| 1. |
- Djursby, Malene, et al.
(författare)
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Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer
- 2022
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 141:12, s. 1925-1933
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Tidskriftsartikel (refereegranskat)abstract
- The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch syndrome-associated mismatch repair (MMR) gene MSH6 (n = 6). In conclusion, screening using a comprehensive cancer gene panel in families with accumulation of late-onset CRC appears not to have a significant clinical value due to the low level of high-risk pathogenic variants detected. Our data suggest that only patients with abnormal MMR immunohistochemistry (IHC) or microsatellite instability (MSI) analyses, suggestive of Lynch syndrome, or a family history indicating another cancer predisposition syndrome should be prioritized for such genetic evaluations. Variants in MSH6 and MUTYH have previously been proposed to be involved in digenic or oligogenic hereditary predisposition to CRC. Accumulation of variants in MSH6 and monoallelic, pathogenic variants in MUTYH in our study indicates that digenic or oligogenic inheritance might be involved in late-onset CRC and warrants further studies of complex types of inheritance.
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| 2. |
- Dominguez, Mev, et al.
(författare)
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Distinct gene expression signatures in lynch syndrome and familial colorectal cancer type x.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects.
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| 3. |
- Dominguez, Mev, et al.
(författare)
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Familial colorectal cancer type X: genetic profiles and phenotypic features.
- 2015
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Ingår i: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 28:1, s. 30-36
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Tidskriftsartikel (refereegranskat)abstract
- Heredity is a major cause of colorectal cancer, but although several rare high-risk syndromes have been linked to disease-predisposing mutations, the genetic mechanisms are undetermined in the majority of families suspected of hereditary cancer. We review the clinical presentation, histopathologic features, and the genetic and epigenetic profiles of the familial colorectal cancer type X (FCCTX) syndrome with the aim to delineate tumor characteristics that may contribute to refined diagnostics and optimized tumor prevention.Modern Pathology advance online publication, 18 April 2014; doi:10.1038/modpathol.2014.49.
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| 4. |
- Dominguez, Mev, et al.
(författare)
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Functional implications of the p.Cys680Arg mutation in the MLH1 mismatch repair protein.
- 2014
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Ingår i: Molecular Genetics & Genomic Medicine. - : Wiley. - 2324-9269. ; 2:4, s. 352-355
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Tidskriftsartikel (refereegranskat)abstract
- In clinical genetic diagnostics, it is difficult to predict whether genetic mutations that do not greatly alter the primary sequence of the encoded protein causing unknown functional effects on cognate proteins lead to development of disease. Here, we report the clinical identification of c.2038 T>C missense mutation in exon 18 of the human MLH1 gene and biochemically characterization of the p.Cys680Arg mutant MLH1 protein to implicate it in the pathogenicity of the Lynch syndrome (LS). We show that the mutation is deficient in DNA mismatch repair and, therefore, contributing to LS in the carriers.
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| 5. |
- Dominguez-Valentin, Mev, et al.
(författare)
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Frequent mismatch-repair defects link prostate cancer to Lynch syndrome
- 2016
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Ingår i: BMC Urology. - : Springer Science and Business Media LLC. - 1471-2490. ; 16:1, s. 15-15
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A possible role for prostate cancer in Lynch syndrome has been debated based on observations of mismatch-repair defective tumors and reports of an increased risk of prostate cancer in mutation carriers. Potential inclusion of prostate cancer in the Lynch syndrome tumor spectrum is relevant for family classification, risk estimates and surveillance recommendations in mutation carriers.METHODS: We used the population-based Danish HNPCC-register to identify all prostate cancers that developed in mutation carriers and in their first-degree relatives from 288 Lynch syndrome families. The tumors were evaluated for clinicopathologic features and mismatch-repair status, and the cumulative risk of prostate cancer was determined.RESULTS: In total, 28 prostate cancers developed in 16 mutation carriers and in 12 first-degree relatives at a median age of 63 years. The majority of the tumors were high-grade tumors with Gleason scores 8-10. Prostate cancer was associated with mutations in MSH2, MLH1 and MSH6 with loss of the respective mismatch repair protein in 69 % of the tumors, though a MSI-high phenotype was restricted to 13 % of the tumors. The cumulative risk of prostate cancer at age 70 was 3.7 % (95 % CI: 2.3-4.9).CONCLUSION: We provide evidence to link prostate cancer to Lynch syndrome through demonstration of MMR defective tumors and an increased risk of the disease, which suggests that prostate cancer should be considered in the diagnostic work-up of Lynch syndrome.
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| 6. |
- Isinger Ekstrand, Anna, et al.
(författare)
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Deranged Wnt signaling is frequent in hereditary nonpolyposis colorectal cancer.
- 2011
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Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 10, s. 239-243
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Tidskriftsartikel (refereegranskat)abstract
- The Wnt signaling pathway is frequently deranged in colorectal cancer and is a key target for future preventive and therapeutic approaches. Colorectal cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome are characterized by wide-spread microsatellite instability, but show few gross genomic alterations. We characterized expression of the Wnt signaling pathway markers β-catenin, E-cadherin, TCF-4, and PTEN using immunohistochemical staining in colorectal cancers from individuals with HNPCC. Reduced membranous staining for β-catenin was found in 64% and for E-cadherin in 80% with strong correlation between these markers (P = 0.001). Nuclear β-catenin staining was detected in 19% of the tumors. Overexpression of TCF-4, which is activated by β-catenin, was found in 89% and downregulation of PTEN, which suppresses nuclear accumulation of β-catenin, was present in 54% of the tumors. In summary, altered expression of target molecules in the Wnt signaling pathway was demonstrated in the vast majority of the HNPCC-associated tumors, which support deranged Wnt-signaling as a central tumorigenic mechanism also in MMR defective colorectal cancer.
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| 7. |
- Joost, Patrick, et al.
(författare)
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Urinary Tract Cancer in Lynch Syndrome; Increased Risk in Carriers of MSH2 Mutations.
- 2015
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Ingår i: Urology. - : Elsevier BV. - 1527-9995 .- 0090-4295. ; 86:6, s. 1212-1217
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate the risk of urothelial cancer in the upper urinary tract and the bladder, determine the contribution from the different mismatch-repair genes and define clinical characteristics of urothelial cancer in Lynch syndrome.
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| 8. |
- Lindberg, Lars J., et al.
(författare)
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Risk of multiple colorectal cancer development depends on age and subgroup in individuals with hereditary predisposition
- 2019
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Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 18:2, s. 183-191
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Tidskriftsartikel (refereegranskat)abstract
- Development of multiple colorectal cancers (CRCs), synchronously or metachronously, is associated with hereditary predisposition for cancer and accurate risk estimates of multiple tumour development are relevant to recommend rational surveillance programs. A cross-sectional study design was used to estimate the risks of synchronous CRC (SCRC) and metachronous CRC (MCRC) based on data from the National Danish Hereditary Nonpolyposis Register. In total, 7100 individuals from families within the subgroups Lynch syndrome, familial CRC (FCC) and moderate risk were used with estimates relative to a non-hereditary population control cohort. SCRC was diagnosed in 7.4% of the Lynch syndrome cases, in 4.2% of FCC cases and 2.5% of the moderate risk cases, which translated to relative risks of 1.9–5.6. The risk of MCRC was distinctively linked to Lynch syndrome with a life-time risk up to 70% and an incidence rate ratio of 5.0. The risk of SCRC was significantly increased in all subgroups of FCC and hereditary CRC, whereas the risk of MCRC was specifically linked to Lynch syndrome. These observations suggest that individuals with FCC or hereditary CRC should be carefully screened for second primary CRC at the time of diagnosis, whereas intensified surveillance for second primary CRC is motivated in Lynch syndrome with lower-intensity programs in families with yet unidentified genetic causes.
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| 9. |
- Nielsen, Henriette Roed, et al.
(författare)
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BRCA1/BRCA2 founder mutations and cancer risks: impact in the western Danish population.
- 2016
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Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 15:4, s. 507-512
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the BRCA1 and BRCA2 genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We used a western Danish clinic-based cohort of 299 BRCA families to study the female cancer risk in mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In BRCA1, the cumulative cancer risk at age 70 was 35 % for breast cancer and 29 % for ovarian cancer. In BRCA2, the cumulative risk was 44 % for breast cancer and 15 % for ovarian cancer. We identified 47 distinct BRCA1 mutations and 48 distinct mutations in BRCA2. Among these, 8 founder mutations [BRCA1 c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and BRCA2 c.6373delA, c.7008-1G>A, c.7617+1G>A and c.8474delC] were found to account for 23 % of the BRCA1 mutations and for 32 % of the BRCA2 mutations. The BRCA1 mutation c.3319G>T was, compared to other BRCA1 mutations, associated with a higher risk for ovarian cancer. In conclusion, founder mutations in BRCA1 and BRCA2 contribute to up to one-third of the families in western Denmark and among these the BRCA1 c.3319G>T mutation is potentially linked to an increased risk of ovarian cancer.
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| 10. |
- Nilbert, Mef, et al.
(författare)
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Sarcomas associated with hereditary nonpolyposis colorectal cancer: broad anatomical and morphological spectrum
- 2009
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Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 8:3, s. 209-213
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary nonpolyposis colorectal cancer (HNPCC) is primarily linked to colorectal and endometrial cancer, but is associated with a broad tumor spectrum. Though not formally part of the syndrome, occasional sarcomas have been reported in individuals with HNPCC. We used the national Danish HNPCC-register to identify HNPCC families in which sarcomas had been diagnosed. Fourteen sarcomas were identified in families with mutations in MSH2, MSH6, and MLH1. The median age at sarcoma diagnosis was 43 (15-74) years. Soft tissue sarcomas predominated followed by uterine sarcomas and eight histopathological subtypes were represented with recurrent diagnoses of liposarcoma, leiomyosarcoma, and carcinosarcoma. Tumor tissue from eight cases was available for analysis of mismatch-repair (MMR) status using immunohistochemical staining and analysis of microsatellite instability, which revealed MMR defects in six of the eight tumors investigated. This suggests that sarcomas may be part of the HNPCC tumor spectrum and that colorectal cancer should be considered in the family history of sarcoma patients.
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| 11. |
- Rasmussen, Maria, et al.
(författare)
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Lynch syndrome-associated epithelial ovarian cancer and its immunological profile
- 2021
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258. ; 162:3, s. 686-693
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Lynch syndrome is a multi-tumor syndrome characterized by mismatch repair deficiency (MMR-d), microsatellite instability (MSI), and increased tumor-infiltrating lymphocytes (TILs) making these tumors candidates for treatment with immune checkpoint inhibitors. However, response may depend on tumor-induced immune evasion mechanisms, e.g. loss of Beta-2-Microglobulin (B2M) or upregulation of programmed death protein ligand 1 (PD-L1). We investigated the immune response and B2M and PD-L1 expression in Lynch syndrome-associated ovarian cancers. Methods: We successfully analyzed 30 Lynch syndrome-associated epithelial ovarian cancers collected through the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) register. MMR-d, MSI, immune response (CD3, CD8, and CD68), and immune evasion mechanisms (B2M and PD-L1) were investigated. Statistical associations between these markers were evaluated in addition to survival in relation to B2M/PD-L1. Results: Of the 29 evaluable tumors, 27 were MMR-d (93.1%). Likewise of 26 evaluable tumors, 14 were MSI (53.8%). MMR-d/MMR-proficiency associated with MSI/MSS in 60.0%. Half of the ovarian tumors presented with high levels of TILs. Loss of B2M expression was observed in 46.7% of the tumors, while expression of PD-L1 was seen in 28.0% of the cases. There was no association between B2M/PD-L1 and MSI/TILs/survival. Loss of B2M was often seen in tumors with low TILs (p = 0.056 or p = 0.059 for CD3 and CD8 positive cells, respectively). Conclusion: MMR-d, MSI, and TILs are also seen in Lynch syndrome-associated ovarian cancers making these potential candidates for checkpoint-based immunotherapy. The clinical impact from immune evasion through loss of B2M needs to be investigated further in larger cohorts.
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| 12. |
- Rasmussen, Maria, et al.
(författare)
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Mismatch repair deficiency testing in Lynch syndrome-associated urothelial tumors
- 2023
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Ingår i: Frontiers in Oncology. - 2234-943X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Lynch syndrome-associated cancer develops due to germline pathogenic variants in one of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 or PMS2. Somatic second hits in tumors cause MMR deficiency, testing for which is used to screen for Lynch syndrome in colorectal cancer and to guide selection for immunotherapy. Both MMR protein immunohistochemistry and microsatellite instability (MSI) analysis can be used. However, concordance between methods can vary for different tumor types. Therefore, we aimed to compare methods of MMR deficiency testing in Lynch syndrome-associated urothelial cancers. Methods: Ninety-seven urothelial (61 upper tract and 28 bladder) tumors diagnosed from 1980 to 2017 in carriers of Lynch syndrome-associated pathogenic MMR variants and their first-degree relatives (FDR) were analyzed by MMR protein immunohistochemistry, the MSI Analysis System v1.2 (Promega), and an amplicon sequencing-based MSI assay. Two sets of MSI markers were used in sequencing-based MSI analysis: a panel of 24 and 54 markers developed for colorectal cancer and blood MSI analysis, respectively. Results: Among the 97 urothelial tumors, 86 (88.7%) showed immunohistochemical MMR loss and 68 were successfully analyzed by the Promega MSI assay, of which 48 (70.6%) were MSI-high and 20 (29.4%) were MSI-low/microsatellite stable. Seventy-two samples had sufficient DNA for the sequencing-based MSI assay, of which 55 (76.4%) and 61 (84.7%) scored as MSI-high using the 24-marker and 54-marker panels, respectively. The concordance between the MSI assays and immunohistochemistry was 70.6% (p = 0.003), 87.5% (p = 0.039), and 90.3% (p = 1.00) for the Promega assay, the 24-marker assay, and the 54-marker assay, respectively. Of the 11 tumors with retained MMR protein expression, four were MSI-low/MSI-high or MSI-high by the Promega assay or one of the sequencing-based assays. Conclusion: Our results show that Lynch syndrome-associated urothelial cancers frequently had loss of MMR protein expression. The Promega MSI assay was significantly less sensitive, but the 54-marker sequencing-based MSI analysis showed no significant difference compared to immunohistochemistry. Data from this study alongside previous studies, suggest that universal MMR deficiency testing of newly diagnosed urothelial cancers, using immunohistochemistry and/or sequencing-based MSI analysis of sensitive markers, offer a potentially useful approach to identification of Lynch syndrome cases.
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| 13. |
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| 14. |
- Therkildsen, Christina, et al.
(författare)
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Broadening risk profile in familial colorectal cancer type X; Increased risk for five cancer types in the national Danish cohort
- 2020
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Familial colorectal cancer type X (FCCTX) is a phenotypically defined subset of hereditary colorectal cancer with unknown and potentially heterogeneous genetic aetiology. FCCTX has been characterized as a colorectal cancer-specific syndrome, which we herein challenge by estimating the risk for extra-colorectal cancer in the Danish FCCTX cohort. Methods: Through the national hereditary non-polyposis colorectal cancer (HNPCC) register, 213 families fulfilling the Amsterdam I criteria and showing retained mismatch repair (MMR) function were identified. In here, sex and age-specific incidence rate ratios (IRR) were calculated for 30 extra-colorectal cancer types in comparison with the general Danish population. Results: In total, 494 extra-colorectal cancers developed with significantly increased risks for cancers of the urinary tract, breast, stomach, pancreas, and eye tumours. The age groups at increased risks were 30-49 years for gastric cancer, 30-69 years for female breast cancer, 50-69 years for ocular melanoma and above age 70 for pancreatic cancer and urothelial cancer. Conclusions: Danish FCCTX families show an increased risk of several extra-colorectal cancer types. This observation may indicate unidentified disease-predisposing genetic variants in this phenotypically defined subset of hereditary colorectal cancer and calls for awareness during genetic counselling and follow-up.
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| 15. |
- Therkildsen, Christina, et al.
(författare)
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Cancer risks and immunohistochemical profiles linked to the Danish MLH1 Lynch syndrome founder mutation
- 2012
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Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 11:4, s. 579-585
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Tidskriftsartikel (refereegranskat)abstract
- Founder mutations with a large impact in distinct populations have been described in Lynch syndrome. In Denmark, the MLH1 c.1667+2_1667_+8TAAATCAdelinsATTT mutation accounts for 25 % of the MLH1 mutant families. We used the national Danish hereditary nonpolyposis colorectal cancer register to estimate the cumulative lifetime risks for Lynch syndrome-associated cancer in 16 founder mutation families with comparison to 47 other MLH1 mutant families. The founder mutation conferred comparable risks for colorectal cancer (relative risks, RR, of 0.99 for males and 0.79 for females) and lower risks for extracolonic cancer (RR of 0.69 for endometrial cancer and 0.39 for all other extracolonic cancers). We also characterized expression of key Wnt-signaling proteins in colorectal cancers with the founder mutation. Aberrant staining affected beta-catenin in 59 %, E-cadherin in 68 %, TCF-4 in 94 % and Cyclin D1 in 68 % with extensive inter-tumor variability despite the same underlying germline mutation. In conclusion, the Danish MLH1 founder mutation that accounts for a significant proportion of Lynch syndrome and is associated with a lower risk for extracolonic cancers.
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| 16. |
- Therkildsen, Christina, et al.
(författare)
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Gain of chromosomal region 20q and loss of 18 discriminates between Lynch syndrome and familial colorectal cancer
- 2013
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 49:6, s. 1226-1235
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Tidskriftsartikel (refereegranskat)abstract
- Lynch syndrome and familial colorectal cancer type X, FCCTX, represent the two predominant colorectal cancer syndromes. Whereas Lynch syndrome is clinically and genetically well defined, the genetic cause of FCCTX is unknown and genomic differences between Lynch syndrome and FCCTX tumours are largely unknown. We applied array-based comparative genomic hybridisation to 23 colorectal cancers from FCCTX with comparison to 23 Lynch syndrome tumours and to 45 sporadic colorectal cancers. FCCTX tumours showed genomic complexity with frequent gains on chromosomes 20q, 19 and 17 and losses of 18, 8p and 15. Gain of genetic material in two separate regions encompassing, 20q12-13.12 and 20q13.2-13.32, was identified in 65% of the FCCTX tumours. Gain of material on chromosome 20q and loss on chromosome 18 significantly discriminated colorectal cancers associated with FCCTX from Lynch syndrome, which likely signifies different preferred tumourigenic pathways. (C) 2012 Elsevier Ltd. All rights reserved.
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| 17. |
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| 18. |
- Therkildsen, Christina, et al.
(författare)
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Molecular subtype classification of urothelial carcinoma in Lynch syndrome
- 2018
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 12:8, s. 1286-1295
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Tidskriftsartikel (refereegranskat)abstract
- Lynch syndrome confers an increased risk for urothelial carcinoma (UC). Molecular subtypes may be relevant to prognosis and therapeutic possibilities, but have to date not been defined in Lynch syndrome-associated urothelial cancer. We aimed to provide a molecular description of Lynch syndrome-associated UC. Thus, Lynch syndrome-associated UCs of the upper urinary tract and the urinary bladder were identified in the Danish hereditary nonpolyposis colorectal cancer (HNPCC) register and were transcriptionally and immunohistochemically profiled and further related to data from 307 sporadic urothelial carcinomas. Whole-genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A (p16) of 37 tumors from patients with Lynch syndrome were generated. Pathological data, microsatellite instability, anatomic location, and overall survival data were analyzed and compared with sporadic bladder cancer. The 41 Lynch syndrome-associated UC developed at a mean age of 61 years with 59% women. mRNA expression profiling and immunostaining classified the majority of the Lynch syndrome-associated UC as urothelial-like tumors with only 20% being genomically unstable, basal/SCC-like, or other subtypes. The subtypes were associated with stage, grade, and microsatellite instability. Comparison to larger datasets revealed that Lynch syndrome-associated UC shares molecular similarities with sporadic UC. In conclusion, transcriptomic and immunohistochemical profiling identifies a predominance of the urothelial-like molecular subtype in Lynch syndrome and reveals that the molecular subtypes of sporadic bladder cancer are relevant also within this hereditary, mismatch-repair defective subset.
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| 19. |
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| 20. |
- Therkildsen, Christina, et al.
(författare)
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The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis
- 2014
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Ingår i: Acta Oncologica. - 1651-226X. ; 53:7, s. 852-864
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Forskningsöversikt (refereegranskat)abstract
- Background. In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways in colorectal cancer is uncertain, which led us to systematically review the impact of alterations in KRAS (outside of exon 2), NRAS, BRAF, PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment. Methods. In total, 22 studies that include 2395 patients formed the basis for a meta-analysis on alterations in KRAS exons 3 and 4, NRAS, BRAF, and PIK3CA and PTEN and outcome of anti-EGFR treatment. Odds ratios for objective response rate (ORR) and hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) were calculated. Results. Mutations in KRAS exons 3 and 4, BRAF, PIK3CA and non-functional PTEN (mutations or loss of protein expression) significantly predicted poor ORR (OR = 0.26, OR = 0.29, OR = 0.39, and OR = 0.41, respectively). Significantly shorter PFS applied to mutations in KRAS exons 3 and 4 (HR = 2.19), NRAS (HR = 2.30) and BRAF (HR = 2.95) and non-functional PTEN (HR = 1.88). Significantly shorter OS applied to mutations in KRAS exons 3 and 4 (HR = 1.78), NRAS (HR = 1.85), BRAF (HR = 2.52), PIK3CA (HR = 1.43) and alterations in PTEN (HR = 2.09). Conclusions. Meta-analysis suggests that mutations in KRAS exons 3 and 4, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in metastatic colorectal cancer.
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| 21. |
- Therkildsen, Christina, et al.
(författare)
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Towards gene-and gender-based risk estimates in Lynch syndrome; Age-specific incidences for 13 extra-colorectal cancer types
- 2017
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 117:11, s. 1702-1710
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Tidskriftsartikel (refereegranskat)abstract
- Background:In Lynch syndrome, inherited mismatch repair (MMR) defects predispose to colorectal cancer and to a wide spectrum of extra-colorectal tumours. Utilising a cohort study design, we aimed to determine the risk of extra-colorectal cancer and to identify yet unrecognised tumour types.Methods:Data from 1624 Lynch syndrome mutation carriers in the Danish hereditary non-polyposis colorectal cancer register were used to estimate the sex-and age-specific incidence rate ratios (IRRs) for 30 extra-colorectal malignancies with comparison to the general population.Results:Significantly increased IRRs were identified for 13 cancer types with differences related to gender, age and disease-predisposing gene. The different cancer types showed variable peak age incidence rates (IRs) with the highest IRs for ovarian cancer at age 30-49 years, for endometrial cancer, breast cancer, renal cell cancer and brain tumours at age 50-69 years, and for urothelial cancer, small bowel cancer, gastric cancer, pancreatic cancer and skin tumours after age 70.Conclusions:The broad spectrum of tumour types that develop at an increased incidence defines Lynch syndrome as a multi-tumour syndrome. The variable incidences in relation to age, gender and gene suggest a need for individualised surveillance.
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| 22. |
- Timshel, Susanne, et al.
(författare)
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An effect from anticipation also in hereditary nonpolyposis colorectal cancer families without identified mutations
- 2009
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Ingår i: Cancer Epidemiology. - : Elsevier BV. - 1877-7821. ; 33:3-4, s. 231-234
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Tidskriftsartikel (refereegranskat)abstract
- Optimal prevention of hereditary cancer is central and requires initiation of surveillance programmes and/or prophylactic measures at a safe age. Anticipation, expressed as an earlier age at onset in successive generations, has been demonstrated in hereditary nonpolyposis colorectal cancer (HNPCC). We specifically addressed anticipation in phenotypic HNPCC families without disease-predisposing mismatch repair (MMR) defects since risk estimates and age at onset are particularly difficult to determine in this cohort. The national Danish HNPCC register was used to identify families who fulfilled the Amsterdam criteria for HNPCC and showed normal MMR function and/or lack of disease-predisposing MMR gene mutation. In total, 319 cancers from 212 parent-child pairs in 99 families were identified. A paired t-test and a bivariate statistical model were used to assess anticipation. Both methods demonstrated an effect from anticipation with cancer diagnosed mean 11.4 years (t-test, p < 0.0001) and mean 5.9 (bivariate model, p = 0.02) years earlier in children than in parents. This observation suggests that anticipation may apply also to families without identified mutations and serves as a reminder to initiate surveillance programmes at young age also in HNPCC families with undefined genetic causes. (C) 2009 Elsevier Ltd. All rights reserved.
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| 23. |
- Walkowska, Joanna, et al.
(författare)
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Immunoprofiles of colorectal cancer from Lynch syndrome
- 2019
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Ingår i: OncoImmunology. - 2162-4011. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors. Lynch syndrome-associated tumors showed an overrepresentation of tumor-infiltrating CD3, CD8 and CD68 positive cells, loss of beta-2-microglobulin (B2M) and up-regulation of PD-L1 on tumor cells. The gene expression signature of Lynch syndrome tumors was characterized by upregulation of genes related to antigen processing and presentation, apoptosis, natural killer cell-mediated cytotoxicity, and T cell activation. Tumors with loss of B2M and up-regulation of PD-L1 showed distinctive immunogenic profiles. In summary, our data demonstrate a complex tumor-host interplay where B2M loss and PD-L1 up-regulation influence immunological pathways and clinical outcome in Lynch syndrome tumors. Immunological classification may thus aid in the preselection of colorectal cancers relevant for treatment with anti-PD-1/PD-L1 therapies.
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