Approximate Profile Maximum Likelihood

We propose an efficient algorithm for approximate computation of the profile maximum likelihood (PML), a variant of maximum likelihood maximizing the probability of observing a sufficient statistic rather than the empirical sample. The PML has appealing theoretical properties, but is difficult to compute exactly. Inspired by observations gleaned from exactly solvable cases, we look for an approximate PML solution, which, intuitively, clumps comparably frequent symbols into one symbol. This amounts to lower-bounding a certain matrix permanent by summing over a subgroup of the symmetric group rather than the whole group during the computation. We extensively experiment with the approximate solution, and find the empirical performance of our approach is competitive and sometimes significantly better than state-of-the-art performance for various estimation problems

Frequency and Variability of Genomic Rearrangements on <i>MSH2</i> in Spanish Lynch Syndrome Families

<div><p>Large genomic rearrangements (LGRs) in DNA-mismatch-repair (MMR) genes, particularly among <i>MSH2</i> gene, are frequently involved in the etiology of Lynch syndrome (LS). The Multiplex Ligation and Probe Amplification assay (MLPA) is commonly used to identify such alterations. However, in most cases, the MLPA-identified alteration is not characterized at the molecular level, which might be important to identify recurrent alterations and to analyze the molecular mechanisms underlying these mutational events. Probands from a cohort of Lynch Syndrome families were screened for point mutation in MMR genes, subsequently the MLPA assay was used for LGR screening. The identified MLPA alteration was confirmed by cDNA, CGH-microarrays or massive parallel sequencing. In this study, we have delimited the region of 11 LGRs variants on <i>MSH2</i> locus. Six of them were fully characterized the breakpoints and 9 of them were considered pathogenic. According to our data, LGR on <i>MSH2</i> locus constituted the 10.8% (9 out of 83) of pathogenic germline alterations found in LS. The frequency of colorectal cancer (CRC) and endometrial cancer (EC) in LGR carriers was 55% and 11% respectively. Analysis of the breakpoint sequences revealed that in 3 cases, deletions appeared to originate from Alu-mediated recombination events. In the remaining cases, sequence alignment failed to detect microhomology around the breakpoints. The present study provides knowledge on the molecular characterization of <i>MSH2</i> LGRs, which may have important implications in LS diagnosis and Genetic Counseling. In addition, our data suggests that nonhomologous events would be more frequently involved in the etiology of <i>MSH2</i> LGRs than expected.</p></div

Genotype-phenotype correlation in MSH2 mutation carriers.

<p>Genotype-phenotype correlation in MSH2 mutation carriers.</p

Gene amplification of exons 8–10.

<p><b>A</b>) array CGH rearrangement characterization. <b>B</b>) Amplification of the junction fragment using the outward facing primers in duplicated head-to-tail interval and electrophoresis gel showing PCR product in a mutation carrier. <b>C</b>) Sequence electropherogram of the junction fragment.</p

Clinical and molecular characteristics of mutation carriers.

a<p>Nomenclature based on mRNA sequence with GenBank Accession Code NM_002354.2.</p>b<p>Nomenclature according to ISCN (2009).</p><p>Abbreviations:Family ID, family identification; Ped ID, pedigree Identification; AMS, Amsterdam criteria; CRC, colorectal cancer; EC, Endometrial cancer; UC, Urothilial cancer; A, Villous Adenoma; MLPA, Multiplex ligation-dependent probe amplification; MPS, Massive Parallel Sequencing.</p

Role of <i>GALNT12</i> in the genetic predisposition to attenuated adenomatous polyposis syndrome

<div><p>The involvement of <i>GALNT12</i> in colorectal carcinogenesis has been demonstrated but it is not clear to what extent it is implicated in familial CRC susceptibility. Partially inactivating variant, NM_024642.4:c.907G>A, p.(D303N), has been previously detected in familial CRC and proposed as the causative risk allele. Since phenotypes of the described carrier families showed not only CRC but also a polyp history, we hypothesized that <i>GALNT12</i> could be involved in adenoma predisposition and consequently, in hereditary polyposis CRC syndromes. For that purpose, we have screened the <i>GALNT12</i> gene in germline DNA from 183 unrelated attenuated polyposis patients. c.907G>A, p.(D303N) was detected in 4 cases (MAF = 1.1%) and no other candidate variants were found. After segregation studies, LOH analyses, glycosylation pattern tests and case-control studies, our results did not support the role of c.907G>A, p.(D303N) as a high-penetrance risk allele for polyposis CRC.</p></div

Additional file 2: of Differential distribution and enrichment of non-coding RNAs in exosomes from normal and Cancer-associated fibroblasts in colorectal cancer

Absolute and average relative counts of reads mapped to each ncRNAs biotype per sample and fraction. (XLSX 15 kb

Additional file 13 of Differential distribution and enrichment of non-coding RNAs in exosomes from normal and Cancer-associated fibroblasts in colorectal cancer

: Multiple alignment of the 42 sncRNAs over represented in CAF-EXO samples. (FASTA 8 kb

Additional file 3: of Differential distribution and enrichment of non-coding RNAs in exosomes from normal and Cancer-associated fibroblasts in colorectal cancer

Excel document with the two count files used as input to EdgeR for differential expression analysis; one with the counts of reads of all samples mapped on the lncRNA references and another with the read counts of reads mapped on scnRNAs. (XLSX 221 kb

Additional file 8: of Differential distribution and enrichment of non-coding RNAs in exosomes from normal and Cancer-associated fibroblasts in colorectal cancer

Mini web site presenting a dynamic venn diagram showing the relationships between the results cellular or exosomal over represented in the two analyses performed between NF- and CAF- exosomes. Clicking on any intersected number, the web site opens a dialog summarizing the ncRNAs species that correspond to the intersection. (HTML 47 kb