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1.
Front Immunol ; 14: 1230306, 2023.
Article de Anglais | MEDLINE | ID: mdl-38022530

RÉSUMÉ

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with Klebsiella pneumoniae, Bifidobacterium animalis, and Adlercreutzia equolifaciens, while certain commensals are depleted. Our findings may suggest impaired B cell function within the GALT of PDAC patients, which could potentially be linked to microbial dysbiosis. Additional investigations are imperative to validate our observations and explore these potential targets of future therapies.


Sujet(s)
Appendice vermiforme , Carcinome du canal pancréatique , Tumeurs du pancréas , Humains , Appendice vermiforme/microbiologie , Appendice vermiforme/anatomopathologie , Dysbiose , Tumeurs du pancréas/anatomopathologie , Carcinome du canal pancréatique/anatomopathologie , Antigènes HLA-G
2.
J Pathol Clin Res ; 9(4): 322-335, 2023 07.
Article de Anglais | MEDLINE | ID: mdl-36971406

RÉSUMÉ

Oesophageal adenocarcinomas may show different histopathological patterns, including excessive acellular mucin pools, signet-ring cells (SRCs), and poorly cohesive cells (PCCs). These components have been suggested to correlate with poor outcomes after neoadjuvant chemoradiotherapy (nCRT), which might influence patient management. However, these factors have not been studied independently of each other with adjustment for tumour differentiation grade (i.e. the presence of well-formed glands), which is a possible confounder. We studied the pre- and post-treatment presence of extracellular mucin, SRCs, and/or PCCs in relation to pathological response and prognosis after nCRT in patients with oesophageal or oesophagogastric junction adenocarcinoma. A total of 325 patients were retrospectively identified from institutional databases of two university hospitals. All patients were scheduled for ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) nCRT and oesophagectomy between 2001 and 2019. Percentages of well-formed glands, extracellular mucin, SRCs, and PCCs were scored in pre-treatment biopsies and post-treatment resection specimens. The association between histopathological factors (≥1 and >10%) and tumour regression grade 3-4 (i.e. >10% residual tumour), overall survival, and disease-free survival (DFS) was evaluated, adjusted for tumour differentiation grade amongst other clinicopathological variables. In pre-treatment biopsies, ≥1% extracellular mucin was present in 66 of 325 patients (20%); ≥1% SRCs in 43 of 325 (13%), and ≥1% PCCs in 126 of 325 (39%). We show that pre-treatment histopathological factors were unrelated to tumour regression grade. Pre-treatment presence of >10% PCCs was associated with lower DFS (hazard ratio [HR] 1.73, 95% CI 1.19-2.53). Patients with post-treatment presence of ≥1% SRCs had higher risk of death (HR 1.81, 95% CI 1.10-2.99). In conclusion, pre-treatment presence of extracellular mucin, SRCs, and/or PCCs is unrelated to pathological response. The presence of these factors should not be an argument to refrain from CROSS. At least 10% PCCs pre-treatment and any SRCs post-treatment, irrespective of the tumour differentiation grade, seem indicative of inferior prognosis, but require further validation in larger cohorts.


Sujet(s)
Adénocarcinome , Tumeurs de l'oesophage , Humains , Mucines , Études rétrospectives , Traitement néoadjuvant
3.
J Crohns Colitis ; 17(2): 221-230, 2023 Mar 18.
Article de Anglais | MEDLINE | ID: mdl-36094558

RÉSUMÉ

BACKGROUND: To prevent recurrence after ileocolonic resection [ICR] in Crohn's disease [CD], postoperative prophylaxis based on risk stratification is recommended in international guidelines. This study aimed to evaluate postoperative CD recurrence after implementation of a clinical management algorithm and to determine the predictive value of clinical and histological risk factors [RFs]. METHODS: In this multicentre, prospective cohort study, CD patients [≥16 years] scheduled for ICR were included. The algorithm advised no postoperative medication for low-risk patients, and treatment with prophylaxis [immunosuppressant/biological] for high-risk patients [≥1 RF: active smoking, penetrating disease, prior ICR]. Clinical and histological RFs [active inflammation, granulomas, plexitis in resection margins] for endoscopic recurrence [Rutgeerts' score ≥i2b at 6 months] were assessed using logistic regression and ROC curves based on predicted probabilities. RESULTS: In total, 213 CD patients after ICR were included [age 34.5 years; 65% women] (93 [44%] low-risk; 120 [56%] high-risk: 45 [38%] smoking; 51 [43%] penetrating disease; 51 [43%] prior ICR). Adherence to the algorithm was 82% in low-risk [no prophylaxis] and 51% in high-risk patients [prophylaxis]. Endoscopic recurrence was higher in patients treated without prophylaxis than with prophylaxis in both low [45% vs 16%, p = 0.012] and high-risk patients [49% vs 26%, p = 0.019]. Clinical risk stratification including the prescription of prophylaxis corresponded to an area under the curve [AUC] of 0.70 (95% confidence interval [CI] 0.61-0.79). Clinical RFs combined with histological RFs increased the AUC to 0.73 [95% CI 0.64-0.81]. CONCLUSION: Adherence to this management algorithm is 65%. Prophylactic medication after ICR prevents endoscopic recurrence in low- and high-risk patients. Clinical risk stratification has an acceptable predictive value, but further refinement is needed.


Sujet(s)
Maladie de Crohn , Humains , Femelle , Adulte , Mâle , Maladie de Crohn/traitement médicamenteux , Maladie de Crohn/chirurgie , Maladie de Crohn/anatomopathologie , Études prospectives , Côlon/chirurgie , Côlon/anatomopathologie , Facteurs de risque , Appréciation des risques , Récidive , Iléum/anatomopathologie
4.
Cancers (Basel) ; 14(13)2022 Jul 01.
Article de Anglais | MEDLINE | ID: mdl-35805012

RÉSUMÉ

Recommendations in Barrett's esophagus (BE) guidelines are mainly based on male patients. We aimed to evaluate sex differences in BE patients in (1) probability of and (2) time to neoplastic progression, and (3) differences in the stage distribution of neoplasia. We conducted a multicenter prospective cohort study including 868 BE patients. Cox regression modeling and accelerated failure time modeling were used to estimate the sex differences. Neoplastic progression was defined as high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Among the 639 (74%) males and 229 females that were included (median follow-up 7.1 years), 61 (7.0%) developed HGD/EAC. Neoplastic progression risk was estimated to be twice as high among males (HR 2.26, 95% CI 1.11-4.62) than females. The risk of HGD was found to be higher in males (HR 3.76, 95% CI 1.33-10.6). Time to HGD/EAC (AR 0.52, 95% CI 0.29-0.95) and HGD (AR 0.40, 95% CI 0.19-0.86) was shorter in males. Females had proportionally more EAC than HGD and tended to have higher stages of neoplasia at diagnosis. In conclusion, both the risk of and time to neoplastic progression were higher in males. However, females were proportionally more often diagnosed with (advanced) EAC. We should strive for improved neoplastic risk stratification per individual BE patient, incorporating sex disparities into new prediction models.

5.
Diagnostics (Basel) ; 12(2)2022 Feb 08.
Article de Anglais | MEDLINE | ID: mdl-35204526

RÉSUMÉ

An increasing number of pathology laboratories are now fully digitised, using whole slide imaging (WSI) for routine diagnostics. WSI paves the road to use artificial intelligence (AI) that will play an increasing role in computer-aided diagnosis (CAD). In melanocytic skin lesions, the presence of a dermal mitosis may be an important clue for an intermediate or a malignant lesion and may indicate worse prognosis. In this study a mitosis algorithm primarily developed for breast carcinoma is applied to melanocytic skin lesions. This study aimed to assess whether the algorithm could be used in diagnosing melanocytic lesions, and to study the added value in diagnosing melanocytic lesions in a practical setting. WSI's of a set of hematoxylin and eosin (H&E) stained slides of 99 melanocytic lesions (35 nevi, 4 intermediate melanocytic lesions, and 60 malignant melanomas, including 10 nevoid melanomas), for which a consensus diagnosis was reached by three academic pathologists, were subjected to a mitosis algorithm based on AI. Two academic and six general pathologists specialized in dermatopathology examined the WSI cases two times, first without mitosis annotations and after a washout period of at least 2 months with mitosis annotations based on the algorithm. The algorithm indicated true mitosis in lesional cells, i.e., melanocytes, and non-lesional cells, i.e., mainly keratinocytes and inflammatory cells. A high number of false positive mitosis was indicated as well, comprising melanin pigment, sebaceous glands nuclei, and spindle cell nuclei such as stromal cells and neuroid differentiated melanocytes. All but one pathologist reported more often a dermal mitosis with the mitosis algorithm, which on a regular basis, was incorrectly attributed to mitoses from mainly inflammatory cells. The overall concordance of the pathologists with the consensus diagnosis for all cases excluding nevoid melanoma (n = 89) appeared to be comparable with and without the use of AI (89% vs. 90%). However, the concordance increased by using AI in nevoid melanoma cases (n = 10) (75% vs. 68%). This study showed that in general cases, pathologists perform similarly with the aid of a mitosis algorithm developed primarily for breast cancer. In nevoid melanoma cases, pathologists perform better with the algorithm. From this study, it can be learned that pathologists need to be aware of potential pitfalls using CAD on H&E slides, e.g., misinterpreting dermal mitoses in non-melanotic cells.

6.
J Clin Pathol ; 74(1): 48-52, 2021 Jan.
Article de Anglais | MEDLINE | ID: mdl-32467320

RÉSUMÉ

AIMS: The histopathological diagnosis of low-grade dysplasia (LGD) in Barrett's oesophagus (BO) is associated with poor interobserver agreement and guidelines dictate expert review. To facilitate nationwide expert review in the Netherlands, a web-based digital review panel has been set up, which currently consists of eight 'core' pathologists. The aim of this study was to evaluate if other pathologists from the Dutch BO expert centres qualify for the expert panel by assessing their performance in 80 consecutive LGD reviews submitted to the panel. METHODS: Pathologists independently assessed digital slides in two phases. Both phases consisted of 40 cases, with a group discussion after phase I. For all cases, a previous consensus diagnosis made by five core pathologists was available, which was used as reference. The following criteria were used: (1) percentage of 'indefinite for dysplasia' diagnoses, (2) percentage agreement with consensus diagnosis and (3) proportion of cases with a consensus diagnosis of dysplasia underdiagnosed as non-dysplastic. Benchmarks were based on scores of the core pathologists. RESULTS: After phase I, 1/7 pathologists met the benchmark score for all quality criteria, yet three pathologists only marginally failed the agreement with consensus diagnosis (score 68.3%, benchmark 69%). After a group discussion and phase II, 5/6 remaining aspirant panel members qualified with all scores within the benchmark range. CONCLUSIONS: The Dutch BO review panel now consists of 14 pathologists, who-after structured assessments and group discussions-can be considered homogeneous in their review of biopsies with LGD.


Sujet(s)
Oesophage de Barrett/anatomopathologie , Anatomopathologistes , Sujet âgé , Référenciation , Biopsie , Oesophage/anatomopathologie , Femelle , Tube digestif/anatomopathologie , Humains , Mâle , Adulte d'âge moyen , Pays-Bas , Biais de l'observateur , Études prospectives
7.
Crit Rev Oncol Hematol ; 150: 102970, 2020 Jun.
Article de Anglais | MEDLINE | ID: mdl-32371339

RÉSUMÉ

To characterize metanephric tumours in children, we performed a literature review investigating paediatric metanephric adenomas (MA), metanephric stromal tumours (MST) and metanephric adenofibromas (MAF). Including two patients from our own institution (MA, MAF), 110 individual cases (41 MA, 20 MAF, 49 MST) were identified. Additionally, fifteen composite tumours were identified, with areas of MA/MAF and Wilms tumour (WT) or papillary carcinoma. No distinct clinical or radiological features could be defined. In pure metanephric tumours, histologically proven distant metastases were reported once (MA), relapse was reported once (MST) and one tumour-related death occurred (MST). Somatic BRAF-V600E mutations were tested in 15 cases, and identified in 3/6 MA, 3/3 MAF, and 6/6 MST. In our institution the MA harboured a somatic KRAS-G12R mutation. Overall, paediatric metanephric tumours are difficult to discriminate from other renal tumours at presentation, behave relatively benign, and the occurrence of composite tumours warrants analysis of underlying (genetic) pathways.


Sujet(s)
Adénomes/génétique , Adénomes/anatomopathologie , Carcinome papillaire/génétique , Carcinome papillaire/anatomopathologie , Tumeurs du rein/génétique , Tumeurs du rein/anatomopathologie , Protéines proto-oncogènes p21(ras)/génétique , Tumeur de Wilms/génétique , Tumeur de Wilms/anatomopathologie , Marqueurs biologiques tumoraux/génétique , Enfant , Analyse de mutations d'ADN , Humains , Immunohistochimie , Immunophénotypage , Récidive tumorale locale
9.
Cancers (Basel) ; 12(3)2020 Mar 19.
Article de Anglais | MEDLINE | ID: mdl-32204536

RÉSUMÉ

Renal tumors comprise approximately 7% of all malignant pediatric tumors. This is a highly heterogeneous group of tumors, each with its own therapeutic management, outcome, and association with germline predispositions. Histopathology is the key in establishing the correct diagnosis, and therefore pathologists with expertise in pediatric oncology are needed for dealing with these rare tumors. While each tumor shows different histologic features, they do have considerable overlap in cell type and histologic pattern, making the diagnosis difficult to establish, if based on routine histology alone. To this end, ancillary techniques, such as immunohistochemistry and molecular analysis, can be of great importance for the correct diagnosis, resulting in appropriate treatment. To use ancillary techniques cost-effectively, we propose a pattern-based approach and provide recommendations to aid in deciding which panel of antibodies, supplemented by molecular characterization of a subset of genes, are required.

10.
Virchows Arch ; 475(4): 533, 2019 Oct.
Article de Anglais | MEDLINE | ID: mdl-31422501

RÉSUMÉ

It has been identified that one of the dosages listed within the above article was incorrectly abbreviated during the production process. This is now presented correctly in this article.

12.
J Pathol Inform ; 10: 6, 2019.
Article de Anglais | MEDLINE | ID: mdl-30972225

RÉSUMÉ

BACKGROUND: Accurate diagnosis of melanocytic lesions is challenging, even for expert pathologists. Nowadays, whole-slide imaging (WSI) is used for routine clinical pathology diagnosis in several laboratories. One of the limitations of WSI, as it is most often used, is the lack of a multiplanar focusing option. In this study, we aim to establish the diagnostic accuracy of WSI for melanocytic lesions and investigate the potential accuracy increase of z-stack scanning. Z-stack enables pathologists to use a software focus adjustment, comparable to the fine-focus knob of a conventional light microscope. MATERIALS AND METHODS: Melanocytic lesions (n = 102) were selected from our pathology archives: 35 nevi, 5 spitzoid tumors of unknown malignant potential, and 62 malignant melanomas, including 10 nevoid melanomas. All slides were scanned at a magnification comparable to use of a ×40 objective, in z-stack mode. A ground truth diagnosis was established on the glass slides by four academic dermatopathologists with a special interest in the diagnosis of melanoma. Six nonacademic surgical pathologists subspecialized in dermatopathology examined the cases by WSI. RESULTS: An expert consensus diagnosis was achieved in 99 (97%) of cases. Concordance rates between surgical pathologists and the ground truth varied between 75% and 90%, excluding nevoid melanoma cases. Concordance rates of nevoid melanoma varied between 10% and 80%. Pathologists used the software focusing option in 7%-28% of cases, which in 1 case of nevoid melanoma resulted in correcting a misdiagnosis after finding a dermal mitosis. CONCLUSION: Diagnostic accuracy of melanocytic lesions based on glass slides and WSI is comparable with previous publications. A large variability in diagnostic accuracy of nevoid melanoma does exist. Our results show that z-stack scanning, in general, does not increase the diagnostic accuracy of melanocytic.

13.
Nat Rev Urol ; 15(11): 693-701, 2018 Nov.
Article de Anglais | MEDLINE | ID: mdl-30310143

RÉSUMÉ

On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP-RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP-RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP-RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP-RTSG pathology panel.


Sujet(s)
Marqueurs biologiques tumoraux/génétique , Tumeurs du rein/génétique , Tumeurs du rein/anatomopathologie , Rein/anatomopathologie , Tumeur de Wilms/génétique , Tumeur de Wilms/anatomopathologie , Biopsie , Enfant , Humains , Tumeurs du rein/diagnostic , Tumeurs du rein/thérapie , Stadification tumorale , Pronostic , Manipulation d'échantillons/normes , Tumeur de Wilms/diagnostic , Tumeur de Wilms/thérapie
14.
Histopathology ; 72(6): 1015-1023, 2018 May.
Article de Anglais | MEDLINE | ID: mdl-29314176

RÉSUMÉ

AIMS: Interobserver agreement for dysplasia in Barrett's oesophagus (BO) is low, and guidelines advise expert review of dysplastic cases. The aim of this study was to assess the added value of p53 immunohistochemistry (IHC) for the homogeneity within a group of dedicated gastrointestinal (GI) pathologists. METHODS AND RESULTS: Sixty-single haematoxylin and eosin (HE) slide referral BO cases [20 low-grade dysplasia (LGD); 20 high-grade dysplasia (HGD); and 20 non-dysplastic BO reference cases] were digitalised and independently assessed twice in random order by 10 dedicated GI pathologists. After a 'wash-out' period, cases were reassessed with the addition of a corresponding p53 IHC slide. Outcomes were: (i) proportion of 'indefinite for dysplasia' (IND) diagnoses; (ii) interobserver agreement; and (iii) diagnostic accuracy as compared with a consensus 'gold standard' diagnosis defined at an earlier stage by five core expert BO pathologists after their assessment of this case set. Addition of p53 IHC decreased the mean proportion of IND diagnoses from 10 of 60 to eight of 60 (P = 0.071). Mean interobserver agreement increased significantly from 0.45 to 0.57 (P = 0.0021). The mean diagnostic accuracy increased significantly from 72% to 82% (P = 0.0072) after p53 IHC addition. CONCLUSION: Addition of p53 IHC significantly improves the histological assessment of BO biopsies, even within a group of dedicated GI pathologists. It decreases the proportion of IND diagnoses, and increases interobserver agreement and diagnostic accuracy. This justifies the use of accessory p53 IHC within our upcoming national digital review panel for BO biopsy cases.


Sujet(s)
Oesophage de Barrett/diagnostic , Marqueurs biologiques/analyse , Interprétation d'images assistée par ordinateur/méthodes , Protéine p53 suppresseur de tumeur/analyse , Biopsie , Humains , Immunohistochimie , Biais de l'observateur
15.
Nat Genet ; 49(10): 1487-1494, 2017 Oct.
Article de Anglais | MEDLINE | ID: mdl-28825729

RÉSUMÉ

We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.


Sujet(s)
Gènes tumoraux , Tumeurs du rein/génétique , Tumeur de Wilms/génétique , Aneuploïdie , Méthylation de l'ADN , Épigenèse génétique , Dosage génique , Régulation de l'expression des gènes tumoraux , Étude d'association pangénomique , Mutation germinale , Humains , microARN/biosynthèse , microARN/génétique , Conformation des protéines , ARN messager/biosynthèse , ARN messager/génétique , ARN tumoral/biosynthèse , ARN tumoral/génétique
16.
Clin Cancer Res ; 22(22): 5582-5591, 2016 Nov 15.
Article de Anglais | MEDLINE | ID: mdl-27702824

RÉSUMÉ

PURPOSE: To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs). EXPERIMENTAL DESIGN: All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs. RESULTS: Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [defined as TP53-wild-type (wt)]. Patients with stage III/IV TP53-wt DAWTs (but not those with stage I/II disease) had significantly lower relapse and death rates than those with TP53 abnormalities. In-depth analysis of a subset of 39 DAWTs showed seven (18%) to be TP53-wt: These demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of TP53-wt DAWT revealed no or very low volume of anaplasia in six of seven tumors. When samples from TP53-wt tumors known to contain anaplasia histologically were available, abnormal p53 protein accumulation was observed by immunohistochemistry. CONCLUSIONS: These data support the key role of TP53 loss in the development of anaplasia in WT, and support its significant clinical impact in patients with residual anaplastic tumor following surgery. These data also suggest that most DAWTs will show evidence of TP53 mutation when samples selected for the presence of anaplasia are analyzed. This suggests that modifications of the current criteria to also consider volume of anaplasia and documentation of TP53 aberrations may better reflect the risk of relapse and death and enable optimization of therapeutic stratification. Clin Cancer Res; 22(22); 5582-91. ©2016 AACR.


Sujet(s)
Anaplasie/génétique , Tumeurs du rein/génétique , Mutation/génétique , Radius/malformations , Protéine p53 suppresseur de tumeur/génétique , Tumeur de Wilms/génétique , Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Enfant , Femelle , Expression des gènes/génétique , Humains , Immunohistochimie/méthodes , Mâle , Adulte d'âge moyen , Études rétrospectives , Jeune adulte
17.
Cancer Cell ; 27(2): 286-97, 2015 Feb 09.
Article de Anglais | MEDLINE | ID: mdl-25670082

RÉSUMÉ

We report the most common single-nucleotide substitution/deletion mutations in favorable histology Wilms tumors (FHWTs) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPGs) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death.


Sujet(s)
Protéines à homéodomaine/génétique , Protéines de tissu nerveux/génétique , Protéines de liaison à l'ARN/génétique , Ribonuclease III/génétique , Tumeur de Wilms/génétique , Régulation de l'expression des gènes tumoraux , Humains , Perte d'hétérozygotie/génétique , microARN/génétique , Mutation , Récidive tumorale locale/génétique , Récidive tumorale locale/anatomopathologie , Polymorphisme de nucléotide simple , Tumeur de Wilms/anatomopathologie
18.
Int J Legal Med ; 128(4): 621-9, 2014 Jul.
Article de Anglais | MEDLINE | ID: mdl-24442913

RÉSUMÉ

Unclassified sudden infant death (USID) is the sudden and unexpected death of an infant that remains unexplained after thorough case investigation including performance of a complete autopsy and review of the circumstances of death and the clinical history. When the infant is below 1 year of age and with onset of the fatal episode apparently occurring during sleep, this is referred to as sudden infant death syndrome (SIDS). USID and SIDS remain poorly understood despite the identification of several environmental and some genetic risk factors. In this study, we investigated genetic risk factors involved in the autonomous nervous system in 195 Dutch USID/SIDS cases and 846 Dutch, age-matched healthy controls. Twenty-five DNA variants from 11 genes previously implicated in the serotonin household or in the congenital central hypoventilation syndrome, of which some have been associated with SIDS before, were tested. Of all DNA variants considered, only the length variation of the polyalanine repeat in exon 3 of the PHOX2B gene was found to be statistically significantly associated with USID/SIDS in the Dutch population after multiple test correction. Interestingly, our data suggest that contraction of the PHOX2B exon 3 polyalanine repeat that we found in six of 160 SIDS and USID cases and in six of 814 controls serves as a probable genetic risk factor for USID/SIDS at least in the Dutch population. Future studies are needed to confirm this finding and to understand the functional effect of the polyalanine repeat length variation, in particular contraction, in exon 3 of the PHOX2B gene.


Sujet(s)
Protéines à homéodomaine/génétique , Peptides/génétique , Séquences répétées d'acides nucléiques , Mort subite du nourrisson/génétique , Facteurs de transcription/génétique , Études cas-témoins , Exons , Femelle , Génotype , Humains , Nourrisson , Nouveau-né , Mâle , Pays-Bas , Études rétrospectives , Facteurs de risque
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