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1.
Eur J Hum Genet ; 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33319852

RESUMO

Pathogenic variants in TP53 have been classically thought to cause Li-Fraumeni syndrome (LFS), a cancer predisposition with high risks for various childhood- and adult-onset malignancies. However, increased genetic testing has lately revealed, that pathogenic variant carriers exhibit a broader range of phenotypes and that penetrance may be dependent both on variant type and modifiers. Using next generation sequencing and short tandem repeat analysis, we identified germline pathogenic variants in TP53 and RAD51C located in cis on chromosome 17 in a 43-year-old male, who has developed a rare sebaceous gland carcinoma (SGC) but so far no tumors of the LFS spectrum. This course mirrors a Trp53-Rad51c-double-mutant cis mouse-model, which similarly develops SGC, while the characteristic Trp53-associated tumor spectrum occurs with significantly lower frequency. Therefore, we propose that co-occurent pathogenic variants in RAD51C and TP53 may predispose to SGC, reminiscent of Muir-Torre syndrome. Further, this report supports the diversity of clinical presentations associated with germline TP53 alterations, and thus, the proposed expansion of LFS to heritable TP53-related cancer syndrome.

2.
BMC Cancer ; 20(1): 1151, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33243186

RESUMO

An amendment to this paper has been published and can be accessed via the original article.

3.
BMC Cancer ; 20(1): 1038, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33115416

RESUMO

BACKGROUND: ß-catenin activation plays a crucial role for tumourigenesis in the large intestine but except for Lynch syndrome (LS) associated cancers stabilizing mutations of ß-catenin gene (CTNNB1) are rare in colorectal cancer (CRC). Previous animal studies provide an explanation for this observation. They showed that CTNNB1 mutations induced transformation in the colon only when CTNNB1 was homozygously mutated or when membranous ß-catenin binding was hampered by E-cadherin haploinsufficiency. We were interested, if these mechanisms are also found in human CTNNB1 mutated CRCs. RESULTS: Among 869 CRCs stabilizing CTNNB1 mutations were found in 27 cases. Homo- or hemizygous CTNNB1 mutations were detected in 74% of CTNNB1 mutated CRCs (13 microsatellite instabile (MSI-H), 7 microsatellite stabile (MSS)) but only in 3% (1/33) of extracolonic CTNNB1 mutated cancers. In contrast to MSS CRC, CTNNB1 mutations at codon 41 or 45 were highly selected in MSI-H CRC. Of the examined three CRC cell lines, ß-catenin and E-cadherin expression was similar in cell lines without or with hetereozygous CTNNB1 mutations (DLD1 and HCT116), while a reduced E-cadherin expression combined with cytoplasmic accumulation of ß-catenin was found in a cell line with homozygous CTNNB1 mutation (LS180). Reduced expression of E-cadherin in human MSI-H CRC tissue was identified in 60% of investigated cancers, but no association with the CTNNB1 mutational status was found. CONCLUSIONS: In conclusion, this study shows that in contrast to extracolonic cancers stabilizing CTNNB1 mutations in CRC are commonly homo- or hemizygous indicating a higher threshold of ß-catenin stabilization to be required for transformation in the colon as compared to extracolonic sites. Moreover, we found different mutational hotspots in CTNNB1 for MSI-H and MSS CRCs suggesting a selection of different effects on ß-catenin stabilization according to the molecular pathway of tumourigenesis. Reduced E-cadherin expression in CRC may further contribute to higher levels of transcriptionally active ß-catenin, but it is not directly linked to the CTNNB1 mutational status.

4.
Cancer Epidemiol Biomarkers Prev ; 29(12): 2719-2728, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33008876

RESUMO

BACKGROUND: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis. METHODS: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC). RESULTS: A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer-specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74-0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68-0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed. CONCLUSIONS: Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients. IMPACT: The implicated genes warrant further investigation.

5.
Int J Cancer ; 147(10): 2801-2810, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32875553

RESUMO

BRAF V600E mutations have been reported as a marker of sporadic microsatellite instability (MSI) colorectal cancer (CRC). Current international diagnostic guidelines recommend BRAF mutation testing in MSI CRC patients to predict low risk of Lynch syndrome (LS). We evaluated the age-specific performance of BRAF testing in LS diagnostics. We systematically compared the prevalence of BRAF mutations in LS-associated CRCs and unselected MSI CRCs in different age groups as available from published studies, databases and population-based patient cohorts. Sensitivity/specificity analysis of BRAF testing for exclusion of LS and cost calculations were performed. Among 969 MSI CRCs from LS carriers in the literature and German HNPCC Consortium, 15 (1.6%) harbored BRAF mutations. Six of seven LS patients with BRAF-mutant CRC and reported age were <50 years. Among 339 of 756 (44.8%) of BRAF mutations detected in unselected MSI CRC, only 2 of 339 (0.6%) BRAF mutations were detected in patients <50 years. The inclusion of BRAF testing led to high risk of missing LS patients and increased costs at age <50 years. BRAF testing in patients <50 years carries a high risk of missing a hereditary cancer predisposition and is cost-inefficient. We suggest direct referral of MSI CRC patients <50 years to genetic counseling without BRAF testing.

6.
BMC Biol ; 18(1): 116, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895052

RESUMO

BACKGROUND: Colorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. However, matching genetic profiles with histological transition requires the analyses of temporal samples from the same patient at key stages of progression. RESULTS: Here, we compared the genetic profiles of 34 early carcinomas with their respective adenomatous precursors to assess timing and heterogeneity of driver alterations accompanying the switch from benign adenoma to malignant carcinoma. In almost half of the cases, driver mutations specific to the carcinoma stage were not observed. In samples where carcinoma-specific alterations were present, TP53 mutations and chromosome 20 copy gains commonly accompanied the switch from adenomatous tissue to carcinoma. Remarkably, 40% and 50% of high-grade adenomas shared TP53 mutations and chromosome 20 gains, respectively, with their matched carcinomas. In addition, multi-regional analyses revealed greater heterogeneity of driver mutations in adenomas compared to their matched carcinomas. CONCLUSION: Genetic alterations in TP53 and chromosome 20 occur at the earliest histological stage in colorectal carcinomas (pTis and pT1). However, high-grade adenomas can share these alterations despite their histological distinction. Based on the well-defined sequence of CRC development, we suggest that the timing of genetic changes during neoplastic progression is frequently uncoupled from histological progression.

7.
Nat Commun ; 11(1): 4740, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958755

RESUMO

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers.


Assuntos
Mutação da Fase de Leitura , Repetições de Microssatélites/genética , Neoplasias/genética , Neoplasias/imunologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antígenos HLA/genética , Humanos , Mutação INDEL , Vigilância Imunológica , Instabilidade de Microssatélites , Taxa de Mutação , Seleção Genética , Microglobulina beta-2/genética
8.
Int J Colorectal Dis ; 2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-32949260

RESUMO

BACKGROUND: In rectal cancer, prediction of tumor response and pathological complete response (pCR) to neoadjuvant treatment could contribute to refine selection of patients who might benefit from a delayed- or no-surgery approach. The aim of this study was to explore the association of clinical and molecular characteristics of rectal cancer with response to neoadjuvant treatment and to compare patient survival according to level of response. METHODS: Resected rectal cancer patients were selected from a population-based cohort study. Molecular tumor markers were determined from the surgical specimen. Tumor response and pCR were defined as downstaging in T or N stage and absence of tumor cells upon pathological examination, respectively. The associations of patient and tumor characteristics with tumor response and pCR were explored, and patient survival was determined by degree of response to neoadjuvant treatment. RESULTS: Among 1536 patients with rectal cancer, 602 (39%) received neoadjuvant treatment. Fifty-five (9%) patients presented pCR, and 239 (49%) and 250 (53%) patients showed downstaging of the T and N stages, respectively. No statistically significant associations were observed between patient or tumor characteristics and tumor response or pCR. Patients who presented any type of response to neoadjuvant treatment had significantly better cancer-specific and overall survival compared with non-responders. CONCLUSION: In this study, patient characteristics were not associated with response to neoadjuvant treatment, and molecular characteristics determined after surgical resection of the tumor were not predictive of pCR or tumor downstaging. Future studies should include molecular biomarkers from biopsy samples before neoadjuvant treatment.

9.
Am J Gastroenterol ; 115(12): 2007-2016, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32858564

RESUMO

INTRODUCTION: In previous studies, the protective effect of colonoscopy was generally stronger for distal colorectal cancer than for proximal colorectal cancer (CRC). This study aimed to investigate whether reduction of CRC risk through colonoscopy varies according to major tumor markers and pathways of CRC. METHODS: This is a population-based case-control study from Germany, including 2,132 patients with a first diagnosis of CRC and information on major molecular tumor markers and 2,486 control participants without CRC. Detailed participant characteristics were collected by standardized questionnaires. Information on previous colonoscopy was derived from medical records. Polytomous logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between previous colonoscopy and subtypes of CRC. RESULTS: Overall, we observed strong risk reduction of CRC after colonoscopy that was weaker for microsatellite instable (MSI) than for non-MSI CRC (OR 0.70, 95% CI 0.50-0.97 vs OR 0.28, 95% CI 0.24-0.33), for CpG island methylator phenotype high CRC than for CpG island methylator phenotype low/negative CRC (OR 0.45, 95% CI 0.34-0.59 vs OR 0.29, 95% CI 0.25-0.34), for BRAF-mutated than for BRAF nonmutated CRC (OR 0.62, 95% CI 0.42-0.91 vs OR 0.30, 95% CI 0.25-0.35), for KRAS nonmutated than for KRAS-mutated CRC (OR 0.34, 95% CI 0.29-0.40 vs OR 0.26, 95% CI 0.20-0.32), and for CRC classified into the sessile serrated pathway than for CRC of the traditional pathway (OR 0.57, 95% CI 0.36-0.91 vs OR 0.30, 95% CI 0.25-0.37). After colonoscopy with the detection of adenomas or hyperplastic polyps, no risk reduction was found for sessile serrated pathway CRC, MSI, and BRAF-mutated subtypes. DISCUSSION: Our study extends the molecular understanding of existing differences in risk reduction of proximal and distal CRCs reported by previous studies and may imply important information for improving strategies for timely detection of relevant precursors.

10.
Int J Cancer ; 2020 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-32683684

RESUMO

Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS-associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals.

11.
Br J Cancer ; 122(11): 1604-1610, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32225169

RESUMO

BACKGROUND: Smoking and alcohol increase risk for colorectal malignancies. However, colorectal cancer (CRC) is a heterogenic disease and associations with the molecular pathological pathways are unclear. METHODS: This population-based case-control study includes 2444 cases with first-diagnosis CRC and 2475 controls. Tumour tissue was analysed for MSI (microsatellite instability), CIMP (CpG island methylator phenotype), BRAF (B-Raf proto-oncogene serine/threonine kinase gene) and KRAS (Kirsten rat sarcoma viral oncogene homologue gene) mutations. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for associations between alcohol and smoking and CRC molecular subtypes and pathways. RESULTS: Current smoking showed higher ORs for MSI-high (OR = 2.79, 95% CI: 1.86-4.18) compared to MSS (OR = 1.41, 1.14-1.75, p-heterogeneity (p-het) = 0.001), BRAF-mutated (mut) (OR = 2.40, 1.41-4.07) compared to BRAF-wild type (wt) (OR = 1.52, 1.24-1.88, p-het = 0.074), KRAS-wt (OR = 1.70, 1.36-2.13) compared to KRAS-mut (OR = 1.26, 0.95-1.68, p-het = 0.039) and CIMP-high (OR = 2.01, 1.40-2.88) compared to CIMP-low/negative CRC (OR = 1.50, 1.22-1.85, p-het=0.101). Current smoking seemed more strongly associated with sessile serrated pathway (CIMP-high + BRAF-mut; OR = 2.39, 1.27-4.52) than with traditional pathway CRC (MSS + CIMP-low/negative + BRAF-wt; OR = 1.50, 1.16-1.94) and no association was observed with alternate pathway CRC (MSS + CIMP-low/negative + KRAS-wt; OR = 1.08, 0.77-1.43). No heterogeneity was observed in alcohol consumption association by molecular subtypes. CONCLUSIONS: In this large case-control study, smoking was more strongly associated with MSI-high and KRAS-wt CRC and with cases showing features of the sessile serrated pathway. Association patterns were less clear for alcohol consumption.

12.
Clin Cancer Res ; 26(14): 3732-3739, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234756

RESUMO

PURPOSE: We performed next-generation sequencing (NGS) in the CONKO-001 phase III trial to identify clinically relevant prognostic and predictive mutations and conducted a functional validation in The Cancer Genome Atlas (TCGA) sequencing data. EXPERIMENTAL DESIGN: Patients of the CONKO-001 trial received curatively intended surgery for pancreatic adenocarcinoma (PDAC) followed by adjuvant chemotherapy with gemcitabine (Gem) or observation only (Obs). Tissue samples of 101 patients were evaluated by NGS of 37 genes. Cox proportional hazard models were applied for survival analysis. In addition, functional genomic analyses were performed in an NGS and RNA-sequencing dataset of 146 pancreatic tumors from TCGA. RESULTS: The most common mutations in the CONKO cohort were KRAS (75%), TP53 (60%), SMAD4 (10%), CDKNA2 (9%), as well as SWI/SNF (12%) complex alterations. In untreated patients, TP53 mutations were a negative prognostic factor for disease-free survival (DFS; HR mut vs. WT 2.434, P = 0.005). With respect to gemcitabine treatment, TP53 mutations were a positive predictive factor for gemcitabine efficacy [TP53mut: HR for DFS Gem vs. Obs, 0.235 (0.130 - 0.423; P < 0.001); TP53wt: HR for DFS Gem vs. Obs, 0.794 (0.417 - 1.513; P = 0.483)] with a significant test for interaction (P = 0.003). In the TCGA dataset, TP53 mutations were associated with shortened DFS. CONCLUSIONS: In CONKO-001, the benefit from adjuvant gemcitabine was confined to the TP53mut patient group. This potentially clinical relevant observation needs to be confirmed in independent prospective studies. The sensitivity of TP53mut PDAC to gemcitabine in CONKO-001 provides a lead for further mechanistic investigations.

14.
Eur Radiol ; 30(6): 3497-3506, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32086574

RESUMO

PURPOSE: To differentiate subtypes of hepatocellular adenoma (HCA) based on enhancement characteristics in gadoxetic acid (Gd-EOB) magnetic resonance imaging (MRI). MATERIALS AND METHODS: Forty-eight patients with 79 histopathologically proven HCAs who underwent Gd-EOB-enhanced MRI were enrolled (standard of reference: surgical resection). Two blinded radiologists performed quantitative measurements (lesion-to-liver enhancement) and evaluated qualitative imaging features. Inter-reader variability was tested. Advanced texture analysis was used to evaluate lesion heterogeneity three-dimensionally. RESULTS: Overall, there were 19 (24%) hepatocyte nuclear factor (HNF)-1a-mutated (HHCAs), 37 (47%) inflammatory (IHCAs), 5 (6.5%) b-catenin-activated (bHCA), and 18 (22.5%) unclassified (UHCAs) adenomas. In the hepatobiliary phase (HBP), 49.5% (39/79) of all adenomas were rated as hypointense and 50.5% (40/79) as significantly enhancing (defined as > 25% intralesional GD-EOB uptake). 82.5% (33/40) of significantly enhancing adenomas were IHCAs, while only 4% (1/40) were in the HHCA subgroup (p < 0.001). When Gd-EOB uptake behavior was considered in conjunction with established MRI features (binary regression model), the area under the curve (AUC) increased from 0.785 to 0.953 for differentiation of IHCA (atoll sign + hyperintensity), from 0.859 to 0.903 for bHCA (scar + hyperintensity), and from 0.899 to 0.957 for HHCA (steatosis + hypointensity). Three-dimensional region of interest (3D ROI) analysis showed significantly increased voxel heterogeneity for IHCAs (p = 0.038). CONCLUSION: Gd-EOB MRI is of added value for subtype differentiation of HCAs and reliably identifies the typical heterogeneous HBP uptake of IHCAs. Diagnostic accuracy can be improved significantly by the combined analysis of established morphologic MR appearances and intralesional Gd-EOB uptake. KEY POINTS: •Gd-EOB-enhanced MRI is of added value for subtype differentiation of HCA. •IHCA and HHCA can be identified reliably based on their typical Gd-EOB uptake patterns, and accuracy increases significantly when additionally taking established MR appearances into account. •The small numbers of bHCAs and UHCAs remain the source of diagnostic uncertainty.


Assuntos
Adenoma de Células Hepáticas/diagnóstico por imagem , Inflamação/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/metabolismo , Adenoma de Células Hepáticas/patologia , Adulto , Cicatriz/diagnóstico por imagem , Cicatriz/patologia , Meios de Contraste , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/patologia , Feminino , Gadolínio DTPA , Fator 1-alfa Nuclear de Hepatócito/genética , Humanos , Inflamação/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Radiologistas , beta Catenina/metabolismo
15.
Int J Cancer ; 147(4): 1018-1026, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31943160

RESUMO

Postmenopausal hormone replacement therapy (HRT) was found to be associated with lower risk of colorectal cancer (CRC). However, little is known regarding associations with molecular subtypes of CRC. The current study includes female participants of a large German population-based case-control study (922 CRC cases and 1,183 controls). Tumor tissue samples were analyzed for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), BRAF and KRAS mutation status. Multivariable logistic regression models were used to assess the association of HRT use with molecular subtypes and pathways. Postmenopausal HRT use was overall associated with reduced risk of CRC (adjusted odds ratio (aOR) 0.62, 95% confidence interval (CI) 0.50-0.76) and no major differences were observed for molecular subtypes or for tumor marker combinations representing molecular pathways. When stratified by median age (≤/>71 years) potentially stronger risk reductions were observed in the older group for subtypes showing MSI (OR = 0.36, 95% CI 0.17-0.76), BRAF mutation (OR = 0.40, 95% CI 0.30-0.83) and CIMP-high (OR = 0.40, 95% CI 0.21-0.73) and for CRC suggestive of the sessile serrated pathway (OR = 0.45, 95% CI 0.20-1.01). In conclusion, postmenopausal use of HRT was similarly associated with risk reduction of major molecular tumor subtypes and pathways of CRC. Potentially stronger risk reductions with CRC subtypes diagnosed at higher ages require confirmation and clarification from other studies. The current study extends the limited understanding of the mechanisms of HRT in CRC prevention.

16.
Gastroenterology ; 158(5): 1326-1333, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31926173

RESUMO

BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.


Assuntos
Adenoma/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Proteínas de Ligação a DNA/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Adenoma/diagnóstico , Adenoma/genética , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Colonoscopia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Análise Mutacional de DNA , Feminino , Finlândia/epidemiologia , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Países Baixos/epidemiologia , Estudos Prospectivos , beta Catenina/genética
17.
Am J Clin Nutr ; 111(3): 562-569, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31897467

RESUMO

BACKGROUND: Observational studies have consistently shown that a high BMI is associated with increased risk of colorectal cancer (CRC). However, the underlying mechanisms linking obesity to CRC remain unclear. OBJECTIVES: To investigate the associations of BMI and CRC by major molecular pathological subtypes of CRC. METHODS: This analysis included 2407 cases and 2454 controls from a large German population-based case-control study. Information on recent weight and height as well as other demographic and lifestyle data were obtained by standardized interviews. Multinomial logistic regression was used to estimate ORs and 95% CIs for the associations between BMI and risk of CRC by major molecular pathological features: microsatellite instability (MSI), CpG island methylator phenotype (CIMP), B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation, and Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation. RESULTS: Among women, a higher BMI was differentially and more strongly associated with risk of MSI CRC (OR per 5 kg/m2: 1.69; 95% CI: 1.34, 2.12; Pheterogeneity ≤ 0.001), CIMP-high CRC (OR per 5 kg/m2: 1.57; 95% CI: 1.30, 1.89; Pheterogeneity ≤ 0.001), BRAF-mutated CRC (OR per 5 kg/m2: 1.56; 95% CI: 1.22, 1.99; Pheterogeneity = 0.04), and KRAS-wildtype CRC (OR per 5 kg/m2: 1.35; 95% CI: 1.17, 1.54; Pheterogeneity = 0.01), compared with the risk of CRC in subjects with the molecular feature counterpart. In men, no meaningful differences in CRC risk were observed for the investigated molecular feature pairs. For the association of BMI with MSI CRC, we observed effect modification by sex (Pinteraction = 0.04). Also, in women, the risk of CRC with the serrated pathway features was more strongly increased with higher BMI than risk of CRC with the traditional pathway features (OR per 5 kg/m2: 1.73; 95% CI: 1.28, 2.34; Pheterogeneity = 0.01). CONCLUSIONS: In women, the relation between BMI and MSI-high CRC seems to be stronger than that between BMI and microsatellite-stable CRC. However, a validation in an independent cohort is needed. This observational study was registered at the German Clinical Trials Register (http://www.drks.de; study ID: DRKS00011793), an approved primary register in the WHO network.


Assuntos
Índice de Massa Corporal , Neoplasias Colorretais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Neoplasias Colorretais/fisiopatologia , Ilhas de CpG , Metilação de DNA , Feminino , Alemanha , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto Jovem
18.
Mol Oncol ; 14(2): 363-372, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31816156

RESUMO

Previous studies have reported conflicting results regarding the benefit of administering 5-FU-based chemotherapy to colon cancer (CC) patients with microsatellite-instable (MSI-high) tumors, and results from stage-specific analyses are scarce. Patients with stage II or III CC were recruited as part of a population-based study between 2003 and 2015. The Cox regression models including propensity score weighting were used to calculate hazard ratios and confidence intervals for the association between chemotherapy and cancer-specific (CSS), relapse-free (RFS), and overall survival (OS) by stage of disease and MSI status of the tumor. Median follow-up was 6.2 years. A total of 1010 CC patients were included in the analysis (54% stage II, 46% stage III, 20% MSI-high). Adjuvant chemotherapy was administered to 48 (8.7%) stage II and 366 (79%) stage III patients. Overall, patients who received adjuvant chemotherapy had better CSS [HR = 0.65 (0.49-0.86)] than those who received surgery alone. Among stage II patients, only 64 (12%) cancer-related deaths occurred, none of which in MSI-high patients who received chemotherapy. Patients with MSI-high tumors who received adjuvant treatment showed better CSS and a tendency toward better RFS compared to MSI-high patients who did not receive chemotherapy [HRCSS  = 0.36 (0.15-0.82), HRRFS  = 0.49 (0.22-1.06)]. Patients with microsatellite-stable (MSS) tumors receiving adjuvant chemotherapy also had significantly better survival [HRCSS  = 0.65 (0.48-0.87) and HRRFS  = 0.68 (0.52-0.88)]. In this population-based study including stage II and III CC patients, we observed a survival benefit of adjuvant chemotherapy for both MSS and MSI-high tumors. Adjuvant chemotherapy seemed to be beneficial among high-risk stage II patients with MSI-high tumors.

19.
Epigenomics ; 11(16): 1765-1778, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31755748

RESUMO

Aim: Use of menopausal hormone therapy (MHT) has been associated with a reduced risk for colorectal cancer, but mechanisms underlying this relationship are not well understood. In the colon, MHT appears to act through estrogen receptor ß (ERß) which may influence DNA methylation by binding to DNA. Using genome-wide methylation profiling data, we aimed to identify genes that may be differentially methylated according to MHT use. Materials & methods: DNA methylation was measured using Illumina HumanMethylation450k arrays in two independent tumor sample sets of colorectal cancer patients. Differential methylation was determined using R/limma. Results: In the discovery analysis, two CpG sites showed differential DNA methylation according to MHT use, both were not replicated. In stratified analyses, 342 CpG sites were associated with current MHT use only in ERß-positive tumors. Conclusion: The suggestive findings of differential methylation according to current MHT use in ERß-positive tumors warrant further investigation.


Assuntos
Neoplasias Colorretais/genética , Metilação de DNA , Terapia de Reposição de Estrogênios , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/metabolismo , Ilhas de CpG , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Menopausa , Pessoa de Meia-Idade
20.
Clin Epigenetics ; 11(1): 109, 2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340858

RESUMO

BACKGROUND: Results of previous studies on the association of the CpG island methylator phenotype (CIMP) with colorectal cancer (CRC) prognosis were inconsistent and mostly based on different CIMP definitions. The current study aimed to comprehensively investigate the associations between DNA methylation on genes previously used to define CIMP status with CRC survival. RESULTS: Patients with CRC followed up for a median of 5.2 years were divided into a study cohort (n = 568) and a validation cohort (n = 308). DNA methylation was measured in tumor tissue using the Illumina Infinium HumanMethylation450 BeadChip and restricted to 43 genes used to define CIMP status in previous studies. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) of survival after CRC, including adjustment for tumor stage, microsatellite instability, and BRAF mutation status. In the study cohort, ten CpG sites were identified to be associated with CRC survival. Seven of these ten CpG sites were also associated with CRC survival in the validation cohort and were used to construct a prognostic score. CRC patients with a prognostic score of the lowest methylation level showed poorer disease-specific survival compared with patients with the highest methylation level in both the study cohort and the validation cohort (HR = 3.11 and 95% CI = 1.97-4.91, and HR = 3.06 and 95% CI = 1.71-5.45, respectively). CONCLUSIONS: A CpG panel consisting of seven CpG sites was found to be strongly associated with CRC survival, independent from important clinical factors and mutations associated with CIMP. Further studies are required to confirm these findings.


Assuntos
Neoplasias Colorretais/mortalidade , Metilação de DNA , Epigenômica/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ilhas de CpG , Feminino , Redes Reguladoras de Genes , Humanos , Masculino , Instabilidade de Microssatélites , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Análise de Regressão , Análise de Sobrevida
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