Genetic studies in familial non-BRCA breast cancer

Family history is an important risk factor for breast cancer, the presence of breast cancer in a first degree relative in general nearly doubles the risk and the risk increases with the number of affected relatives. Pathogenic mutations in BRCA1, BRCA2 and other high- and moderate risk-genes account for 25% of the familial risk for breast cancer. About 180 low-risk variants explain an additional 18% of the excess familial risk. The remainder of the genetic contribution to familial breast cancer is unexplained. A polygenic model, where pathogenic mutations with differential impact together confer an increased risk for breast cancer, has been suggested. The aim of this thesis has been to study and better understand how breast cancer is inherited and to identify underlying genetic factors that contribute to the risk in familial breast cancer without pathogenic mutations in BRCA1 or BRCA2 (non-BRCA families). In paper I tumour spectrum was investigated in our cohort of non-BRCA families with at least 2 cases of breast cancer and one case of other tumour type in first-, second degree relatives or first cousins. Distribution of tumour types, other than breast cancer, was compared with the distribution in Sweden in two reference years. We found an overrepresentation of endometrial cancer in the non-BRCA families with a 6.36 % proportion (CI 4.67–8.2) compared to the proportion in the general population in the reference years 1970 (3.07 %) and 2010 (2.64 %). The main finding of the study was the strong support for a breast- and endometrial cancer syndrome, which is a first step towards detecting new susceptibility variants. In paper II we investigated if breast cancer prognosis is affected by parent-of-origin in our cohort of non-BRCA families. A difference in prognosis may indicate an influence of a genetic mechanism that produces inter-lineage effects, such as genomic imprinting. No significant difference in overall or recurrence-free survival between maternal and paternal inheritance of breast cancer was observed with HRs of 0.99 (95% CI=0.54 to 1.80) and 1.22 (95% CI=0.78 to 1.92) respectively. An interesting finding in paper II was the predominance of maternally inherited cases, which indicates that parent-of-origin may not have an effect on breast cancer prognosis, but rather the risk of being affected. The protein truncating mutation CHEK2*1100delC is a moderate-risk variant associated with a 2-3 fold increased risk of developing breast cancer, but the risk is considerably higher in carriers with a family history. The individual risk for breast cancer in carriers of CHEK2*1100delC is thereby difficult to predict. In paper III we performed whole-exome sequencing in cases of CHEK2*1100delC carriers in search of genetic variants that may modify breast cancer risk in this patient group. All non-synonymous mutations were evaluated and 11 candidate alleles were selected and tested in a validation. No CHEK2 specific modifier could be identified though, as none of the variants showed significant difference in allele frequency in CHEK2*1100delC carriers compared to controls. Continuous studies of genetic modifiers are of importance to improve breast cancer risk prediction for CHEK2*1100delC carriers

Kanalrally eller medvetet val - om hur unga finlandssvenskar lyssnar på radio

Only abstract. Paper copies of master’s theses are listed in the Helka database (http://www.helsinki.fi/helka). Electronic copies of master’s theses are either available as open access or only on thesis terminals in the Helsinki University Library.Vain tiivistelmä. Sidottujen gradujen saatavuuden voit tarkistaa Helka-tietokannasta (http://www.helsinki.fi/helka). Digitaaliset gradut voivat olla luettavissa avoimesti verkossa tai rajoitetusti kirjaston opinnäytekioskeilla.Endast sammandrag. Inbundna avhandlingar kan sökas i Helka-databasen (http://www.helsinki.fi/helka). Elektroniska kopior av avhandlingar finns antingen öppet på nätet eller endast tillgängliga i bibliotekets avhandlingsterminaler.I denna Pro Gradu-avhandling har jag undersökt vilket plats radion har i finlandssvenska ungdomars vardag. Utgångspunkten var att ta reda på vilken bild de unga har av olika radiokanaler, samt att reda ut hur den relativt nya radiokanalen Extrem har klarat sig i den hårdnande konkurrensen på radiofältet. För att få svar på dessa frågor lät jag 94 ungdomar i 17-års åldern dels skriva en uppsats om sina radiovanor och dels fylla i bakgrundsfrågor bl a om vilka kanaler de lyssnar på och hur ofta. Jag har även haft stor hjälp av de undersökningar som FSR (Finlands Svenska Radio) gjort. För analysen av uppsatserna använde jag mig av grov diskursanalys, i övrigt av traditionell kvantitativ analys. Konklusionen av arbetet är i korthet följande: För det första är de regionala skillnaderna rätt stora i fråga om kanalval - här kan man t ex jämföra Österbotten och huvudstadsregionen. I uppsatserna kommer det fram att skillnaderna inte bara har med språkkunskaper att göra, snarare beror olikheterna på variationer i det finlandssvenska samt på det som vi kunde kalla finlandssvensk identitet. För det andra uppfattar ungdomarna kanalerna Nova, Extrem och Mafia som mycket olika. Det visar sig, att Nova upplevs som kompromisskanalen medan Mafia verkar vara den mest kontroversiella kanalen av de tre, en "pojkarnas kanal". Extrem, i sin tur, uppfattas av sina trogna lyssnare (dessa finns främst i Österbotten och i Väst-Nyland som en skämtsam och humorspäckad radiokanal. Ungdomarna i Helsingforstrakten, som inte just lyssnar på finlandssvensk radio, karaktäriserade Extrem som en kanal som man bara inte lyssnar på - eftersom språket är svenska! Sist men inte minst har jag tagit upp olika teoretiska synpunkter på radions roll i vår moderna värld och jämfört detta med hur ungdomarna i min undersökning uppfattade sin egen radiokonsumtion. Dessutom har jag försökt sätta fingret på hur olika typer av program går hem och varför. Målet har således varit att ta upp faktorer som gör en radiokanal populär, samt att beskriva hur finlandssvenska unga och ungdomar över lag använder sig av radion

Production of Recombinant Peanut Allergen Ara h 2 using Lactococcus lactis

<p>Abstract</p> <p>Background</p> <p>Natural allergen sources can supply large quantities of authentic allergen mixtures for use as immunotherapeutics. However, such extracts are complex, difficult to define, vary from batch to batch, which may lead to unpredictable efficacy and/or unacceptable levels of side effects. The use of recombinant expression systems for allergen production can alleviate some of these issues. Several allergens have been tested in high-level expression systems and in most cases show immunereactivity comparable to their natural counterparts. The gram positive lactic acid bacterium <it>Lactococcus lactis </it>is an attractive microorganism for use in the production of protein therapeutics. <it>L. lactis </it>is considered food grade, free of endotoxins, and is able to secrete the heterologous product together with few other native proteins. Hypersensitivity to peanut represents a serious allergic problem. Some of the major allergens in peanut have been described. However, for therapeutic usage more information about the individual allergenic components is needed. In this paper we report recombinant production of the Ara h 2 peanut allergen using <it>L. lactis</it>.</p> <p>Results</p> <p>A synthetic ara h 2 gene was cloned into an <it>L. lactis </it>expression plasmid containing the P170 promoter and the SP310mut2 signal sequence. Flask cultures grown overnight showed secretion of the 17 kDa Ara h 2 protein. A batch fermentation resulted in 40 mg/L recombinant Ara h 2. Purification of Ara h 2 from the culture supernatant was done by hydrophobic exclusion and size separation. Mass spectrometry and N-terminal analysis showed a recombinant Ara h 2 of full length and correctly processed by the signal peptidase. The immunological activity of recombinant Ara h 2 was analysed by ELISA using antibodies specific for native Ara h 2. The recombinant Ara h 2 showed comparable immunereactivity to that of native Ara h 2.</p> <p>Conclusion</p> <p>Recombinant production of Ara h 2 using <it>L. lactis </it>can offer high yields of secreted, full length and immunologically active allergen. The <it>L. lactis </it>expression system can support recombinant allergen material for immunotherapy and component resolved allergen diagnostics.</p

A search for modifying genetic factors in CHEK2 : c.1100delC breast cancer patients

The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.Peer reviewe

The association between weight at birth and breast cancer risk revisited using Mendelian randomisation.

Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10-8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval 0.73-1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, genetically-predicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk

Incorporating progesterone receptor expression into the PREDICT breast prognostic model

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe