To know or not to know, that is the question – screening for BRCA

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Correction : Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Non peer reviewe

The BRCA1 c.4096+3A>G Variant Displays Classical Characteristics of Pathogenic BRCA1 Mutations in Hereditary Breast and Ovarian Cancers, But Still Allows Homozygous Viability

Publisher's version (útgefin grein).Mutations in BRCA1 result in predisposal to breast and ovarian cancers, but many variants exist with unknown clinical significance (VUS). One is BRCA1 c.4096+3A>G, which affects production of the full-length BRCA1 transcript, while augmenting transcripts lacking most or all of exon 11. Nonetheless, homozygosity of this variant has been reported in a healthy woman. We saw this variant cosegregate with breast and ovarian cancer in several family branches of four Icelandic pedigrees, with instances of phenocopies and a homozygous woman with lung cancer. We found eight heterozygous carriers (0.44%) in 1820 unselected breast cancer cases, and three (0.15%) in 1968 controls (p = 0.13). Seeking conclusive evidence, we studied tumors from carriers in the pedigrees for wild-type-loss of heterozygosity (wtLOH) and BRCA1-characteristic prevalence of estrogen receptor (ER) negativity. Of 15 breast and six ovarian tumors, wtLOH occurred in nine breast and all six ovarian tumours, and six of the nine breast tumors with wtLOH were ER-negative. These data accord with a pathogenic BRCA1-mutation. Our findings add to the current knowledge of BRCA1, and the role of its exon 11 in cancer pathogenicity, and will be of use in clinical genetic counselling.This research was funded by the Landspitali University Hospital Research Fund, grant A-2019-001, and by the Icelandic association "Walking for Breast Cancer Research" (Göngum saman).Peer Reviewe

Viðhorf til viðskiptavildar

Viðskiptavild hefur mikið verið í umræðunni síðastliðin ár í tengslum við lausafjárkrísu íslensku bankanna síðari hluta árs 2008. Hefur gætt misskilnings í umræðunni, þar sem ekki eru allir með það á hreinu hvernig viðskiptavild myndast í bókhaldi fyrirtækja. Einnig telja rannsakendur að viðskipavild hafi beðið töluverðan álitshnekki í þjóðfélagsumræðunni undanfarið, þar sem hún hafði aukist umtalsvert á mjög stuttum tíma í aðdraganda lausafjárkrísunnar. Lausafjárkrísu bankanna töldu margir að hægt væri að rekja til uppblásinna eignareikninga fyrirtækja af völdum viðskiptavildar, sem bankarnir lánuðu svo út á. Þessar eignir reyndust síðan verðlausar þegar rekstur fyrirtækjanna stóð ekki undir skuldsetningunni. Áhugavert er að skoða hvort munur sé á viðhorfi þeirra sem við viðskiptavild fást í sínu starfi, þá er aðallega litið til endurskoðenda sem fást við ársreikninga fyrirtækja og fjármálastjóra stærstu fyrirtækjanna á Íslandi. Rannsóknin leiddi í ljós að munur var á viðhorfum þeirra tveggja hópa sem rannsóknin náði til. Viðhorfum til viðskiptavildar almennt, núverandi reikningsskilalegra meðferða viðskiptavildar og breytinga þar á. Breytingarnar voru sumar hverjar eingöngu smávægilegar miðað við núverandi fyrirkomulag á reikningsskilalegri meðferð viðskiptavildar meðan aðrar voru heldur róttækari í framsetningu. Leiða má líkur að því að viðhorf stjórnenda, sem þurfa að svara til hluthafa og almennings, gæti litast meira af þjóðfélagsumræðunni og almennu viðhorfi til viðskiptavildar heldur en endurskoðenda. Þar sem endurskoðendur eru opinberir eftirlitsaðilar og sérfræðingar, sem taka út ársreikninga, meðal annars með tilliti til fylgni stjórnenda við ársreikningalög og alþjóðlega reikningsskilastaðla í reikningsskilum. Þess vegna ætti viðhorf endurskoðenda að vera hlutlægara í garð viðskiptavildar heldur en viðhorf stjórnenda

Brca1 promoter methylation status in 1031 primary breast cancers predicts favorable outcomes following chemotherapy

The authors would like to thank The Icelandic Research Fund (www.rannis.is) (14193–051 and 152077–051) and Gongum saman (www.gongumsaman.is) for funding. Publisher Copyright: © 2020 Oxford University Press. All rights reserved.Background: Breast Cancer 1 gene (BRCA1) is known to be inactivated in breast tumors by promoter methylation. Tumor cells in patients carrying a germline mutation in BRCA1 are sensitive to cytotoxic drugs that cause DNA double strand breaks. However, very little is known on whether patients with BRCA1 promoter methylated tumors are similarly sensitive to cytotoxic drugs. In this study, we address this by making use of extensive follow-up data on patients treated with cyclophosphamide, methotrexate, and fluorouracil in Iceland between 1976 and 2007. Methods: We analyzed BRCA1 promoter methylation by pyrosequencing DNA from tumor samples from 1031 patients with primary breast cancer. Of those, 965 were sporadic cases, 61 were BRCA2, and five were BRCA1 germline mutation carriers. All cases were examined with respect to clinicopathological parameters and breast cancer-specific survival in patients treated with cytotoxic drugs. Information on chemotherapy treatment in noncarriers was available for 26 BRCA1 methylated tumors and 857 unmethylated tumors. Results: BRCA1 was promoter methylated in 29 sporadic tumors or in 3.0% of cases (29 of 965), whereas none of the tumors derived from BRCA germline mutation carriers were promoter methylated. Important to note, patients with BRCA1 promoter methylation receiving chemotherapeutic drug treatment show highly improved breast cancer-specific survival compared with unmethylated controls (hazard ratio 0.10, 95% confidence interval 0.01 to 0.75, two-sided P .02). Conclusions: BRCA1 promoter methylation is predictive of improved disease outcome in patients receiving cyclophosphamide, methotrexate, and fluorouracil drug treatment. Our results support the use of markers indicative of "BRCAness" in sporadic breast cancers to identify patients that are likely to benefit from the use of DNA-damaging agents.Peer reviewe

Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations

BRCA1 and BRCA2 mutations confer increased risk for development of breast cancer, but a number of additional, currently largely unknown, somatic genetic defects must also accumulate in the breast epithelial cells before malignancy develops. To evaluate the nature of these additional somatic genetic defects, we performed a genome-wide survey by comparative genomic hybridization on breast cancers from 21 BRCA1 mutation carriers, 15 BRCA2 mutation carriers, and 55 unselected controls. The total number of genetic changes was almost two times higher in tumors from both BRCA1 and BRCA2 mutation carriers than in the control group. In BRCA1 tumors, losses of 5q (86%), 4q (81%), 4p (64%), 2q (40%), and 12q (40%) were significantly more common than in the control group (7-13%). BRCA2 tumors were characterized by a higher frequency of 13q (73%) and 6q (60%) losses and gains of 17q22-q24 (87%) and 20q13 (60%) as compared to the prevalence of these changes in the control group (12-18%). In conclusion, accumulation of somatic genetic changes during tumor progression may follow a unique pathway in individuals genetically predisposed to cancer, especially by the BRCA1 gene. Activation or loss of genes in the affected chromosomal regions may be selected for during tumor progression in cells lacking functional BRCA1 or BRCA2. Identification of such genes could provide targets for therapeutic intervention and early diagnosis.This study was supported by the Finnish Science Academy, Sigrid Juselius Foundation, Finnish Cancer Society, Tampere University Hospital Fund, Nordic Cancer Union Fund, Swedish Cancer Society, GAE Nilsson's Foundation, and B. Kamprad's Foundation. In addition, M.T. was supported by personal grants from the Pirkanmaa Cancer Society, as well as Finnish and Pirkanmaa Cultural Foundations

High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients

Studies on Icelandic breast cancer families have shown that most of them segregate a 999del5 BRCA2 mutation. Here, we report the frequency of the 999del5 BRCA2 mutation in an Icelandic control population and four different groups of cancer patients diagnosed with (a) breast cancer; (b) ovarian cancer; (c) prostate cancer (patients younger than 65 years); and (d) other cancer types, The proportions of individuals carrying the mutation were 0.4% in the control population and in the patient groups 8.5%, 7.9%, 2.7%, and 1.0%, respectively, Our results indicate that BRCA2 confers a very high risk of breast cancer and is responsible for a substantial fraction of breast and ovarian cancer in Iceland, but only a small proportion of other cancers.This work was supported by the Nordic Cancer Union, Science Fund of Iceland and the Memorial Fund of Bergthora Magnusdottir and Jakob B. Bjarnason