| 1. |
- Carneiro, Ana, et al.
(författare)
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Prognostic impact of array-based genomic profiles in esophageal squamous cell cancer
- 2008
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 8:98
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Tidskriftsartikel (refereegranskat)abstract
- Background: Esophageal squamous cell carcinoma (ESCC) is a genetically complex tumor type and a major cause of cancer related mortality. Although distinct genetic alterations have been linked to ESCC development and prognosis, the genetic alterations have not gained clinical applicability. We applied array-based comparative genomic hybridization (aCGH) to obtain a whole genome copy number profile relevant for identifying deranged pathways and clinically applicable markers. Methods: A 32 k aCGH platform was used for high resolution mapping of copy number changes in 30 stage I-IV ESCC. Potential interdependent alterations and deranged pathways were identified and copy number changes were correlated to stage, differentiation and survival. Results: Copy number alterations affected median 19% of the genome and included recurrent gains of chromosome regions 5p, 7p, 7q, 8q, 10q, 11q, 12p, 14q, 16p, 17p, 19p, 19q, and 20q and losses of 3p, 5q, 8p, 9p and 11q. High-level amplifications were observed in 30 regions and recurrently involved 7p11 (EGFR), 11q13 (MYEOV, CCND1, FGF4, FGF3, PPFIA, FAD, TMEM16A, CTTS and SHANK2) and 11q22 (PDFG). Gain of 7p22.3 predicted nodal metastases and gains of 1p36.32 and 19p13.3 independently predicted poor survival in multivariate analysis. Conclusion: aCGH profiling verified genetic complexity in ESCC and herein identified imbalances of multiple central tumorigenic pathways. Distinct gains correlate with clinicopathological variables and independently predict survival, suggesting clinical applicability of genomic profiling in ESCC.
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| 2. |
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| 3. |
- Halvarsson, Britta, et al.
(författare)
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Clinicopathologic factors identify sporadic mismatch repair-defective colon cancers.
- 2008
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Ingår i: American Journal of Clinical Pathology. - 1943-7722. ; 129:2, s. 238-244
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Tidskriftsartikel (refereegranskat)abstract
- Identification of sporadic mismatch repair (MMR)-defective colon cancers is increasingly demanded for decisions on adjuvant therapies. We evaluated clinicopathologic factors for the identification of these prognostically favorable tumors. Histopathologic features in 238 consecutive colon cancers were linked to MMR status based on immunostaining and BRAF mutation status.MMR defects were identified in 22.7% of the tumors, with 46 classified as sporadic. When the clinical parameters of age, sex, and proximal tumor location were combined with the morphologic features with the highest relative risks (RRs), eg, mucinous differentiation (RR, 9.0), tumor-infiltrating lymphocytes (RR, 7.5), absence of necrosis (RR, 7.5), and expanding growth pattern (RR, 5.0) into a 7-factor index, the presence of at least 4 features identified the MMR-defective tumors with 92.3% sensitivity and 75.3% specificity and excluded 61.5% of the tumors from MMR testing. This clinicopathologic index thus successfully selects MMR-defective colon cancers.
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| 4. |
- Halvarsson, Britta, et al.
(författare)
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Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer.
- 2005
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Ingår i: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 18:8, s. 1095-1101
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal adenomas occur at younger age, at increased frequency and have a greater tendency for malignant transformation in patients with hereditary nonpolyposis colorectal cancer (HNPCC). We performed immunostaining for the mismatch repair proteins MLH1, PMS2, MSH2 and MSH6 in 35 colorectal adenomas from 26 patients with HNPCC and identified loss of immunostaining in 23/35 (0.66) adenomas. Loss of mismatch repair protein immunostaining was particularly frequent in large (>5 mm) (14/16) and proximally located (13/15) adenomas, whereas the gene mutated - MLH1 or MSH2 - and the type of mutation did not seem to affect the results. We conclude that loss of mismatch repair protein immunostaining is detected at a lower rate in adenomas than in carcinomas associated with HNPCC. Adenomatous tissue can thus be used for immunostaining of mismatch repair proteins in clinical investigations of HNPCC, but whereas loss of immunostaining may pinpoint the gene affected and thereby guide mutation analysis, retained staining cannot exclude that the adenoma developed as part of the syndrome due to reduced sensitivity. However, the analysis has a greater chance of being informative if large and proximally located adenomas are selected.
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| 5. |
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| 6. |
- Halvarsson, Britta
(författare)
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Morphological Features and Mismatch Repair in Colorectal Tumors
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Corlorectal cancer affects 5% of individuals in the Western world and heredity is estimated to cause at least 10% of the tumors. Defective mismatch repair (MMR) is a tumorigenic mechanism through which about 15% of colorectal cancer develops and this feature characterizes tumors associated with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome. The underlying molecular mechanism in HNPCC is a germline mutation in one of the MMR genes MLH1, PMS2, MSH2 or MSH6 and these tumors are characterized by microsatellite instability (MSI) and loss of immunostaining for the affected MMR protein. The aims of these thesis were to investigate the use of immunostaining for the identification of MMR defective adenocarcinomas (studies I-II) and adenomas (study III), to assess morphologic heterogeneity in tumors caused by the same underlying germline mutation (study IV), and to evaluate whether morphology can be used to identify MMR defective tumors (study V). In study I immunostaining for MLH1, MSH2 and MSH6 identified MMR defects with a sensitivity of 92% and a specificity of 100%. When PMS2 immunostaining was added in study II the sensitivity raised to >95%. Hence, MMR protein immunostaining reliably pinpoints the mutated gene and thereby facilitates mutation analysis. I study III, HNPCC-associated adenomas were studied and immunostaining identified MMR defects with a sensitivity of 66%, although higher frequencies were found in larger and proximally located adenomas. Study IV assessed morphological heterogeneity in tumors from two HNPCC-families and demonstrated extensive variability in tumors from the same individual as well as from the same family. This indicates that other mechanisms than the underlying germline mutation influence the tumor phenotype. In study V, 238 tumors were morphologically characterized with specific focus on features associated with MMR defective tumors. Overall, a MMR defective phenotype was identified in 23% of the tumors. A proximal tumor location, an expanding growth pattern, poor differentiation, absence of necrosis, a Crohn's like reaction, peritumoral lymphocytes, and tumor-infiltrating lymphocytes were significantly more often found in the MMR defective tumors and an index combinding these features was constructed for the identification of tumors that develop through defective MMR.
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| 7. |
- Halvarsson, Britta, et al.
(författare)
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Phenotypic heterogeneity in hereditary nonpolyposis colorectal cancer: identical germline mutations associated with variable tumor morphology and immunohistochemical expression.
- 2007
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 60:7, s. 781-786
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is associated with high risks for colorectal and endometrial cancer, young age at onset and an increased risk of multiple primary tumours. Colorectal cancer in HNPCC is characterised by poor tumour differentiation, an expanding growth pattern, and a pronounced lymphocytic reaction with tumour-infiltrating lymphocytes. Aims and METHODS: The mutation spectrum in HNPCC is diverse and in order to clarify whether the HNPCC tumour phenotype is influenced by the underlying genetic alteration, 29 colorectal cancers and 12 adenomas from 24 individuals in two HNPCC families were morphologically and immunohistochemically characterised. RESULTS: The tumour morphology as well as the immunohistochemical expression of beta-catenin varied extensively within the families as well as between synchronous/metachronous colorectal cancers from the same individual. Poor tumour differentiation, an expanding growth pattern, and tumour-infiltrating lymphocytes occurred at higher frequencies in proximal tumours, whereas distal colorectal cancers often lacked distinct HNPCC-associated morphological features. CONCLUSIONS: The clinical, morphological and immunohistochemical variability observed within these families indicates that other mechanisms than the underlying germline mutation influence the HNPCC phenotype. Since morphological features linked to HNPCC are less frequent in distal cancers, it may be particularly relevant to obtain family history and age of onset in these tumours in order to identify individuals with HNPCC.
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| 8. |
- Halvarsson, Britta, et al.
(författare)
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The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer.
- 2006
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Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 5:4, s. 353-358
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Tidskriftsartikel (refereegranskat)abstract
- dentification and characterization of the genetic background in patients with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is important since control programmes can in a cost-effective manner prevent cancer development in high-risk individuals. HNPCC is caused by germline mismatch repair (MMR) gene mutations and the genetic analysis of HNPCC therefore includes assessment of microsatellite instability (MSI) and immunohistochemical MMR protein expression in the tumor tissue. MSI is found in >95% of the HNPCC-associated tumors and immunostaining using antibodies against the MMR proteins MLH1, MSH2, and MSH6 has been found to correctly pinpoint the affected gene in about 90% of the cases. The PMS2 antibody was the most recently developed and we have in a clinical material assessed the added value of PMS2 immunostaining in 213 patients with suspected hereditary colorectal cancer. All 119 MSS tumors showed retained expression for all four antibodies and PMS2 did thus not identify any underlying MMR defect in these cases. However, PMS2 immunostaining contributed to the characterization of the MMR defect in a subset of the MSI tumors. Concomitant loss of MLH1 and PMS2, which functionally interact in the MutL alpha complex, was found in 98% of the tumors from patients with germline MLH1 mutations. Among the 12 MSI-high tumors with retained expression of MLH1, MSH2 and MSH6, 8 tumors showed loss of PMS2 staining, and mutations in MLH1 were identified in 2 and mutations in PMS2 in 3 of these individuals. In summary, isolated loss of PMS2 was found in 8% of the MSI-high tumors in our series, including 8/12 previously unexplained MSI-high tumors, in which mutations either in MLH1 or in PMS2 were identified in five cases.
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| 9. |
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| 10. |
- Ivarsson, Anneli, et al.
(författare)
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Prevalence of Childhood Celiac Disease and Changes in Infant Feeding
- 2013
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Ingår i: Pediatrics. - : American Academy of Pediatrics. - 0031-4005 .- 1098-4275. ; 131:3, s. E687-E694
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Between 1984 and 1996, Sweden experienced an "epidemic" of clinical celiac disease in children andlt;2 years of age, attributed partly to changes in infant feeding. Whether infant feeding affects disease occurrence and/or the clinical presentation remains unknown. We investigated and compared the total prevalence of celiac disease in 2 birth cohorts of 12-year-olds and related the findings to each cohorts ascertained infant feeding. less thanbrgreater than less thanbrgreater thanMETHODS: A 2-phase cross-sectional screening study was performed in which 13 279 children from 2 birth cohorts participated: children born during the epidemic (1993) and children born after the epidemic (1997). Previously diagnosed cases were reported and confirmed. Blood samples were analyzed for serological markers and children with positive values were referred for small intestinal biopsy. Infant feeding practices in the cohorts were ascertained via questionnaires. Prevalence comparisons were expressed as prevalence ratios. less thanbrgreater than less thanbrgreater thanRESULTS: The total prevalence of celiac disease was 29 in 1000 and 22 in 1000 for the 1993 and 1997 cohorts, respectively. Children born in 1997 had a significantly lower risk of having celiac disease compared with those born in 1993 (prevalence ratio: 0.75; 95% confidence interval: 0.60-0.93; P = .01). The cohorts differed in infant feeding (specifically, in the proportion of infants introduced to dietary gluten in small amounts during ongoing breastfeeding). less thanbrgreater than less thanbrgreater thanCONCLUSIONS: A significantly reduced prevalence of celiac disease in 12-year-olds indicates an option for disease prevention. Our findings suggest that the present infant feeding recommendation to gradually introduce gluten-containing foods from 4 months of age, preferably during ongoing breastfeeding, is favorable. Pediatrics 2013;131:e687-e694
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