Genomic subtypes of breast cancer identified by array comparative genomic hybridization display distinct molecular and clinical characteristics

Abstract Introduction Breast cancer is a profoundly heterogeneous disease with respect to biologic and clinical behavior. Gene-expression profiling has been used to dissect this complexity and to stratify tumors into intrinsic gene-expression subtypes, associated with distinct biology, patient outcome, and genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes. Methods We applied global DNA copy number and gene-expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene-expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy-number aberrations and genomic subgroups of breast cancer. Results We identified 31 genomic regions that were highly amplified in > 1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions revealed six genomic subtypes, termed 17q12, basal-complex, luminal-simple, luminal-complex, amplifier, and mixed subtypes. Four of them had striking similarity to intrinsic gene-expression subtypes and showed associations to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having a better prognosis, whereas the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene-expression subtypes, the former being enriched for 8p12-amplified cases, whereas the mixed subtype included many tumors with predominantly DNA copy-number losses and poor prognosis. Conclusions Global DNA copy-number analysis integrated with gene-expression data can be used to dissect the complexity of breast cancer. This revealed six genomic subtypes with different clinical behavior and a striking concordance to the intrinsic subtypes. These genomic subtypes may prove useful for understanding the mechanisms of tumor development and for prognostic and treatment prediction purposes

Bättre avfallshantering i Sundsvall : Mittuniversitetets slutrapport från förstudien

Förstudien syftar till att tillsammans med MittSverige Vatten &amp; Avfall (MSVA) ta fram verktyg för att informera om vinsterna med källsortering och påverka för att nå en bättre, mer hållbar avfallshantering i Sundsvall. En hållbar avfallshantering bidrar till att ge förutsättningar för en hållbartillväxt och god livsmiljö i Sundsvall. I förstudien presenteras exempel och förslag på hur visualiseringar kan bidra till att förbättra avfallshanteringen i Sundsvalls kommun. Inom ramen för studien har också en Återbruksfestival genomförts i syfte att undersöka och uppmärksamma vad som slängs samt ge konkreta exempel på återvinning och återbruk. Vidare genomfördes ett seminarium baserat på underliggande arbete kring hur papper och kartong kan användas som material för att ersätta hushållsförpackningar i plast. Förstudien utgör också en del i arbetet mot visionen att initiera forskning i samverkan med de aktörer i regionen som kan se nytta av design och visualisering i sin egen verksamhet. Förstudien har också bidragit till att ge underlag för framtida inriktningar, förutsättningar, och forskningsfrågor inom visualisering och design.Projektledare: Mattias Andersson, Institutionen för design, Mittuniversitetet</p

Bättre avfallshantering i Sundsvall : Mittuniversitetets slutrapport från förstudien

Förstudien syftar till att tillsammans med MittSverige Vatten &amp; Avfall (MSVA) ta fram verktyg för att informera om vinsterna med källsortering och påverka för att nå en bättre, mer hållbar avfallshantering i Sundsvall. En hållbar avfallshantering bidrar till att ge förutsättningar för en hållbartillväxt och god livsmiljö i Sundsvall. I förstudien presenteras exempel och förslag på hur visualiseringar kan bidra till att förbättra avfallshanteringen i Sundsvalls kommun. Inom ramen för studien har också en Återbruksfestival genomförts i syfte att undersöka och uppmärksamma vad som slängs samt ge konkreta exempel på återvinning och återbruk. Vidare genomfördes ett seminarium baserat på underliggande arbete kring hur papper och kartong kan användas som material för att ersätta hushållsförpackningar i plast. Förstudien utgör också en del i arbetet mot visionen att initiera forskning i samverkan med de aktörer i regionen som kan se nytta av design och visualisering i sin egen verksamhet. Förstudien har också bidragit till att ge underlag för framtida inriktningar, förutsättningar, och forskningsfrågor inom visualisering och design.Projektledare: Mattias Andersson, Institutionen för design, Mittuniversitetet</p

Slutrapport : Universell utformning av Foodtech

I samverkan mellan Mittuniversitetet och Härnösands kommun</p

Slutrapport : Universell utformning av Foodtech

I samverkan mellan Mittuniversitetet och Härnösands kommun</p

Slutrapport : Universell utformning av Foodtech

I samverkan mellan Mittuniversitetet och Härnösands kommun</p

A gene to organism approach-assessing the impact of environmental pollution in eelpout (Zoarces viviparus) females and larvae

A broad biomarker approach was applied to study the effects of marine pollution along the Swedish west coast using the teleost eelpout (Zoarces viviparus) as the sentinel species. Measurements were performed on different biological levels, from the molecular to the organismal, including measurements of messenger RNA (mRNA), proteins, cellular and tissue changes, and reproductive success. Results revealed that eelpout captured in Stenungsund had significantly higher hepatic ethoxyresorufin O-deethylase activity, high levels of both cytochrome P4501A and diablo homolog mRNA, and high prevalence of dead larvae and nuclear damage in erythrocytes. Eelpout collected in G\uf6teborg harbor displayed extensive macrovesicular steatosis, whereby the majority of hepatocytes were affected throughout the liver, which could indicate an effect on lipid metabolism. Results also indicate that eelpouts collected at polluted sites might have an affected immune system, with lower mRNA expression of genes involved in the innate immune system and a higher number of lymphocytes. Biomarker assessment also was performed on livers dissected from unborn eelpout larvae collected from the ovary of the females. No significant differences were noted, which might indicate that the larvae to some extent are protected from effects of environmental pollutants. In conclusion, usage of the selected set of biological markers, covering responses from gene to organism, has demonstrated site-specific biomarker patterns that provided a broad and comprehensive picture of the impact of environmental stressors

A gene to organism approach-assessing the impact of environmental pollution in eelpout (Zoarces viviparus) females and larvae

A broad biomarker approach was applied to study the effects of marine pollution along the Swedish west coast using the teleost eelpout (Zoarces viviparus) as the sentinel species. Measurements were performed on different biological levels, from the molecular to the organismal, including measurements of messenger RNA (mRNA), proteins, cellular and tissue changes, and reproductive success. Results revealed that eelpout captured in Stenungsund had significantly higher hepatic ethoxyresorufin O-deethylase activity, high levels of both cytochrome P4501A and diablo homolog mRNA, and high prevalence of dead larvae and nuclear damage in erythrocytes. Eelpout collected in G\uf6teborg harbor displayed extensive macrovesicular steatosis, whereby the majority of hepatocytes were affected throughout the liver, which could indicate an effect on lipid metabolism. Results also indicate that eelpouts collected at polluted sites might have an affected immune system, with lower mRNA expression of genes involved in the innate immune system and a higher number of lymphocytes. Biomarker assessment also was performed on livers dissected from unborn eelpout larvae collected from the ovary of the females. No significant differences were noted, which might indicate that the larvae to some extent are protected from effects of environmental pollutants. In conclusion, usage of the selected set of biological markers, covering responses from gene to organism, has demonstrated site-specific biomarker patterns that provided a broad and comprehensive picture of the impact of environmental stressors

The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we used gene expression profiling to molecularly subtype 577 breast tumors, including 73 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated, and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter methylation but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1-deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1 hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer but rarely in BRCA2 hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings show the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1 status.Swedish Cancer Society Knut & Alice Wallenberg Foundation Foundation for Strategic Research through the Lund Centre for Translational Cancer Research (CREATE Health) Mrs. Berta Kamprad Foundation American Cancer Society Gunnar Nilsson Cancer Foundation Swedish Research Council Lund University Hospital Research Funds IngaBritt and Arne Lundberg Foundation Icelandic Research Fund Landspitali University Hospital Research Fund Walking Together Research Fund Nordic Cancer Union Helsinki University Central Hospital Research Fund Sigrid Juselius Foundation Finnish Cancer Society Academy of Finland 132473 European Community's Seventh Framework Programme 223175 (HEALTH-F2-2009-223175