Publications by authors named "Sarah Ariansen"

14 Publications

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BRCA1 Norway: comparison of classification for BRCA1 germline variants detected in families with suspected hereditary breast and ovarian cancer between different laboratories.

Fam Cancer 2022 Jan 4. Epub 2022 Jan 4.

Western Norway Familial Cancer Center, Haukeland University Hospital, Bergen, Norway.

Pathogenic germline variants in Breast cancer susceptibility gene 1 (BRCA1) predispose carriers to hereditary breast and ovarian cancer (HBOC). Through genetic testing of patients with suspected HBOC an increasing number of novel BRCA1 variants are discovered. This creates a growing need to determine the clinical significance of these variants through correct classification (class 1-5) according to established guidelines. Here we present a joint collection of all BRCA1 variants of class 2-5 detected in the four diagnostic genetic laboratories in Norway. The overall objective of the study was to generate an overview of all BRCA1 variants in Norway and unveil potential discrepancies in variant interpretation between the hospitals, serving as a quality control at the national level. For a subset of variants, we also assessed the change in classification over a ten-year period with increasing information available. In total, 463 unique BRCA1 variants were detected. Of the 126 variants found in more than one hospital, 70% were interpreted identically, while 30% were not. The differences in interpretation were mainly by one class (class 2/3 or 4/5), except for one larger discrepancy (class 3/5) which could affect the clinical management of patients. After a series of digital meetings between the participating laboratories to disclose the cause of disagreement for all conflicting variants, the discrepancy rate was reduced to 10%. This illustrates that variant interpretation needs to be updated regularly, and that data sharing and improved national inter-laboratory collaboration greatly improves the variant classification and hence increases the accuracy of cancer risk assessment.
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http://dx.doi.org/10.1007/s10689-021-00286-6DOI Listing
January 2022

The intronic BRCA1 c.5407-25T>A variant causing partly skipping of exon 23-a likely pathogenic variant with reduced penetrance?

Eur J Hum Genet 2020 08 20;28(8):1078-1086. Epub 2020 Mar 20.

Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.

Rare sequence variants in the non-coding part of the BRCA genes are often reported as variants of uncertain significance (VUS), which leave patients and doctors in a challenging position. The aim of this study was to determine the pathogenicity of the BRCA1 c.5407-25T>A variant found in 20 families from Norway, France and United States with suspected hereditary breast and ovarian cancer. This was done by combining clinical and family information with allele frequency data, and assessment of the variant's effect on mRNA splicing. Mean age at breast (n = 12) and ovarian (n = 11) cancer diagnosis in female carriers was 49.9 and 60.4 years, respectively. The mean Manchester score in the 20 families was 16.4. The allele frequency of BRCA1 c.5407-25T>A was 1/64,566 in non-Finnish Europeans (gnomAD database v2.1.1). We found the variant in 1/400 anonymous Norwegian blood donors and 0/784 in-house exomes. Sequencing of patient-derived cDNA from blood, normal breast and ovarian tissue showed that BRCA1 c.5407-25T>A leads to skipping of exon 23, resulting in frameshift and protein truncation: p.(Gly1803GlnfsTer11). Western blot analysis of transiently expressed BRCA1 proteins in HeLa cells showed a reduced amount of the truncated protein compared with wild type. Noteworthily, we found that a small amount of full-length transcript was also generated from the c.5407-25T>A allele, potentially explaining the intermediate cancer burden in families carrying this variant. In summary, our results show that BRCA1 c.5407-25T>A leads to partial skipping of exon 23, and could represent a likely pathogenic variant with reduced penetrance.
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http://dx.doi.org/10.1038/s41431-020-0612-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382492PMC
August 2020

Diagnostic mRNA splicing assay for variants in and identified two novel pathogenic splicing aberrations.

Hered Cancer Clin Pract 2019 22;17:14. Epub 2019 May 22.

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

Background: Pathogenic variants in and cause hereditary breast and ovarian cancer. Screening of these genes has become easily accessible in diagnostic laboratories. Sequencing and copy number analyses are used to detect pathogenic variants, but also lead to identification of variants of unknown clinical significance (VUS). If the effect of a VUS can be clarified, it has direct consequence for the clinical management of the patient and family members. A splicing assay is one of several tools that might help in the classification of VUS. We therefore established mRNA analyses for and in the diagnostic laboratory in 2015. We hereby report the results of mRNA analysis variants in and after three years.

Methods: Variants predicted to alter splicing and variants within the canonical splice sites were selected for splicing analyses. Splicing assays were performed by reverse transcription-PCR of patient RNA. A biallalic expression analysis was carried out whenever possible.

Results: Twenty-five variants in and were analyzed by splicing assays; nine showed altered transcripts and 16 showed normal splicing patterns. The two novel pathogenic variants in c.4484 + 3 A > C and c.5407-10G > A were characterized.

Conclusions: We conclude that mRNA analyses are useful in characterization of variants that may affect splicing. The results can guide classification of variants from unknown clinical significance to pathogenic or benign in a diagnostic laboratory, and thus be of direct clinical importance.
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http://dx.doi.org/10.1186/s13053-019-0113-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532242PMC
May 2019

Trans-activation-based risk assessment of BRCA1 BRCT variants with unknown clinical significance.

Hum Genomics 2018 11 20;12(1):51. Epub 2018 Nov 20.

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

Background: Deleterious variants in the tumour suppressor BRCA1 are known to cause hereditary breast and ovarian cancer syndrome (HBOC). Missense variants in BRCA1 pose a challenge in clinical care, as their effect on protein functionality often remains unknown. Many of the pathogenic missense variants found in BRCA1 are located in the BRCA1 C-terminal (BRCT) domains, domains that are known to be vital for key functions such as homologous recombination repair, protein-protein interactions and trans-activation (TA). We investigated the TA activity of 12 BRCA1 variants of unknown clinical significance (VUSs) located in the BRCT domains to aid in the classification of these variants.

Results: Twelve BRCA1 VUSs were investigated using a modified version of the dual luciferase TA activity assay (TA assay) that yielded increased sensitivity and sample throughput. Variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria using TA assay results and available data. In combining our TA-assay results and available data, in accordance with the ACMG guidelines for variant classification, we proposed the following variant classifications: c.5100A>G, c.5326C>T, c.5348T>C and c.5477A>T as likely benign (class 2) variants. c.5075A>C, c.5116G>A and c.5513T>G were likely pathogenic (class 4), whereas c.5096G>A likely represents a likely pathogenic variant with moderate penetrance. Variants c.5123C>T, c.5125G>A, c.5131A>C and c.5504G>A remained classified as VUSs (class 3).

Conclusions: The modified TA assay provides efficient risk assessment of rare missense variants found in the BRCA1 BRCT-domains. We also report that increased post-transfection incubation time yielded a significant increase in TA assay sensitivity.
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http://dx.doi.org/10.1186/s40246-018-0183-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247502PMC
November 2018

mutation carrier detection. A model-based cost-effectiveness analysis comparing the traditional family history approach and the testing of all patients with breast cancer.

ESMO Open 2018 13;3(3):e000328. Epub 2018 Apr 13.

Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.

Background: Identification of mutation carriers among patients with breast cancer (BC) involves costs and gains. Testing has been performed according to international guidelines, focusing on family history (FH) of breast and/or ovarian cancer. An alternative is testing all patients with BC employing sequencing of the genes and Multiplex Ligation Probe Amplification (MLPA).

Patients And Methods: A model-based cost-effectiveness analysis, employing data from Oslo University Hospital, Ullevål (OUH-U) and a decision tree, was done. The societal and the healthcare perspectives were focused and a lifetime perspective employed. The comparators were the traditional FH approach used as standard of care at OUH-U in 2013 and the intervention (testing all patients with BC) performed in 2014 and 2015 at the same hospital. During the latter period, 535 patients with BC were offered testing with sequencing and MLPA. National 2014 data on mortality rates and costs were implemented, a 3% discount rate used and the costing year was 2015. The incremental cost-effectiveness ratio was calculated in euros (€) per life-year gained (LYG).

Results: The net healthcare cost (healthcare perspective) was €40 503/LYG. Including all resource use (societal perspective), the cost was €5669/LYG. The univariate sensitivity analysis documented the unit cost of the test and the number of LYGs the prominent parameters affecting the result.Diagnostic testing of all patients with BC was superior to the FH approach and cost-effective within the frequently used thresholds (healthcare perspective) in Norway (€60 000-€80 000/LYG).
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http://dx.doi.org/10.1136/esmoopen-2018-000328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905828PMC
April 2018

mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway.

Hered Cancer Clin Pract 2018 10;16. Epub 2018 Jan 10.

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

Background: Founder mutations in the two breast cancer genes, and , have been described in many populations, among these are Ashkenazi-Jewish, Polish, Norwegian and Icelandic. Founder mutation testing in patients with relevant ancestry has been a cost-efficient approach in such populations. Four Norwegian founder mutations were defined by haplotyping in 2001, and accounted for 68% of mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both and in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the carrier population of the largest clinic of hereditary cancer in Norway.

Methods: A total of 2430 carriers from 669 different families, and 1092 carriers from 312 different families were included in a quality of care study. All variants were evaluated regarding pathogenicity following ACMG/ENIGMA criteria. The variants were assessed in AlaMut and supplementary databases to determine whether they were known to be founder mutations in other populations.

Results: There were 120 different and 87 different variants among the mutation carriers. Forty-six per cent of the registered families (454/981) had a previously reported Norwegian founder mutation. The majority of mutations (71%) were rare, each found in only one or two families. Fifteen per cent of families and 25% of families had one of these rare variants. The four well-known Norwegian founder mutations previously confirmed through haplotyping were still the four most frequent mutations in carriers, but the proportion of mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described.

Conclusions: The spectrum of and mutations in the carrier population at Norway's largest cancer genetics clinic is diverse, and with a weaker founder effect than previously described. As a consequence, retesting the families that previously have been tested with specific tests/founder mutation tests should be a prioritised strategy to find more mutation positive families and possibly prevent cancer in healthy relatives.
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http://dx.doi.org/10.1186/s13053-017-0085-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761139PMC
January 2018

Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers.

BMC Cancer 2017 Jun 21;17(1):438. Epub 2017 Jun 21.

Section for Breast- and Endocrine Surgery, Department of Cancer, Oslo University Hospital, Oslo, Norway.

Background: Identification of BRCA mutations in breast cancer (BC) patients influences treatment and survival and may be of importance for their relatives. Testing is often restricted to women fulfilling high-risk criteria. However, there is limited knowledge of the sensitivity of such a strategy, and of the clinical aspects of BC caused by BRCA mutations in less selected BC cohorts. The aim of this report was to address these issues by evaluating the results of BRCA testing of BC patients in South-Eastern Norway.

Methods: 1371 newly diagnosed BC patients were tested with sequencing and Multi Ligation Probe Amplification (MLPA). Prevalence of mutations was calculated, and BC characteristics among carriers and non-carriers compared. Sensitivity and specificity of common guidelines for BRCA testing to identify carriers was analyzed. Number of identified female mutation positive relatives was evaluated.

Results: A pathogenic BRCA mutation was identified in 3.1%. Carriers differed from non-carriers in terms of age at diagnosis, family history, grade, ER/PR-status, triple negativity (TNBC) and Ki67, but not in HER2 and TNM status. One mutation positive female relative was identified per mutation positive BC patient. Using age of onset below 40 or TNBC as criteria for testing identified 32-34% of carriers. Common guidelines for testing identified 45-90%, and testing all below 60 years identified 90%. Thirty-seven percent of carriers had a family history of cancer that would have qualified for predictive BRCA testing. A Variant of Uncertain Significance (VUS) was identified in 4.9%.

Conclusions: Mutation positive BC patients differed as a group from mutation negative. However, the commonly used guidelines for testing were insufficient to detect all mutation carriers in the BC cohort. Thirty-seven percent had a family history of cancer that would have qualified for predictive testing before they were diagnosed with BC. Based on our combined observations, we suggest it is time to discuss whether all BC patients should be offered BRCA testing, both to optimize treatment and improve survival for these women, but also to enable identification of healthy mutation carriers within their families. Health services need to be aware of referral possibility for healthy women with cancer in their family.
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http://dx.doi.org/10.1186/s12885-017-3422-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480128PMC
June 2017

[Mutation testing for non-small-cell lung cancer].

Tidsskr Nor Laegeforen 2012 Apr;132(8):952-5

Avdeling for kreftbehandling, Oslo universitetssykehus, Radiumhospitalet, Norway.

Background: Epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) are a relatively new class of drugs for treatment of non-small-cell lung cancer. The national professional group for lung cancer, The Norwegian Lung Cancer Group, recommends that patients with non-small-cell lung cancer are tested for mutations in the EGFR gene. Here, we report the experience collected after the introduction of such testing in Norway in 2010.

Material And Method: Information on the number of patients tested, gender distribution, histopathological data and analysis results have been collected from the molecular-pathology laboratories at the university hospitals in Tromsø, Trondheim, Bergen and Oslo for the period from May 2010 to May 2011.

Results: During this period, altogether 1,058 patients with lung cancer were tested for mutations in the EGFR gene, equal to approximately half of all those who were diagnosed with non-small-cell lung cancer. A mutation was detected in 123 patients (11.6 per cent). There was a higher proportion of mutation-positive women than men (17.6 per cent, compared to 6.3 per cent, p < 0.001), and a lower proportion with squamous cell carcinoma than for other histopathological subtypes (3.0 per cent, compared to 12.9 per cent, p < 0.001). Of a total of 80 cytological tests, nine (11.3 per cent) were positive.

Interpretation: In light of the relatively high mutation frequency and a considerable number of positives in the group with squamous cell carcinoma, we recommend to continue the practice of mutation-testing all patients with non-small-cell lung cancer.
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http://dx.doi.org/10.4045/tidsskr.11.1017DOI Listing
April 2012

EGFR gene alterations in a Norwegian cohort of lung cancer patients selected for surgery.

J Thorac Oncol 2011 May;6(5):947-50

Department of Clinical Oncology, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.

Introduction: Lung cancer is the leading cause of cancer-related deaths worldwide. New therapies targeting the epidermal growth factor receptor (EGFR) tyrosine kinase are promising and show high response rates in the subset of patients with activating mutations in EGFR. The frequency of these mutations is largely unknown in unselected Caucasian patients.

Methods: Mutation analysis of EGFR exons 18-21 was performed on 240 lung cancer samples using the TheraScreen EGFR mutation kit and denaturing high-performance liquid chromatography in addition to sequencing.

Results: In a cohort of 240 Norwegian lung cancer patients selected for surgery, we identified 18 tumors with EGFR-activating mutations (7.5%, 14 women and 4 men), of which 14 were adenocarcinomas, 2 squamous cell carcinomas, and 2 bronchoalveolar carcinomas. Five of the mutations were found in patients with more than 20 pack-years of smoking history.

Conclusion: The frequency of EGFR mutations is lower in our cohort than among Asian lung cancer patients and present in both men and women and smokers and never-smokers. However, the frequency is significantly higher among women and never-smokers and among patients with adenocarcinomas.
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http://dx.doi.org/10.1097/JTO.0b013e31820db209DOI Listing
May 2011

Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers.

J Med Genet 2010 Sep 28;47(9):579-85. Epub 2010 Jun 28.

Department of Pathology and Medical Genetics, St Olavs University Hospital, Trondheim, Norway.

Background: Reported prevalence, penetrance and expression of deleterious mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, may reflect differences in the clinical criteria used to select families for DNA testing. The authors have previously reported that clinical criteria are not sensitive enough to identify MMR mutation carriers among incident colorectal cancer cases.

Objective: To describe the sensitivity of the criteria when applied to families with a demonstrated MMR mutation.

Methods: Families with an aggregation of colorectal cancers were examined for deleterious MMR mutations according to the Mallorca guidelines. All families with a detected MMR mutation as of November 2009 were reclassified according to the Amsterdam and Bethesda criteria.

Results: Sixty-nine different DNA variants were identified in a total of 129 families. The original Amsterdam clinical criteria were met by 38%, 12%, 78% and 25% of families with mutations in MSH2, MSH6, MLH1 and PMS2, respectively. Corresponding numbers for the revised Amsterdam criteria were 62%, 48%, 87% and 38%. Similarly, each of the four clinical Bethesda criteria had low sensitivity for identifying MSH6 or PMS2 mutations.

Conclusion: Amsterdam criteria and each of the Bethesda criteria were inadequate for identifying MSH6 mutation-carrying kindreds. MSH6 mutations may be more common than currently assumed, and the penetrance/expression of MSH6 mutations, as derived from families meeting current clinical criteria, may be misleading. To increase detection rate of MMR mutation carriers, all cancers in the Lynch syndrome tumour spectrum should be subjected to immunohistochemical analysis and/or analysis for microsatellite instability.
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http://dx.doi.org/10.1136/jmg.2010.077677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976029PMC
September 2010

APC mutation spectrum of Norwegian familial adenomatous polyposis families: high ratio of novel mutations.

J Cancer Res Clin Oncol 2009 Oct 15;135(10):1463-70. Epub 2009 May 15.

Pathology Division, University Hospital of Oslo-Rikshospitalet, N0027 Oslo, Norway.

Introduction: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disease caused by mutations in the adenomatous polyposis coli (APC) gene. Massive formation of colorectal adenomas, of which some will inevitably develop into adenocarcinomas, is the hallmark of the disease. Characterization of causative APC mutations allows presymptomatic diagnosis, close follow-up and prophylactic intervention in families. To date more than 900 different germline mutations have been characterized worldwide demonstrating allelic heterogeneity.

Purpose: The germline mutation spectrum of APC identified in 69 apparently unrelated Norwegian FAP families are presented and discussed with reference to clinical phenotype and novel mutation rate.

Methods: Different methods have been used over the years. However, all mutations were confirmed detectable by an implemented denaturing high-performance liquid chromatography screening approach. Multiplex ligation-dependent probe amplification analysis was employed for potential gross rearrangements.

Results: Fifty-three distinctive mutations were detected, of which 22 have been detected in Norway exclusively. Except for two major deletion mutations encompassing the entire APC, all mutations resulted in premature truncation of translation caused by non-sense (31%) or change in reading frame (69%).

Conclusion: A high ratio of novel APC mutations continues to contribute to APC mutation heterogeneity causing FAP. This is the first comprehensive report of APC germline mutation spectrum in Norway.
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http://dx.doi.org/10.1007/s00432-009-0594-4DOI Listing
October 2009

Do mitochondrial mutations cause recurrent miscarriage?

Mol Hum Reprod 2009 May 18;15(5):295-300. Epub 2009 Mar 18.

Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.

The cause of recurrent miscarriage (RM) can be identified in approximately 50% of cases, whereas in others, unknown genetic factors are actively being sought. As mitochondrial functions, and therefore also the mitochondrial genome [mitochondrial DNA (mtDNA)], have an important role in human development, through ATP production and participation in apoptosis, we aimed to study the role of mtDNA variations in RM. We screened 48 women with RM and 48 age-matched control women for heteroplasmic mitochondrial mutations using denaturing high performance liquid chromatography, a sensitive method that can detect approximately 5% heteroplasmy. As a result, we detected a heteroplasmic mtDNA variation in 13 RM women (27%) and in 9 control women (19%). Seven synonymous and five non-synonymous changes were detected within coding regions. In addition, seven heteroplasmic variations were detected within the non-coding control region. We were also able to show the presence of the variations in eight placental samples from three heteroplasmic women. In three of these cases, the proportion of variant mtDNA was higher in the placenta compared with that in the mother. We conclude that our sensitive methodology revealed a higher frequency of samples with heteroplasmic variations than expected in women with both RM and controls. However, no apparent increased frequency of heteroplasmic mtDNA variations or amounts of aberrant mtDNA was detected in the RM group. In addition, none of the detected variations were previously known to be pathogenic and therefore they are an unlikely cause of miscarriage.
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http://dx.doi.org/10.1093/molehr/gap021DOI Listing
May 2009

Population-based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas.

Genes Chromosomes Cancer 2008 Feb;47(2):175-84

Department of Dermatology, Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway.

The presence of multiple primary cutaneous melanomas (MPM) has been advocated as guidance to identifying melanoma families. Frequencies of CDKN2A mutations in materials of sporadic MPM cases from pigmented lesion clinics vary between 8 and 15%. Patients with MPM have therefore been regarded as good candidates for CDKN2A mutational screening. We describe a population-based study where all persons in Norway diagnosed with MPM between 1953 and 2004 (n = 738 alive per April 2004) were invited to participate. Three-hundred-and-ninety patients (52.8%) responded confidentially. Mutations in CDKN2A were found in 6.9% of the respondents. Eighty-one MPM patients (20.8%) reported that they belonged to melanoma families, and 17 (21.0%) of these harboured a CDKN2A mutation, compared to 3.2% of the nonfamilial cases. The probability of finding a CDKN2A mutation increased when the patients had three or more melanomas, or a young age of onset of first melanoma. We identified five novel CDKN2A variants (Ala57Gly, Pro81Arg, Ala118Val, Leu130Val, and Arg131Pro) and four that previously have been reported in melanoma families (Glu27X, Met53Ile, Arg87Trp, and Ala127Pro). A large deletion (g.13623_23772del10150) encompassing exon 1alpha and the 5' part of exon 2 was detected in six patients with a family history of melanoma. Three patients, belonging to the same family, had the CDK4 Arg24His mutation. The frequency of CDKN2A mutations was lower than previously reported in other studies, an observation which probably is due to the population-based design of our study.
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http://dx.doi.org/10.1002/gcc.20518DOI Listing
February 2008

Chromosomal 20q gain in the DNA diploid component of aneuploid colorectal carcinomas.

Int J Cancer 2007 Jun;120(12):2734-8

The Pathology Clinic, University of Oslo, Rikshospitalet-Radiumhospitalet Medical Center, 0027 Oslo, Norway.

The order of appearance of different genetic aberrations during the shift from diploidy/near-diploidy to aneuploidy in colorectal cancers is not yet clear. We studied genetic alterations in flow cytometrically-sorted DNA diploid and corresponding aneuploid epithelial cell populations from each of 20 colorectal tumors using comparative genomic hybridization, FISH, and PCR. Analysis of the 19 cases in which aberrations were found in the flow-sorted diploid population indicated that large-scale aneuploidization in colorectal cancer was preceded by amplification of oncogene(s) localized to chromosome 20q13.2 and by KRAS mutations, but not by TP53 deletions or losses of large chromosomal regions such as 4q, 8p and 18q.
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http://dx.doi.org/10.1002/ijc.22537DOI Listing
June 2007
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