipients (RTRs) and human immunodeficiency virus (HIV)-positive patients. From 2005 to 2012, 84 patients with PJP (RTR n = 24; HIV n = 60) were included in this retrospective multicentre study. Written informed consent was obtained. CT scans and CXRs were recorded within 2 weeks after the onset of symptoms. PJP diagnosis was confirmed either by cytology/histology or successful empirical treatment. Two blinded radiologists analysed the conventional chest films and CT images, and recorded the radiological lung parenchyma patterns, lymph node enlargement and pleural pathologies (pneumothorax, effusion). The radiological features of the two subgroups were compared. Consolidations and solid nodules prevailed on CT in RTRs (91.7 &amp;plusmn; 5.6% vs 58.3 &amp;plusmn; 6.4% with HIV, p = 0.019 and 91.7 &amp;plusmn; 5.6% vs 51.6 &amp;plusmn; 6.5% with HIV, p = 0.005). HIV-positive patients with PJP showed more atelectasis (41.7 &amp;plusmn; 6.4% vs 4.2 &amp;plusmn; 4.1% in RTRs, p = 0.017) and hilar lymph node enlargement (23.3 &amp;plusmn; 5.5% vs 0.0 &amp;plusmn; 0.0% in RTRs, p = 0.088). Ground glass opacification was found in all cases. Pneumothorax was a rare complication, occurring in 3% of the HIV-positive patients; no pneumothorax was found in the RTRs. On CXR, the basal lungs were more affected in HIV-positive patients as compared with RTRs (p = 0.024). PJP on CT differs substantially between RTRs and HIV-positive patients. Physicians should be aware of such differences in order not to delay treatment, particularly in renal transplant recipients

Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study.

BACKGROUND &amp; AIMS: Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy. METHODS: The analysis included 1362 individuals: 1015 with chronic hepatitis C and 347 who spontaneously cleared the virus (448 were coinfected with human immunodeficiency virus [HIV]). Responses to pegylated interferon alfa and ribavirin were assessed in 465 individuals. Associations between more than 500,000 single nucleotide polymorphisms (SNPs) and outcomes were assessed by multivariate logistic regression. RESULTS: Chronic hepatitis C was associated with SNPs in the IL28B locus, which encodes the antiviral cytokine interferon lambda. The rs8099917 minor allele was associated with progression to chronic HCV infection (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.74-3.06; P = 6.07 x 10(-9)). The association was observed in HCV mono-infected (OR, 2.49; 95% CI, 1.64-3.79; P = 1.96 x 10(-5)) and HCV/HIV coinfected individuals (OR, 2.16; 95% CI, 1.47-3.18; P = 8.24 x 10(-5)). rs8099917 was also associated with failure to respond to therapy (OR, 5.19; 95% CI, 2.90-9.30; P = 3.11 x 10(-8)), with the strongest effects in patients with HCV genotype 1 or 4. This risk allele was identified in 24% of individuals with spontaneous HCV clearance, 32% of chronically infected patients who responded to therapy, and 58% who did not respond (P = 3.2 x 10(-10)). Resequencing of IL28B identified distinct haplotypes that were associated with the clinical phenotype. CONCLUSIONS: The association of the IL28B locus with natural and treatment-associated control of HCV indicates the importance of innate immunity and interferon lambda in the pathogenesis of HCV infection

Determinants of HIV-1 reservoir size and long-term dynamics during suppressive ART

The HIV-1 reservoir is the major hurdle to a cure. We here evaluate viral and host characteristics associated with reservoir size and long-term dynamics in 1,057 individuals on suppressive antiretroviral therapy for a median of 5.4 years. At the population level, the reservoir decreases with diminishing differences over time, but increases in 26.6% of individuals. Viral blips and low-level viremia are significantly associated with slower reservoir decay. Initiation of ART within the first year of infection, pretreatment viral load, and ethnicity affect reservoir size, but less so long-term dynamics. Viral blips and low-level viremia are thus relevant for reservoir and cure studies