• Adenocarcinoma of the prostate in Iceland: a population-based study of stage, Gleason grade, treatment and long-term survival in males diagnosed between 1983 and 1987

      Jonsson, E; Sigbjarnarson, H P; Tomasson, J; Benediktsdottir, K R; Tryggvadottir, L; Hrafnkelsson, J; Olafsdottir, E J; Tulinius, H; Jonasson, J G (Taylor & Francis, 2006-09-01)
      OBJECTIVE: To investigate adenocarcinoma of the prostate in a single population with an extended follow-up period. MATERIAL AND METHODS: Using the Icelandic Cancer Registry, we identified all Icelandic men diagnosed with prostate cancer between 1983 and 1987. Disease stage, initial treatment and follow-up information were obtained from hospital records and death certificates. A critical evaluation was made of the accuracy of the death certificates regarding prostate cancer. All available histology information was reviewed and graded according to the Gleason grading system. RESULTS: A total of 414 men were diagnosed with adenocarcinoma of the prostate. Of these, 370 were alive at the time of diagnosis and stage could be determined. Four stage groups were defined: focal incidental (n=50); localized (n=164); local advanced (n=32); and metastatic disease (n=124). The mean age at diagnosis was 74.4 years (range 53-94 years). The combined Gleason score was 2-5 in 89, 6-7 in 117, 8-10 in 117 and unknown in 47 cases. The median follow-up period for the group was 6.15 years (range 0.3-19.8 years). Thirty men received treatment with curative intent: radiation therapy, n=20; and radical prostatectomy, n=10. A total of 334 patients died during the follow-up period, of whom 168 (50%) died of prostate cancer. Prostate cancer-specific survival at 10 and 15 years was 100% and 90.6%, respectively for focal incidental cancer; 73.1% and 60.8% for men with localized disease; 23.4% and 11.7% for local advanced disease; and 6.81% and 5.45% for metastatic disease. A Cox multivariate analysis showed age, stage and Gleason score to be independent predictors of prostate cancer death. A total of 104 patients with localized disease and a Gleason score of
    • Altered expression of E-cadherin in breast cancer patterns, mechanisms and clinical significance

      Asgeirsson, K S; Jonasson, J G; Tryggvadottir, L; Olafsdóttir, K; Sigurgeirsdottir, J R; Ingvarsson, S; Ogmundsdóttir, H M; Molecular and Cell Biology Laboratory, Icelandic Cancer Society, PO Box 5420, Reykjavík, Iceland. (Elsevier Science Ltd, 2000-06-01)
      Reduced cell adhesion brought about by altered surface expression of E-cadherin has been implicated in invasive and metastatic malignant growth. We investigated the patterns of immunohistochemical E-cadherin expression in 120 breast carcinomas. Furthermore, we analysed DNA from the same samples for loss of heterozygosity (LOH) using three separate microsatellite markers on chromosome 16q22.1. Finally, the clinical outcome was ascertained for 108 patients. 19% (18/97) of infiltrating ductal carcinomas showed complete loss of E-cadherin expression compared with 64% (9/14) of infiltrating lobular carcinomas. LOH was detected in 46% (24/52) of infiltrating ductal carcinomas and 89% (8/9) of infiltrating lobular carcinomas. In the infiltrating lobular carcinomas, LOH was associated with complete loss of cell membrane expression of E-cadherin, although a cytoplasmic expression pattern was evident. In contrast, this association was not seen in the infiltrating ductal carcinomas. In a multivariate analysis, loss of E-cadherin expression was shown to be a significant independent risk factor for a poorer disease-free survival (P=0.019), in particular in the node-negative subset of patients (P=0.029). Significance was also approached for breast cancer corrected survival (P=0.056). We conclude that different mechanisms are involved in the altered E-cadherin expression seen in different subtypes of breast carcinomas. Furthermore, we implicate loss of E-cadherin, regardless of the genetic causes, as an independent prognostic marker for disease recurrence, especially in node-negative breast cancer patients, irrespective of the histological type.
    • Basal cell carcinoma: an emerging epidemic in women in Iceland.

      Adalsteinsson, J A; Ratner, D; Olafsdóttir, E; Grant-Kels, J; Ungar, J; Silverberg, J I; Kristjansson, A K; Jonasson, J G; Tryggvadottir, L; 1University of Iceland, Saemundargata 2, 101 Reykjavik, Iceland. 2University of Connecticut Department of Dermatology, 263 Farmington Ave, Farmington, CT, 06003, USA. 3NYU Langone Health, Department of Dermatology, New York, NY, 10016, USA. 4Icelandic Cancer Registry, Skogarhlid 8, 105 Reykjavik, Iceland. 5Mount Sinai Department of Dermatology, One Gustave L. Levy Place, NY, 10029, USA. 6The George Washington University School of Medicine and Health Sciences, Washington, DC, USA. 7Faculty of Medicine, University of Iceland, Saemundargata 2, 101 Reykjavik, Iceland. 8Department of Pathology, Landspitali National-University Hospital, Hringbraut 101, 101 Reykjavik, Iceland. (Wiley, 2020-02-07)
      Background: An epidemic of basal cell carcinoma (BCC) has led to a significant healthcare burden in white populations. Objectives: To provide an update on incidence rates and tumour burden in an unselected, geographically isolated population that is exposed to a low level of ultraviolet radiation. Methods: This was a whole-population study using a cancer registry containing records of all cases of BCC in 1981-2017. We assessed BCC incidence according to age, residence and multiplicity and assessed trends using join-point analysis. Age-standardized and age-specific incidence rates were calculated along with cumulative and lifetime risks. Results: During the study period, the age-standardized incidence rates increased from 25·7 to 59·9 for men, and from 22·2 to 83·1 for women (per 100 000). Compared with the single-tumour burden, the total tumour burden in the population was 1·72 times higher when accounting for multiplicity. At the beginning of the study period, the world-standardized rates in men and women were similar, but by the end of the study period the rates were 39% higher in women (83·1 per 100 000, 95% confidence interval 77·9-88·3) than in men (59·9 per 100 000, 95% confidence interval 55·6-64·2). This increase was most prominent in women on sites that are normally not exposed to ultraviolet radiation in Iceland: the trunk and legs. Conclusions: This is the only reported population in which the incidence of BCC is significantly higher in women than in men. The period of notable increase in BCC lesions correlates with the period of an increase in tanning beds and travel popularity. The high multiplicity rates suggest that the total tumour burden worldwide might be higher than previously thought.
    • BRCA2 mutation in Icelandic prostate cancer patients

      Sigurdsson, S; Thorlacius, S; Tomasson, J; Tryggvadottir, L; Benediktsdottir, K; Eyfjord, J E; Jonsson, E; Molecular and Cell Biology Research Laboratory, Icelandic Cancer Society, Reykjavik. (Springer International, 1997-10-01)
      Molecular genetic analysis of prostate cancer has gained considerable attention in recent years. The hope is to find genetic markers that can help to determine which patients are likely to develop a progressive or lethal disease and would therefore benefit from early treatment. The BRCA2 gene on chromosome 13 has been associated with familial male and female breast cancer. A founder mutation in this gene has been detected in the Icelandic population. This is a 5-bp deletion that leads to an early termination and truncated protein. Clustering of prostate cancers in some of the Icelandic BRCA2 families implies that mutation carriers are at increased risk of developing cancer of the prostate. The aim of the study was to investigate this mutation in Icelandic prostate cancer patients related to BRCA2 positive breast cancer probands and to estimate the prevalence of this mutation in unselected prostate cancer patients. To examine the potential role of this mutation in prostate cancer we analyzed prostate cancer cases from 16 BRCA2 families and all available samples from individuals diagnosed with prostate cancer in Iceland over a period of 1 year. The risk ratio of prostate cancer was 4.6 (1.9-8.8) in first-degree relatives and 2.5 (1.2-4.6) in second-degree relatives of the 16 BRCA2 positive breast cancer probands. Of 26 prostate cancer cases found in these families 12 were analyzed, and 8 of these (66.7%) had the BRCA2 mutation. All of these patients developed an advanced disease, and all have died of prostate cancer (median survival 22.5 months). Among unselected cases 3.1% (2/65) had the mutation and developed an advanced disease as well. This specific mutation in the BRCA2 gene is found in a subset of Icelandic prostate cancer cases and appears to be a marker for poor prognosis.
    • Cutaneous melanoma in Iceland: changing Breslow's tumour thickness.

      Stefansson, H; Tryggvadottir, L; Olafsdottir, E J; Mooney, E; Olafsson, J H; Sigurgeirsson, B; Jonasson, J G; Univ Iceland, Fac Med, Reykjavik, Iceland, Landspitali, Dept Med, Reykjavik, Iceland, Iceland Canc Registry, Reykjavik, Iceland, Laekning, Dermatol, Reykjavik, Iceland, Hudlaeknastodin, Dermatol, Reykjavik, Iceland, Univ Iceland, Dermatol Sect, Fac Med, Reykjavik, Iceland, Landspitali, Dept Pathol, Reykjavik, Iceland (Wiley, 2015-02)
      The incidence of cutaneous melanoma increased dramatically in Iceland during the last two decades of the 20th century.
    • CYP17 promoter polymorphism and breast cancer risk in males and females in relation to BRCA2 status.

      Gudmundsdottir, K; Thorlacius, S; Jonasson, J G; Sigfusson, B F; Tryggvadottir, L; Eyfjord, J E; Molecular and Cell Biology Research Laboratory, Icelandic Cancer Society, 125-Reykjavik, Iceland. (Nature Publishing Group on behalf of Cancer Research UK, 2003-03-24)
      A T-C polymorphism in the promoter region of the CYP17 gene has been associated with male and female breast cancer risk as well as early-onset familial breast cancer. The potential role of this polymorphism was investigated in relation to breast cancer risk in Icelandic male and female carriers and noncarriers of a BRCA2 mutation. The study population consisted of 39 male and 523 female breast cancer cases and 309 male and 395 female controls. Of the cases, 15 males and 55 females carried a BRCA2 mutation. We did not find a significant association between male breast cancer risk and CYP17 genotypes. Among male breast cancer cases, the frequency of the CC genotype was higher among carriers of the 999del5 mutation (33.3%) than noncarriers (16.7%), although this difference also did not reach a statistical significance. No association was observed with breast cancer risk among females irrespective of menopausal status, stage of the disease or BRCA2 status. Our findings do not indicate a role for the CYP17 T-C polymorphism in female breast cancer, but a role in male carriers of a BRCA2 mutation could not be excluded because of the small sample size.
    • Electronically ascertained extended pedigrees in breast cancer genetic counseling.

      Stefansdottir, V; Skirton, H; Johannsson, O Th; Olafsdottir, H; Olafsdottir, G H; Tryggvadottir, L; Jonsson, J J; 1 Department of Genetics and Molecular Medicine, Landspitali - National University Hospital, Hringbraut, 101, Reykjavik, Iceland. 2 Department of Biochemistry and Molecular Biology, Univ. of Iceland, Reykjavik, Iceland. 3 Faculty of Health and Human Sciences, Plymouth University, Plymouth, UK. 4 Department Of Medical Oncology, Landspitali - National University Hospital, Reykjavik, Iceland. 5 Icelandic Cancer Registry, Icelandic Cancer Society, Reykjavik, Iceland. 6 Faculty of Medicine, Univ. of Iceland, Reykjavik, Iceland. 7 Department of Genetics and Molecular Medicine, Landspitali - National University Hospital, Hringbraut, 101, Reykjavik, Iceland. jonjj@hi.is. 8 Department of Biochemistry and Molecular Biology, Univ. of Iceland, Reykjavik, Iceland. jonjj@hi.is. 9 Genetical Committee of the University of Iceland, Reykjavik, Iceland. jonjj@hi.is. (Springer, 2019-04)
      A comprehensive pedigree, usually provided by the counselee and verified by medical records, is essential for risk assessment in cancer genetic counseling. Collecting the relevant information is time-consuming and sometimes impossible. We studied the use of electronically ascertained pedigrees (EGP). The study group comprised women (n = 1352) receiving HBOC genetic counseling between December 2006 and December 2016 at Landspitali in Iceland. EGP's were ascertained using information from the population-based Genealogy Database and Icelandic Cancer Registry. The likelihood of being positive for the Icelandic founder BRCA2 pathogenic variant NM_000059.3:c.767_771delCAAAT was calculated using the risk assessment program Boadicea. We used this unique data to estimate the optimal size of pedigrees, e.g., those that best balance the accuracy of risk assessment using Boadicea and cost of ascertainment. Sub-groups of randomly selected 104 positive and 105 negative women for the founder BRCA2 PV were formed and Receiver Operating Characteristics curves compared for efficiency of PV prediction with a Boadicea score. The optimal pedigree size included 3° relatives or up to five generations with an average no. of 53.8 individuals (range 9-220) (AUC 0.801). Adding 4° relatives did not improve the outcome. Pedigrees including 3° relatives are difficult and sometimes impossible to generate with conventional methods. Pedigrees ascertained with data from pre-existing genealogy databases and cancer registries can save effort and contain more information than traditional pedigrees. Genetic services should consider generating EGP's which requires access to an accurate genealogy database and cancer registry. Local data protection laws and regulations have to be addressed.
    • Familial risk of prostate cancer in Iceland

      Eldon, B J; Jonsson, E; Tomasson, J; Tryggvadottir, L; Tulinius, H (Blackwell Science, 2003-12-01)
      OBJECTIVE: To estimate the risk of prostate and other types of cancer among relatives of Icelandic men diagnosed with prostate cancer over a 5-year period. PATIENTS AND METHODS: The risk ratio (RR) was used to estimate the risk among relatives of 371 patients with prostate cancer, all of whom lived in Iceland and were diagnosed when alive over a 5-year interval (1983-7). Information on cancer incidence was obtained from the population-based Icelandic Cancer Registry, and information on families from a comprehensive genealogical database covering the population of Iceland. RESULTS: First-degree male relatives were at a 1.7-fold greater age-adjusted risk of prostate cancer (1832 men; 95% confidence interval, CI, 1.28-2.34). The risk was independent of proband's age at diagnosis. First-degree male relatives of patients who died from prostate cancer were at a statistically significantly greater risk of the disease (784 men; RR 2.17; 95% CI 1.34-3.53) and relatives of patients with incidental disease (T1a) were at a greater risk but not statistically significant so (261; RR 1.86; 95% CI 0.75-4.58). Female first-degree relatives were not at greater risk of breast cancer. The risk of kidney cancer was higher in first- and second-degree female relatives, with an RR (n, CI) of 2.50 (1780, 1.10-5.66) and 2.67 (5534, 1.04-6.81), respectively. The risk of kidney cancer was not statistically significantly greater in male relatives. CONCLUSION: Family history is a risk factor for prostate cancer in Icelandic men. The risk is potentially higher for relatives of patients who die from the disease. Female relatives are not at greater risk of breast cancer but they may be at greater risk of kidney cancer.
    • Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche

      Sulem, P; Gudbjartsson, D F; Rafnar, T; Holm, H; Olafsdottir, E J; Olafsdottir, G H; Jonsson, T; Alexandersen, P; Feenstra, B; Boyd, H A; et al. (Nature Pub. Co., 2009-05-17)
      Earlier menarche correlates with shorter adult height and higher childhood body fat. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 x 10(-14)). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI) and 5 of those associated with earlier AAM.
    • Genomic instability and poor prognosis associated with abnormal TP53 in breast carcinomas. Molecular and immunohistochemical analysis

      Valgardsdottir, R; Tryggvadottir, L; Steinarsdottir, M; Olafsdottir, K; Jonasdottir, S; Jonasson, J G; Ogmundsdottir, H M; Eyfjord, J E; Molecular and Cell Biology Research Laboratory, Icelandic Cancer Society, Reykjavik, Iceland. (Blackwell Publishing Inc, 1997-01)
      Alterations of the TP53 gene were analyzed in samples from 87 primary breast cancer patients, using molecular and immunohistochemical approaches. Mutations were detected in 17% of the samples, using polymerase chain reaction (PCR) and constant denaturant gel electrophoresis (CDGE) on exons 5-8 of the TP53 gene, and were confirmed by sequencing. Abnormal TP53 protein staining was found in 55% of the primary samples, using the monoclonal TP53 antibody DO7. A statistically significant association was found between TP53 mutations and abnormal protein staining (p = 0.002). Our results suggest that dysfunction of the TP53 protein is associated with tumor progression, as we found an association between TP53 abnormalities and accumulation of genetic lesions, measured as overall allelic imbalance (AI), homogeneously staining regions (HSR) and strong ERBB2 overexpression. Furthermore, patients with TP53 mutation had a highly elevated risk of dying from breast cancer during the study period (p < 0.001, RR = 10.68) at a median follow-up time of 42 months. Abnormal TP53 staining was much more frequent than the mutations, but it was not of prognostic significance, whereas strong staining was an independent prognostic factor. We therefore conclude that loss of functional TP53 leads to genetic instability, resulting in poorer short-term prognosis, and that only strong staining of TP53, and not abnormal protein staining in general, is of prognostic significance.
    • Invasive and in situ squamous cell carcinoma of the skin: a nationwide study in Iceland.

      Adalsteinsson, J A; Olafsdottir, E; Ratner, D; Waldman, R; Feng, H; Ungar, J; Silverberg, J I; Kristjansson, A K; Jonasson, J G; Tryggvadottir, L; et al. (Wiley, 2021-02-20)
      1Faculty of Medicine, University of Iceland, Saemundargata 2, Reykjavik, 101, Iceland. 2Department of Dermatology, University of Connecticut, 21 South Road, Farmington, CT, USA. 3Icelandic Cancer Registry, Skogarhlid 8, Reykjavik, 105, Iceland. 4Department of Dermatology, NYU Langone Health, New York, NY, USA. 5Department of Dermatology, The Mount Sinai Hospital, 1 Gustave L. Levy Place, NY, USA. 6The George Washington University School of Medicine and Health Sciences, Washington, DC, USA. 7Department of Pathology, Landspitali National-University Hospital, Hringbraut, Reykjavik, 101, Iceland.
    • Linkage to BRCA2 region in hereditary male breast cancer.

      Thorlacius, S; Tryggvadottir, L; Olafsdottir, G H; Jonasson, J G; Ogmundsdottir, H M; Tulinius, H; Eyfjord, J E; Molecular and Cell Biology Research Laboratory, Reykjavik, Iceland. (Lancet Publishing Group, 1995-08-26)
      Breast cancer is rare in men, and family history of the disease is a risk factor. The recently discovered BRCA2 gene on chromosome 13q is thought to account for some families with increased risk of breast cancer, including male breast cancer. We describe a family with multiple cases of male breast cancer but, interestingly, no increase in female breast cancer. Linkage to the BRCA2 region is demonstrated and all the affected men share the same haplotype for the BCRA2 markers and loss of the other alleles in their tumours.
    • Positive association between plasma antioxidant capacity and n-3 PUFA in red blood cells from women

      Thorlaksdottir, A Y; Skuladottir, G V; Petursdottir, A L; Tryggvadottir, L; Ogmundsdottir, H M; Eyfjord, J E; Jonsson, J J; Hardardottir, I (AOCS Press, 2006-02-01)
      PUFA are susceptible to oxidation. However, the chain-reaction of lipid peroxidation can be interrupted by antioxidants. Whether an increased concentration of PUFA in the body leads to decreased antioxidant capacity and/or increased consumption of antioxidants is not known. To elucidate the relationship between plasma total antioxidant capacity (TAC), the concentration of antioxidant vitamins, and the proportion of PUFA in red blood cells (RBC), plasma TAC was measured by a Trolox equivalent antioxidant capacity assay in blood samples from 99 Icelandic women. Concentrations of tocopherols and carotenoids in the plasma were determined by HPLC, and the FA composition of RBC total lipids was analyzed by GC. Plasma TAC and the plasma concentration of α-tocopherol correlated positively with the proportion of total n-3 PUFA, 20:5n-3, and 22:6n-3 in RBC, whereas the plasma lycopene concentration correlated negatively with the proportion of total n-3 PUFA and 20:5n-3. On the other hand, plasma TAC correlated negatively with the proportion of n-6 PUFA in RBC. Plasma TAC also correlated positively with the plasma concentration of α-tocopherol, alcohol consumption, and age. Both the plasma concentration of α-tocopherol and age correlated positively with the proportion of n-3 PUFA in RBC; however, n-3 PUFA contributed independently to the correlation with plasma TAC. Because the proportion of n-3 PUFA in RBC reflects the consumption of n-3 PUFA, these results suggest that dietary n-3 PUFA do not have adverse effects on plasma TAC or the plasma concentration of most antioxidant vitamins.
    • Positive association between plasma antioxidant capacity and n-3 PUFA in red blood cells from women.

      Thorlaksdottir, A Y; Skuladottir, G V; Petursdottir, A L; Tryggvadottir, L; Ogmundsdottir, H M; Eyfjord, J E; Jonsson, J J; Hardardottir, I; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, Reykjavik, Iceland. (American Oil Chemists Society, 2006-02-01)
      PUFA are susceptible to oxidation. However, the chain-reaction of lipid peroxidation can be interrupted by antioxidants. Whether an increased concentration of PUFA in the body leads to decreased antioxidant capacity and/or increased consumption of antioxidants is not known. To elucidate the relationship between plasma total antioxidant capacity (TAC), the concentration of antioxidant vitamins, and the proportion of PUFA in red blood cells (RBC), plasma TAC was measured by a Trolox equivalent antioxidant capacity assay in blood samples from 99 Icelandic women. Concentrations of tocopherols and carotenoids in the plasma were determined by HPLC, and the FA composition of RBC total lipids was analyzed by GC. Plasma TAC and the plasma concentration of alpha-tocopherol correlated positively with the proportion of total n-3 PUFA, 20:5n-3, and 22:6n-3 in RBC, whereas the plasma lycopene concentration correlated negatively with the proportion of total n-3 PUFA and 20:5n-3. On the other hand, plasma TAC correlated negatively with the proportion of n-6 PUFA in RBC. Plasma TAC also correlated positively with the plasma concentration of alpha-tocopherol, alcohol consumption, and age. Both the plasma concentration of alpha-tocopherol and age correlated positively with the proportion of n-3 PUFA in RBC; however, n-3 PUFA contributed independently to the correlation with plasma TAC. Because the proportion of n-3 PUFA in RBC reflects the consumption of n-3 PUFA, these results suggest that dietary n-3 PUFA do not have adverse effects on plasma TAC or the plasma concentration of most antioxidant vitamins.
    • TP53 mutation analyses on breast carcinomas: a study of paraffin-embedded archival material.

      Gretarsdottir, S; Tryggvadottir, L; Jonasson, J G; Sigurdsson, H; Olafsdottir, K; Agnarsson, B A; Ogmundsdottir, H; Eyfjord, J E; Molecular and Cell Biology Research Laboratory, Icelandic Cancer Society, Reykjavik, Iceland. (Nature Publishing Group, 1996-08-01)
      The aim of this investigation was to examine the possibility of analysing TP53 mutations in archival paraffin-embedded material with the constant denaturant gel electrophoresis (CDGE) method. We extracted DNA from 193 archival primary breast carcinoma samples, diagnosed in 1981-83; further analysis was possible for 186 of these. TP53 mutations in exons 5-8 were detected with CDGE in 30 samples (16.1%) and 17 of these mutations were confirmed by sequencing. Immunohistochemistry demonstrated TP53 nuclear accumulation in 58 tumours (31%). A strong association between the presence of TP53 mutations and TP53 immunostaining was observed (P < 0.001). Our mutation and immunohistochemistry results are in agreement with other findings based on fresh tumour tissue. TP53 abnormalities were significantly related to high S-phase fraction, low oestrogen receptor (ER) content and high tumour grade. Survival of patients with TP53 abnormalities, in the group as a whole, did not differ from patients with normal TP53. Our study did, however, show that patients with abnormal TP53 had a significantly shorter post-recurrence survival (P = 0.005) than patients with normal TP53.
    • TP53 mutations and abnormal p53 protein staining in breast carcinomas related to prognosis

      Thorlacius, S; Thorgilsson, B; Bjornsson, J; Tryggvadottir, L; Börresen, A L; Ogmundsdottir, H M; Eyfjord, J E; Molecular and Cell Biology Research Laboratory, Icelandic Cancer Society, Reykjavik, Iceland. (Elsevier Science, 1995-10)
      Abnormalities in the TP53 tumour suppressor gene were evaluated in 106 unselected breast carcinomas and compared to clinical outcome of the disease. Tumours were screened for p53 abnormalities using immunohistochemical staining and polymerase chain reaction-constant denaturant gel electrophoresis (PCR-CDGE) analysis, followed by PCR and direct sequencing. Allelic loss at the TP53 locus was determined with polymorphic markers by comparing normal and tumour DNA. For approximately half of the patients, abnormal p53 protein expression in serum was determined by an ELISA assay. p53 abnormalities, detected as mutations and/or nuclear staining, were found in 37.6 (38/101) of cases. Nuclear staining for p53 protein could be identified in 33.7% of the tumours. Mutations in exons 5-8 were detected in 18.9% of the tumours, and an association was found between mutations and nuclear staining. Allelic loss in the TP53 region on 17p was more frequent in tumours showing changes in the TP53 gene (72.7%) compared to tumours with no mutation (45.8%). Serum levels of p53 antibodies showed no association with either TP53 mutations or nuclear staining. Women with TP53 mutations in their tumours had an elevated risk of dying during the study period (RR (relative risk) = 3.4, P = 0.014). The effects of p53 positive staining were similar (RR = 3.2, P = 0.013). Considering all abnormalities, mutation and/or staining, the relative risk of dying from breast cancer was 3.5 (P = 0.008).