A mutation in POLE predisposing to a multi-tumour phenotype

Somatic mutations in the POLE gene encoding the catalytic subunit of DNA polymerase epsilon have been found in sporadic colorectal cancers (CRCs) and are most likely of importance in tumour development and/or progression. Recently, families with dominantly inherited colorectal adenomas and colorectal cancer were shown to have a causative heterozygous germline mutation in the proofreading exonuclease domain of POLE. The highly penetrant mutation was associated with predisposition to CRC only and no extra-colonic tumours were observed. We have identified a mutation in a large family in which the carriers not only developed CRC, they also demonstrate a highly penetrant predisposition to extra-intestinal tumours such as ovarian, endometrial and brain tumours. The mutation, NM_006231.2:c.1089C>A, p.Asn363Lys, also located in the proofreading exonuclease domain is directly involved in DNA binding. Theoretical prediction of the amino acid substitution suggests a profound effect of the substrate binding capability and a more severe impairment of the catalytic activity compared to the previously reported germline mutation. A possible genotype to phenotype correlation for deleterious mutations in POLE might exist that needs to be considered in the follow-up of mutation carriers

The value of genome-wide analysis in craniosynostosis

Background: This study assessed the diagnostic yield of high-throughput sequencing methods in a cohort of craniosynostosis (CS) patients not presenting causal variants identified through previous targeted analysis.Methods: Whole-genome or whole-exome sequencing (WGS/WES) was performed in a cohort of 59 patients (from 57 families) assessed by retrospective phenotyping as having syndromic or nonsyndromic CS.Results: A syndromic form was identified in 51% of the unrelated cases. A genetic cause was identified in 38% of syndromic cases, with novel variants detected in FGFR2 (a rare Alu insertion), TWIST1, TCF12, KIAA0586, HDAC9, FOXP1, and NSD2. Additionally, we report two patients with rare recurrent variants in KAT6A and YY1 as well as two patients with structural genomic aberrations: one with a 22q13 duplication and one with a complex rearrangement involving chromosome 2 (2p25 duplication including SOX11 and deletion of 2q22). Moreover, we identified potentially relevant variants in 87% of the remaining families with no previously detected causal variants, including novel variants in ADAMTSL4, ASH1L, ATRX, C2CD3, CHD5, ERF, H4C5, IFT122, IFT140, KDM6B, KMT2D, LTBP1, MAP3K7, NOTCH2, NSD1, SOS1, SPRY1, POLR2A, PRRX1, RECQL4, TAB2, TAOK1, TET3, TGFBR1, TCF20, and ZBTB20.Conclusion: These results confirm WGS/WES as a powerful diagnostic tool capable of either targeted in silico or broad genomic analysis depending on phenotypic presentation (e.g., classical or unusual forms of syndromic CS)

Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing

Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1

Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition

Purpose: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes. Methods: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of similar to 1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility. Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability. Conclusion: Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.Peer reviewe

Hereditary Colorectal Cancer; Identification, Characterization and Classification of Mutations

Hereditary factors are thought to play are role in 20-30% of all colorectal cancers Around 6% are found as high penetrant disease-causing mutations in genes correlated to hereditary polyposis or hereditary non-polyposis syndromes. The aim of this thesis was to identify new causative genes and variants and also mutation mechanisms in families presenting a polyposis, atypical polyposis or nonpolyposis CRC phenotype. In classical familial adenomatous polyposis (FAP) 100% of the disease-causing mutations were found in patients from the Swedish Polyposis Registry. The mutation underlying the lowered expression of the APC gene in one family was identified by SNP array analysis, the mutation was a split deletion of 61Kb including half of the promoter 1B. Investigation of the significance of this promoter for expression of the APC gene demonstrated considerably higher expression compared with the established promoter 1A. In order to establish a sensitive method for mosaic-mutation detection a comparison of mutation detection methods was performed. Low frequency mosaic mutations were detected down to 1 % by use of massively parallel sequencing (MPS). Whole exome sequencing in four families with attenuated FAP (AFAP), atypical polyposis or non-polyposis syndromes identified two high penetrant disease-causing mutations. One was found in the upstream regulatory region of GREM1and one in the exonuclease domain of POLE. Variants in low-penetrant genes possibly contributing to CRC development were also proposed from the exome sequencing and gene specific analyses of 107 patients. Sixty-seven of these patients were analyzed in a panel of 19 selected CRC predisposing genes. Truncating mutations were found in the BMPR1A and SMAD4 genes in patients with a classical FAP, atypical FAP or non-polyposis phenotype. Classification of found non-synonymous variants was also performed. In summary, using a combination of different molecular screening techniques, 100% of diseasecausing mutations in classical FAP can be found. With MPS it is possible to detect low-frequency mosaic mutations down to 1% by absolute quantification. Whole exome analyses identified mutations in the new causative genes POLE and GREM1. It was also concluded that patients without identified mutations, based on phenotypical CRC classification, can have mutations in genes not included in the primary routine analysis. These results will lead to improved mutation detection analysis for diagnostic and carrier testing

And woman : A critical analysis of media's discursive representation of female politicians.

The aim of this paper is to describe, visualise- and analyse media\u92s discursive representations of female politicians in Swedish printed media. The focus of the analysis is to show if, and how these images can be understood and interpreted in terms of a socially constructed gender stereotyped suborder. The paper takes it's theoretical and methodological departure in the discourse analysis, which is combined with feminist political theory. Feminist political theory is concretised in the use of what Yvonne Hirdman calls the "gender system" which arranges the sexes into their respective genders and is based upon two rules/principles/logics: 1) the rule of distinctive separation, and 2) the male norm. Closely related to the aim of the paper lies also the critical theoretic assumption that people has to be aware of their own part in the production and reproduction of the discourse in order to change make a change. Language is perceived as intimately tied to power in that language defines and gives the reality meaning. Media is therefore, by it's presence in all Swedish homes perceived as channel for the exercise of power through it's discourse. Drawing on 20 articles from different newspapers and magazines, the results of this paper shows, through the use of discourse analysis, that female politicians are portrayed as politicians and women. The analysis concludes that media's image of the female politician rests on gender stereotypes which as a consequent reduces the female politician to her biological gender and therefore gives her, in comparison with her male counterpart a lower hierarchic position

A novel classification system for assessment of approximal caries lesion progression in bitewing radiographs

OBJECTIVES: To design and pilot a novel classification system for the assessment of caries lesion progression in bitewing radiography and to report rater agreement of the system. METHODS: A classification system with drawings and text was designed to assess caries lesion progression. Guidelines for Reporting Reliability and Agreement Studies were used to study and report rater agreement. Pairs of posterior bitewing radiographs (baseline and 1-year follow-up) with different status concerning caries lesion progression were selected from files from public dental health clinics. 10 raters, 5 general dental practitioners and 5 specialists in oral and maxillofacial radiology were asked to assess the radiographs with the aid of the classification system. Seven raters repeated their assessments. Rater agreement was expressed as percentage of agreement and kappa. RESULTS: Kappa for the interrater agreement of 10 raters assessing progression was 0.61, indicating substantial agreement. Agreement was moderate for progression in the outer half of the dentine (kappa 0.55) and within enamel (kappa 0.44). Pairwise interrater agreement varied (range 69-92%; kappa 0.42-0.84). For about half of the pairs of raters, kappa was substantial (≥0.61). Intrarater agreement assessing progression was substantial (kappa 0.66-0.82). CONCLUSIONS: We demonstrated the applicability of the proposed classification system on caries lesion progression with respect to rater agreement. This system can provide a common framework for clinical decision-making on caries interventional methods and patient visiting intervals. Scientifically, this system allows for a comparative analysis of different methods of prevention and treatment of caries as well as of different caries risk assessment methods