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Yves Krumenacker dir. Histoire , ISBN EUR 22, Eva Labouvie Hg. Alain J. Actes du colloque de Mulhouse, 16 et 17 novembre , Rennes Presses universitaires de Rennes , p.

Ursula Machoczek Bearb. Deutsche Reichsakten. La Renaissance? Des Renaissances? Geoffrey Parker, Felipe II. Bruno Petey-Girard, Le sceptre et la plume.

Biblioteca della Rivista di storia e letteratura religiosa. Rengenier C. Rittersma, Egmont da capo.

Eine mythogenetische Studie, Münster Waxmann , S. Ulinka Rublack, Dressing Up. Daniel Schläppi Hg.

Wolfgang Schmale Hg. Dieter Winkler , S. Das achtzehnte Jahrhundert und Österreich. Jonathan Spangler, The Society of Princes. Barry Stephenson, Performing the Reformation.

Winfried Baumgart, Wörterbuch historischer und politischer Begriffe des Des voies de structuration durable? Peter Lang , p.

Michael Gehler, Silvio Vietta Hg. Alfred Gottwaldt, Die Reichsbahn und die Juden — Antisemitismus bei der Eisenbahn in der Vorkriegszeit, Wiesbaden marixverlag , S.

Victoria Harris, Selling Sex in the Reich. Hans-Walter Herrmann, Püttlingen in bewegter Zeit. Annette Jantzen, Priester im Krieg.

Jürgen Osterhammel, Die Verwandlung der Welt. Eine Geschichte des Jahrhunderts, München C. Rezensiert von Joachim C.

Tilmann Robbe, Historische Forschung und Geschichtsvermittlung. Ingrid Sharp, Matthew Stibbe ed. History of Warfare, Andrew David Stedman, Alternatives to Appeasement.

Jonathan Steinberg, Bismarck. Rita Stöckli, Der Savoyerhandel von Industrielle Beziehungen, Arbeitskämpfe und der Sozialstaat.

Bernd Zielinski, Brigitte Krulic dir. Peter Lang , VI— p. Redaktion: hsk. ISSN: DE EN. Francia-Recensio , 4. Deutsches Historisches Institut Paris.

Paris perspectivia. Herausgeber d. Deutsches Historisches Institut Paris Prof. This work may be copied and redistributed for non-commercial, educational purposes, if permission is granted by the author and usage right holders.

For permission please contact hsk. Ohne epochalen Schwerpunkt. Ohne thematischen Schwerpunkt. Zeitschriften mit kostenfreiem Volltextangebot.

ZDB WorldCat. J Natl Cancer Inst — Int J Cancer — Cell — Human Mutation 35 1 ; Teniendo en cuenta estos indicios nosotros quisimos estudiar el gen en familias de alto riesgo agrupadas como CCRf-X.

Se identificaron un total de 20 variantes en 90 pacientes, ocho de ellas localizadas en las regiones codificantes. Chanock Received 3 July ; accepted revised manuscript 23 September Published online 1 October in Wiley Online Library www.

DOI: We sequenced the coding regions of the gene in probands of fCRC-X families, finding no functionally relevant mutations.

C Wiley Periodicals, Inc. Hum Mutat —3, These individuals are at increased risk of developing CRC and therefore require strict cancer surveillance strategy.

Several dominantly actAdditional Supporting Information may be found in the online version of this article. This gene, whose protein product is involved in the O-glycosylation of mucin-type glycans, shows high expression levels in the normal colon and is downregulated in a significant proportion of colorectal tumors [Guo et al.

In , Guda et al. Of note, no mutations were present in cancer-free controls. Recently, Clarke et al. They identified two missense mutations present in four different Bethesda-positive families.

However, no mutations were detected in 26 probands that met the Amsterdam I criteria. Of all families, The mean age at cancer diagnosis was Table S1 shows the characteristics of the families included in the study.

All exons and exon—intron boundaries were sequenced using a standard protocol for automated direct Sanger sequencing.

Primer sequences and PCR conditions are available upon request. Table 1. G46R p. EV p. Most intronic changes are not covered. G46R c.

EV c. DN rs rs Intron 2 Exon 4 — Neutral 0. SS, splice site; bp, base pairs; WT, wild-type; A, acceptor consensus splice site; D, donor consensus splice site; D2, new donor splice site; NR, splice site not recognized.

A total of 20 variants were identified in 90 patients. Of the 20 variants, eight were located in protein-coding regions, seven in introns, and five in the 3 -UTR.

Three of the eight changes in protein-coding regions, c. G46R , c. EV , and c. DN , were nonsynonymous. The change p. DN in 2, and p.

G46R in 1 patient. The three variants had been previously described in public databases with population minor allele frequencies of 0.

Also, previous studies identified these three variants both in cancer cases and controls [Clarke et al.

No relevant effects on the protein were predicted by the in silico algorithms SIFT and Condel, while PolyPhen-2 predicted functional effects for p.

EV score 0. Nevertheless, Guda et al. The remaining five variants in protein-coding regions predicted to translate into synonymous amino-acid changes, affecting codons 79, , , , and All but two, c.

The population allelic frequencies reported for other two, c. The in silico algorithm NNSplice [Reese et al. However, the generation of this new donor splice site was not predicted by other algorithms, such as NetGene2 [Hebsgaard et al.

Moreover, this variant did not segregate with the disease in the family: the father of the proband, diagnosed with rectal cancer at age 64, did not carry the variant, being therefore absent in the CRC-affected family branch.

Of the intronic variants identified, only one, c. Likewise, the change c. Despite their proximity to the corresponding consensus splice sites, no relevant effect on the splicing process was predicted Table 2.

Regarding c. Unfortunately, no cosegregation analysis could be performed for c. In summary, no functionally relevant variants were identified in any of the fCRC-X families evaluated.

DN and c. YC in 4 families that met the revised Bethesda criteria [Clarke et al. The c. Moreover, the evidence of cosegregation of c.

The second missense variant identified, c. YC , is not reported in public databases, is located in the catalytic domain of the protein, and in silico algorithms predict it to be functionally relevant [Clarke et al.

All reported patients carrying inactivating germline mutations developed CRC later in life median age: 71 , and half of them were diagnosed with multiple primary epithelial tumors, including breast and colon cancers [Guda et al.

Further studies are required to provide a definitive answer about the role of GALNT12 mutations in this subset of familial cancer cases.

Either germline mutations in GALNT12, as a moderate-risk gene, or in other genes located within the 9q linkage peak might still explain some familial CRC cases.

Acknowledgment Disclosure statement: The authors declare no conflict of interest. SpliceDB: database of canonical and noncanonical mammalian splice sites.

Nucleic Acids Res 29 1 — Hum Mutat 33 7 — Confirmation of linkage to and localization of familial colon cancer risk haplotype on chromosome 9q Cancer Res 70 13 — Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers.

Expression of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase in gastric and colonic cancer cell lines and in human colorectal cancer.

Oncology 67 3—4 : — FEBS Lett 1—3 — Splice site prediction in Arabidopsis thaliana pre-mRNA by combining local and global sequence information.

Nucleic Acids Res 24 17 — Evidence of linkage to chromosome 9q Cancer Res 66 10 — Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X.

Mod Pathol 25 8 — Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications.

Clin Genet 76 1 :1— Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q. BMC Cancer Improved splice site detection in Genie.

J Comput Biol 4 3 — Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q J Med Genet 43 2 :e7.

Inherited susceptibility to colorectal adenomas and carcinomas: evidence for a new predisposition gene on 15qq Gastroenterology 4 — A subset of familial colorectal neoplasia kindreds linked to chromosome 9q Puente, Guido Plotz, Laura Valle.

Gut Publicado online: 1 Abril However, the study was performed on clinic-based series ascertained based on the inheritance model or the presence of polyps, which may miss additional phenotypes relevant to improve the disease characterisation and therefore, its genetic diagnosis.

To illustrate this, we report a family with a clinical phenotype that resembled Lynch syndrome but was caused by MUTYH mutations.

By exome sequencing performed on four cancer-affected II. The functional studies performed for c. KRAS c. G12D table 1. The features of this family suggest that the selection criteria proposed for MUTYH testing,6 might fail to detect a number of mutated families due to infrequent phenotypes.

First, MUTYH heterozygous mutations may, probably in the presence of other cancer risk factors, provide an increased risk of developing cancer in heterozygous carriers,5 7 and thereby disguise the MUTYH recessive inheritance to look like autosomal-dominant.

One should be suspicious when an extreme anticipation in the age of cancer onset is observed between two affected generations.

Second, absence or scarcity of polyps, even at relatively advanced ages early 50 s and with a prior CRC diagnosis, can occur in biallelic mutation carriers.

When this occurs in several cancer-affected Figure 1 Family pedigree. Filled symbol, CRC; numbers within the symbols, number of children; arrow, index case.

Downloaded from gut. G12C c. G12D c. G12C n. In the studied family, no polyps had been detected at CRC diagnosis and at genetic counselling in any of the three MUTYH compound heterozygotes, however, several years later a total of 34 and 7 polyps 21 and 3 adenomas, respectively were reported in two of them.

Targeted next generation sequencing using comprehensive panels of genes applied to routine genetic testing of familial cancers will overcome the problem of overlapping phenotypes and complex patterns of inheritance.

LV and GP wrote the manuscript. Provenance and peer review Not commissioned; internally peer reviewed. Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence.

Gut ;— Gut ; —8. Nat Genet ;— MUTYH gene expression and alternative splicing in controls and polyposis patients. Hum Mutat ; — Crit Rev Oncol Hematol ;— MUTYHassociated polyposis.

Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet ;— Clin Cancer Res ;— Prevalence and characteristics of MUTYH-associated polyposis in patients with multiple adenomatous and serrated polyps.

The potential impact of this novel variant on the function of the protein was assessed using different prediction servers PolyPhen-2, SIFT and Condel; all of them predicting damaging functional effects for p.

To assess the functional effect of c. This analysis revealed large inter-individual variation in MUTYH expression, overall and isoform-specific.

When compared to controls and c. Figure 1. It has been previously observed that the expression of MUTYH nuclear transcripts is much lower in lymphocytes than in intestinal cells.

Figure 2A , probably triggered by growth signals present under culture conditions. Figure 2B. Nevertheless, this expression reduction does not represent the complete loss of mRNA expression of the c.

Transcript-specific reverse transcription RT -PCR and sequencing confirmed these results, showing subtle or no mRNA expression reduction of nuclear isoforms in the c.

Figure 3. Moreover, isoform-specific qPCRs performed in cultured lymphocytes treated with puromycin, which blocks the nonsense-mediated mRNA decay NMD mechanism, did not show any difference compared to untreated lymphocytes of c.

Regarding protein effects, the genetic change c. This protein, however, has no relevant functional elements since a highly conserved loop that binds the misincorporated adenine during the repair process is missing, and it is extremely unstable.

In brief, 3. Fragment size bp and quantity were checked with the Agilent Bioanalyzer chip. Fragmented DNA was end-repaired, adenylated and ligated to Agilent indexing-specific paired-end adaptors.

In silico functional prediction of genetic variants Protein damage prediction of missense genetic variants was performed by using the in silico algorithms PolyPhen-2,[5] SIFT,[6] and Condel.

PCRs were performed according to standard conditions. Direct automated sequencing For segregation analysis, exons 2 and 12 of MUTYH and their corresponding flanking regions were sequenced using a standard protocol for automated direct Sanger sequencing.

Hum Mutat ; Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics ; Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.

Nature ; A method and server for predicting damaging missense mutations. Nat Methods ; Ng PC, Henikoff S. Accounting for human polymorphisms predicted to affect protein function.

Genome Res ; Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am J Hum Genet ; J Comput Biol ; Rare or unreported genetic variants identified by exome sequencing shared by the studied cancer-affected family members.

ANXA6 c. ProLeu Exon 40 C22orf33 c. Figure 2. A Overall and relative mRNA expression of the , , and transcripts quantified with transcript-specific qPCR in cDNA obtained from cultured non-immortalized lymphocytes of three wildtype controls, one c.

B Expression of the nuclear transcripts and. The expression of and transcripts in the c. The comparisons were performed using t-test.

Bars indicate the standard errors of the means. Resumen: Parte de los factores heredables de susceptibilidad al CCR permanecen desconocidos.

The identification of new genes associated with hereditary cancer will facilitate the management of patients whose predisposition is yet unexplained.

These findings link colorectal cancer predisposition to the Fanconi Anemia DNA repair pathway, further strengthening the connection between maintenance of genome integrity and cancer risk.

However, much of the observed heritability and familial aggregation of the disease has not been explained.

Four additional unreported or rare genetic variants were identified in Amsterdam-positive families: a truncating mutation, c.

DY , c. PS and c. RW Fig. Unfortunately, no information about personal or family history of cancer is available.

Mutation carrier status could be assessed in 14 family members: all 11 cancer-affected 10 CRC and 1 breast cancer were carriers, two unaffected 21 and 43 year-old individuals were carriers and one unaffected 53 year-old was non-carrier Fig.

The identification of two truncating mutations in GEN1X prompted us to investigate whether the other three variants might also affect the protein function Table 1.

In silico algorithms predicted damaging effects for c. RW , being the R residue evolutionary conserved during evolution Supplementary Fig.

Three-dimensional 3D structure predictions of the region indicated that R is located in an exposed loop that connects two -helices, in the vicinity of a DNA-binding domain Supplementary Fig.

While in silico predictors are not conclusive for c. Therefore, most germline GEN1X mutations identified are predicted to have a functional effect.

Five colorectal tumors developed by GEN1X mutation carriers three c. This mutation burden corresponds to that of non-hypermutant CRCs6.

On the other hand, no clear evidence of somatic GEN1X second hits was obtained. Furthermore, neither loss of RNA expression of the wildtype allele nor reduction of expression of the GEN1X protein were observed in a tumor developed by a c.

Altogether, our results point to a GEN1X haploinsufficiency that might cause a bias towards a specific type of errors due to defective DNA maintenance.

Study of additional GEN1X-mutated tumors is required to validate this hypothesis. We tested the survival in response to MMC of the lymphobastoid cell lines derived from: a c.

To test whether GEN1X silencing also contributes to tumor growth, tumors derived from the subcutaneous implantation in athymic mice of Caco-2 cell lines with and without GEN1X sh-GEN1X and sh-empty were grafted in the cecum of athymic mice.

Likewise, a thorough analysis of genetic and genomic alterations found in GEN1X-associated tumors will clarify the underlying repair defects accumulated and therefore the mechanism of action of GEN1X haploinsufficiency in colorectal carcinogenesis.

Kastrinos, F. Cancer J 17, Palles, C. Nat Genet 45, Jaeger, E. Nat Genet 44, Cannavo, E. J Biol Chem , Seattle, WA.

Cancer Genome Atlas Network. Nature , Quesada, V. Ke, S. Genome Res 21, Pedigrees of the families with germline GEN1X mutations.

CRC, colorectal cancer; End, endometrial cancer; BC, breast cancer; Gli, glioma; Panc, pancreatic cancer; unk, cancer of unknown location; GI, gastrointestinal tumor; mtx, metastasis; y, years.

Error bars indicate SEM. In bold, the evidence that supports the damaging nature of the variants. DY Benign 0. PS Benign 0. This data processing was carried out to search for germline mutations in Family 1 and to characterize the somatic mutations located in transcribed sequences present in the tumor of a GEN1X mutation carrier Family 1, proband.

SNPs were removed using the pool of normal samples and the Genomes database. All identified variants were analyzed, also including intronic and intergenic changes.

Mutation screening of GEN1X c. DNA samples from controls and consecutively recruited CRC patients from the same geographical area were analyzed Patterns differing from the wildtype were analyzed by direct automated sequencing of the corresponding exonic fragment.

Also, GEN1X c. All families fulfilled the Amsterdam I The mean age at cancer diagnosis was 48 years for the sequenced patients Supplementary Table 2.

Likewise, we studied the index CRC patients of 71 MMR-proficient CRC families characterized by the presence of two first-degree relatives affected with CRC or other related tumors, one of which diagnosed before the age of 50, or by the presence of three relatives with CRC or other related tumors independent of the age at diagnosis Supplementary Table 2.

Informed consent was obtained from all subjects. Direct automated sequencing Exons and intron-exon boundaries of GEN1X were sequenced using a standard protocol for automated direct Sanger sequencing.

Sanger sequencing was used to validate the results obtained by massive parallel sequencing exome and gene targeted sequencing , and to sequence GEN1X in FFPE samples and in blood DNA from 85 Amsterdam-positive and 71 Bethesda-positive index cases.

Mutation identification in pooled samples The remaining of 91 Amsterdam-positive MMR-proficient index patients were screened for new mutations in GEN1X by using a combination of pooled samples, PCR amplification and high-throughput sequencing, as previously described In silico functional prediction of genetic variants Protein damage prediction of missense genetic variants was performed by using the in silico algorithms PolyPhen-2, SIFT and Condel Possible alterations of the splice sites were evaluated using NNSplice0.

The functional impact of c. This approach has been proven to be very sensitive in predicting the effect of variants in exon skipping.

A total ESRseq score change lower than Interestingly, amino acid regions present in all these 3D models show different topologies, which supports their low reliabilities.

We identified two regions with disordered structure: residues and The missense mutations DY and PS are located in the second structural-disordered region.

They were exposed to increasing concentrations of MMC nM until they had reach at least three population doublings. Subsequently, cells for each MMC concentration were counted using a cell counter and size analyzer Beckman-Coulter Z2.

Three experimental replicates in which each condition was performed in duplicate were carried out.

Li, H. Bioinformatics 25, Puente, X. Moreno, V. Clin Cancer Res 12, Adzhubei, I. Nat Methods 7, Kumar, P. Nat Protoc 4, Gonzalez-Perez, A.

Am J Hum Genet 88, Reese, M. J Comput Biol 4, Dogan, R. BMC Bioinformatics 8, Di Giacomo, D. Hum Mutat 34, Protein sequence and 3D structure of the region containing R Supplementary Figure 2.

Mutation spectrum of the colon tumor of a GEN1X c. The lower panel depicts the tumor developed by the p. Supplementary Figure 3.

The LOH was studied by using three microsatelites, microsatellite 1, microsatellite 2 and an intragenic microsatellite, as well as the mutation assessed by SNaPshot.

DY mutation carriers Family 3, proband and individual II. Supplementary Figure 4. Figure 5. Tumors developed after the orthotopic implantation in the cecum of athymic mice of tumors previously originated after subcutaneous implantation in athymic mice of Caco-2 cell lines with sh-GEN1X and without sh-empty silencing of GEN1X.

Rare or unreported genetic variants identified by exome sequencing in all the studied cancer-affected family members Family 1.

Deleterious 0, BRCA1 c. ProAla Exon 14 rs n. C2orf16 c. ArgGln Exon 1 rs n. GlyLys Exon 2 n. LRRC14B c. GlyAsp Exon 3 n. ArgGln Exon 18 n.

LeuPhe Exon 1 0. Neutral 0 PKP3 c. Arg96Trp Exon 4 0. RAPH1 c. ArgGln Exon 6 0. Arg80Trp Exon 4 n.

SPECC1 c. MetLys Exon 4 0. ValIle Exon 2 0. Abbreviations: MAF, population minor allele frequency; n. Table 2. Characteristics of the CRC families and patients studied.

Age at cancer diagnosis of the individual where GEN1X was sequenced 2. Family 1 belongs to the Amsterdam I-positive families of Catalan origin.

Characterized by the presence of two first-degree relatives affected with CRC or other related tumors, one of which diagnosed before the age of 50, or by the presence of three relatives with CRC or other related tumors independent of the age at diagnosis.

Table 3. Table 4. Somatic mutations indentified in the tumor developed by a GEN1X c. Por ello, se han establecido unos criterios para disminuir en lo posible los factores confusores externos que pueden sesgar los estudios retrospectivos, sobre todo los que tienen que ver con el origen, procesamiento y almacenamiento de las muestras Prescott et al.

Tal y como se esperaba Lindsey et al. Esto hace patente la importancia de realizar un estudio prospectivo, aun teniendo en cuenta las dificultades que ello conlleva.

Como resultado, identificamos un total de 20 variantes en 90 pacientes. EV y c. DN , observadas en uno, 18 y 2 individuos respectivamente.

DN valor 1 y p. EV valor 0,8, en la modalidad HumanDiv. Para el cambio c. El cambio c. El otro cambio identificado en un caso de CCR familiar, c.

YC , no ha sido descrito en otros estudios. Finalmente, cabe considerar que otros genes situados dentro del pico de ligamiento 9q M15V, incluido el familiar con el tumor con IMS.

GD y p. YC Cleary et al. En base a estos datos resulta plausible pensar que variantes de MUTYH en heterocigosis pudiesen estar asociadas a un riesgo moderado a desarrollar CCR.

G12C , tal y como ya se ha propuesto anteriormente van Puijenbroek et al. Por ellos, el cambio c.

DY, c. PS y c. Por un lado, el cambio c. En el caso de p. PS es clasificada como neutra por todos ellos. DY , altamente sugestivo de alteraciones en el mecanismo de corte y empalme para esta variante.

Dominios funcionales y regiones desordenadas de GEN1X. Dos de las variantes de cambio de sentido identificadas p.

DY y p. De hecho, en el caso del afecto III. Los tumores del TCGA se han considerado separadamente los hipermutados de los no hipermutados.

La variante c. Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations.

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