Sykliinien merkitys rintasyövässä

Breast cancer is the most common malignancy in women in Western countries. It is a heterogeneous disease with varying biological characteristics and aggressiveness. Family history is one of the strongest predisposing factors for breast cancer. The known susceptibility genes explain only around 25% of all familial breast cancers. At least part of the unknown familial aggregation may be caused by several low-penetrance variants that occur commonly in the general population. Cyclins are cell cycle-regulating proteins. Cyclin expression oscillates during the cell cycle and is under strict control. In cancer cells, cyclin expression often becomes deregulated, leading to uncontrolled cell division and proliferation, one of the hallmarks of cancer. In this study, we investigated the role of cyclins in breast cancer predisposition, pathogenesis, and tumor behavior. Cyclin A immunohistochemistry was evaluated both on traditional large sections and on tissue microarrays (TMA). The concordance of the results was good, indicating that TMA is a reliable method for studying cyclin expression in breast cancer. The expression of cyclins D1, E, and B1 was studied among 1348 invasive breast cancers on TMA. Familial BRCA1/2-mutation negative tumors had significantly more often low cyclin E and high cyclin D1 expression than BRCA1/2 related or sporadic tumors. Unique cyclin E and D1 expression patterns among familial non-BRCA1/2 breast cancers may reflect different predisposition and pathogenesis in these groups and help to differentiate mutation-positive from mutation-negative familial cancers. High cyclin E expression was associated with an aggressive breast cancer phenotype and was an independent marker of poor metastasis-free survival. High cyclin D1 was associated with high grade and high proliferation among estrogen receptor (ER)-positive but with low grade and low proliferation among ER-negative breast cancers. Among ER-positive cancers not treated with chemotherapy, high cyclin D1 showed a trend towards shorter metastasis-free survival. These results suggest that different mechanisms may drive proliferation in ER-negative and -positive breast cancers and that cyclin D1 has a particularly important role in tumorigenesis of hormone receptor-positive breast cancer. High cyclin B1 expression was associated with aggressive breast cancer features and had an independent impact on survival. The results suggest that cyclin B1 immunohistochemistry is a method that could easily be adapted for routine use and is an independent prognostic factor, adding specificity to prognostic evaluation conducted with traditional markers. A commonly occurring cyclin D1 gene polymorphism A870G was associated with increased breast cancer risk in a large material of Finnish and Canadian breast cancer patients. The interaction of the high-activity alleles of cyclin D1 gene and estrogen metabolism gene COMT conferred an even higher risk. These results show that cyclin D1 and COMT act synergistically to contribute to breast cancer progression and that individual risk for breast cancer can be altered by the combined effect of polymorphisms with low-penetrance alleles. By investigating critical cell cycle regulator protein cyclins, we revealed new aspects of breast cancer predisposition, pathogenesis, and clinical course.Rintasyöpä on suomalaisten naisten yleisin syöpä, johon sairastuu vuosittain yli 4000 naista. Rintasyöpä on monimuotoinen sairaus: suurimmassa osassa rintasyövistä ennuste on hyvä ja yli 85 % rintasyöpään sairastuneista naisista on tautivapaita viiden vuoden kuluttua sairauden toteamisesta. Kuitenkin osa rintasyövistä metastasoi ja johtaa kuolemaan jopa nopeasti toteamisen jälkeen. Periytyvä alttius on yksi vahvimmista rintasyövälle altistavista tekijöistä. Tunnetut alttiusgeenit selittävät yhteensä vain noin 25 % periytyvästä rintasyöpäalttiudesta. Sykliinit ovat solun jakautumissyklin, solusyklin, säätelijäproteiineja. Solusyklin säätelyn häiriintyminen on yleistä syöpäsoluissa. Tässä tutkimuksessa selvitettiin sykliinien merkitystä rintasyövässä. Tulokset tuovat lisätietoa rintasyöpäalttiudesta, rintasyövän patogeneesistä ja ennusteen arvioinnista. Sykliini A proteiinin ilmentymistä tutkittiin mikrokudoslevystöllä (tissue micro array, TMA) ja perinteisistä histologisista leikkeistä. Tulokset vastasivat toisiaan osoittaen että TMA-tekniikka soveltuu hyvin sykliinien ilmentymisen tutkimiseen rintasyövässä. Sykliini D1 geenin G870A polymorfismi oli yleisempi rintasyöpään sairastuneilla naisilla kuin terveillä verrokeilla. Tämä väestössä yleisesti esiintyvä geenivariantti voi yksin ja etenkin estrogeenimetaboliaan liittyvän COMT-geenin Met108/158Val-polymorfismin kanssa esiintyessään lisätä riskiä sairastua rintasyöpään. Geenivarianttien yhteisvaikutus voi selittyä niiden molempien rooleilla estrogeenivaikutuksen säätelyssä. Korkea sykliini E-proteiinin ilmentyminen liittyi aggressiivisen rintasyövän ominaisuuksiin ja oli itsenäinen lyhyemmän metastaasivapaan ajan ennustaja. Korkea sykliini D1-proteiinin ilmentyminen liittyi matalaan proliferaation ja erilaistumisasteeseen estrogeenireseptorinegatiivisessa, mutta korkeaan proliferaatioon ja erilaistumisasteeseen estrogeenireseptoripositiivisessa rintasyövässä. Tulokset viittaavat siihen, että proliferaation säätely ja solusyklin kontrolloimaton eteneminen on erilaista hormonireseptoripositiivisessa ja negatiivisessa rintasyövässä. Matala sykliini E ja korkea sykliini D1 ilmentyminen oli yleisempää perinnöllisten BRCA1/2 negatiivisten kuin sporadisten tai BRCA1- tai BRCA2 mutaatiopositiivisten potilaiden kasvaimissa. Poikkeava sykliini E- ja D1-proteiinien ilmentyminen saattaa viitata siihen, että ainakin osalla näistä taustaltaan tuntemattomista perinnöllisistä rintasyövistä on yhteinen patogeneesi ja voi auttaa erottamaan mutaatiopositiiviset kasvaimet kaikkien perinnöllisten rintasyöpäkasvaimien joukosta. Korkea sykliini B1-proteiinin ilmentyminen oli yleisempää aggressiivisessa rintasyövässä ja oli itsenäinen huonoa ennustetta määrittävä tekijä. Kasvaimen sykliini B1 määritys on yksinkertainen ja helposti rutiinikäyttöön soveltuva menetelmä, joka saattaa lisätä perinteisten ennustekijöiden avulla tehtävän rintasyövän aggressiivisuuden ja ennusteen määrityksen tarkkuutta, ja auttaa valitsemaan ne potilaat, jotka eniten hyötyvät liitännäissolunsalpaajahoidosta

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English summaryPeer reviewe

Perinnöllinen retinoblastooma ja Li-Fraumenin oireyhtymä - mitä kliinikon pitäisi huomioida?

Vertaisarvioitu.Retinoblastooman perinnöllinen muoto ja Li-Fraumenin oireyhtymä (LFS) ovat klassisia periytyvän syövän oireyhtymiä. Geenivirhe ituradassa tekee kudoksista syövän synnyn kannalta haavoittuvia, kun elämän aikana sattumalta tuleva hankinnainen toinen "isku" Knudsonin hypoteesin mukaisesti muuttaa solun perimää. Näiden oireyhtymien geenivirheen kantajat sairastuvat jo nuorina, ja yleensä kyse on harvinaisesta syövästä. Suvun syöpähistoria on usein poikkeuksellinen ja herättää epäilyn periytyvästä syövästä. Kantajien strukturoitu tehostettu seuranta on parantanut ennustetta ja kokonaiselossaolo-osuutta 2010-luvulta alkaen.Peer reviewe

Perinnöllinen retinoblastooma ja Li-Fraumenin oireyhtymä - mitä kliinikon pitäisi huomioida?

Vertaisarvioitu.Retinoblastooman perinnöllinen muoto ja Li-Fraumenin oireyhtymä (LFS) ovat klassisia periytyvän syövän oireyhtymiä. Geenivirhe ituradassa tekee kudoksista syövän synnyn kannalta haavoittuvia, kun elämän aikana sattumalta tuleva hankinnainen toinen "isku" Knudsonin hypoteesin mukaisesti muuttaa solun perimää. Näiden oireyhtymien geenivirheen kantajat sairastuvat jo nuorina, ja yleensä kyse on harvinaisesta syövästä. Suvun syöpähistoria on usein poikkeuksellinen ja herättää epäilyn periytyvästä syövästä. Kantajien strukturoitu tehostettu seuranta on parantanut ennustetta ja kokonaiselossaolo-osuutta 2010-luvulta alkaen.Peer reviewe

Suuren riskin rintasyöpäalttiuden seuranta on geenikohtaista

Suuren riskin rintasyöpäalttiutta naiselle aiheuttaviin geeneihin luetaan Suomessa geenit, joiden patogeenisiin variantteihin liittyy yli 40 %:n elinikäinen rintasyöpäriski. Tällaisia ovat BRCA1, BRCA2, PALB2, PTEN, TP53, STK11 ja CDH1. • Varianttien kantajien seuranta vaihtelee geenikohtaisesti. • Miesten rintasyöpään ovat yhteydessä ainakin BRCA1, BRCA2 ja PALB2. • Geeneihin liittyy lisääntynyt riski sairastua moniin muihinkin syöpiin.Peer reviewe

Effect of image compression and scaling on automated scoring of immunohistochemical stainings and segmentation of tumor epithelium

<p>Abstract</p> <p>Background</p> <p>Digital whole-slide scanning of tissue specimens produces large images demanding increasing storing capacity. To reduce the need of extensive data storage systems image files can be compressed and scaled down. The aim of this article is to study the effect of different levels of image compression and scaling on automated image analysis of immunohistochemical (IHC) stainings and automated tumor segmentation.</p> <p>Methods</p> <p>Two tissue microarray (TMA) slides containing 800 samples of breast cancer tissue immunostained against Ki-67 protein and two TMA slides containing 144 samples of colorectal cancer immunostained against EGFR were digitized with a whole-slide scanner. The TMA images were JPEG2000 wavelet compressed with four compression ratios: lossless, and 1:12, 1:25 and 1:50 lossy compression. Each of the compressed breast cancer images was furthermore scaled down either to 1:1, 1:2, 1:4, 1:8, 1:16, 1:32, 1:64 or 1:128. Breast cancer images were analyzed using an algorithm that quantitates the extent of staining in Ki-67 immunostained images, and EGFR immunostained colorectal cancer images were analyzed with an automated tumor segmentation algorithm. The automated tools were validated by comparing the results from losslessly compressed and non-scaled images with results from conventional visual assessments. Percentage agreement and kappa statistics were calculated between results from compressed and scaled images and results from lossless and non-scaled images.</p> <p>Results</p> <p>Both of the studied image analysis methods showed good agreement between visual and automated results. In the automated IHC quantification, an agreement of over 98% and a kappa value of over 0.96 was observed between losslessly compressed and non-scaled images and combined compression ratios up to 1:50 and scaling down to 1:8. In automated tumor segmentation, an agreement of over 97% and a kappa value of over 0.93 was observed between losslessly compressed images and compression ratios up to 1:25.</p> <p>Conclusions</p> <p>The results of this study suggest that images stored for assessment of the extent of immunohistochemical staining can be compressed and scaled significantly, and images of tumors to be segmented can be compressed without compromising computer-assisted analysis results using studied methods.</p> <p>Virtual slides</p> <p>The virtual slide(s) for this article can be found here: <url>http://www.diagnosticpathology.diagnomx.eu/vs/2442925476534995</url></p

Mast cells and eosinophils in invasive breast carcinoma

<p>Abstract</p> <p>Background</p> <p>Inflammatory cells in the tumour stroma has gained increasing interest recently. Thus, we aimed to study the frequency and prognostic impact of stromal mast cells and tumour infiltrating eosinophils in invasive breast carcinomas.</p> <p>Methods</p> <p>Tissue microarrays containing 234 cases of invasive breast cancer were prepared and analysed for the presence of stromal mast cells and eosinophils. Tumour infiltrating eosinophils were counted on hematoxylin-eosin slides. Immunostaining for tryptase was done and the total number of mast cells were counted and correlated to the proliferation marker Ki 67, positivity for estrogen and progesterone receptors, clinical parameters and clinical outcome.</p> <p>Results</p> <p>Stromal mast cells were found to correlate to low grade tumours and estrogen receptor positivity. There was a total lack of eosinophils in breast cancer tumours.</p> <p>Conclusion</p> <p>A high number of mast cells in the tumours correlated to low-grade tumours and estrogen receptor positivity. Eosinophils are not tumour infiltrating in breast cancers.</p

Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk

<p>Abstract</p> <p>Background</p> <p>Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Several studies have also shown the relationship between estrogen and cell cycle progression through activation of CCND1 transcription.</p> <p>Methods</p> <p>In this study, we have investigated the independent and the combined effects of commonly occurring CCND1 (Pro241Pro, A870G) and COMT (Met108/158Val) polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario (1228 breast cancer cases and 719 population controls) and Finland (728 breast cancer cases and 687 population controls). Both COMT and CCND1 polymorphisms have been previously shown to impact on the enzymatic activity of the coded proteins.</p> <p>Results</p> <p>Here, we have shown that the high enzymatic activity genotype of CCND1^High(AA) was associated with increased breast cancer risk in both the Ontario [OR: 1.3, 95%CI (1.0–1.69)] and the Finland sample [OR: 1.4, 95%CI (1.01–1.84)]. The heterozygous COMT^Medium(MetVal) and the high enzymatic activity of COMT^High(ValVal) genotype was also associated with breast cancer risk in Ontario cases, [OR: 1.3, 95%CI (1.07–1.68)] and [OR: 1.4, 95%CI (1.07–1.81)], respectively. However, there was neither a statistically significant association nor increased trend of breast cancer risk with COMT^High(ValVal) genotypes in the Finland cases [OR: 1.0, 95%CI (0.73–1.39)]. In the combined analysis, the higher activity alleles of the COMT and CCND1 is associated with increased breast cancer risk in both Ontario [OR: <b>2.22</b>, 95%CI (1.49–3.28)] and Finland [OR: <b>1.73</b>, 95%CI (1.08–2.78)] populations studied. The trend test was statistically significant in both the Ontario and Finland populations across the genotypes associated with increasing enzymatic activity.</p> <p>Conclusion</p> <p>Using two independent Caucasian populations, we have shown a stronger combined effect of the two commonly occurring CCND1 and COMT genotypes in the context of breast cancer predisposition.</p

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C8197/A16565), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program and the Ministry of Economic Development, Innovation and Export Trade of Quebec, grant PSR-SIIRI-701. Combination of the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative, grant 1 U19 CA148065-01 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.324