Mikael Eriksson - Academia.edu (original) (raw)

Papers by Mikael Eriksson

Research paper thumbnail of Cohort profile: The Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA)

International journal of epidemiology, Jan 9, 2017

Research paper thumbnail of Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

The American Journal of Human Genetics, 2018

Research paper thumbnail of Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort

International journal of cancer, Jan 2, 2018

Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not cl... more Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose of this study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi-Seq 2500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were co...

Research paper thumbnail of A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Nature genetics, Jan 18, 2018

The breast cancer risk variants identified in genome-wide association studies explain only a smal... more The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new ins...

Research paper thumbnail of Associations between childhood body size and seventeen adverse outcomes: analysis of 65,057 European women

Scientific reports, Jan 5, 2017

Large childhood body size has been consistently shown to be associated with decreased breast canc... more Large childhood body size has been consistently shown to be associated with decreased breast cancer risk. However, it is important to consider the effects of a large childhood body size on other adult diseases. It is not clear if the associations between childhood body size and adult diseases will persist if they later attain healthy weight. The associations between body size at age 7 and 17 adverse outcomes in adulthood were examined using Cox models in a Swedish study of 65,057 women. Large body size at age 7, when compared to small body size, was associated with decreased risk for breast cancer (HR [95% CI]: 0.81 [0.70-0.93]) and increased risks for anorexia (2.13 [1.63-2.77]) and bulimia (1.91 [1.35-2.70]). Neither adjusting for adult BMI nor restricting the dataset to lean adults (BMI < 25 kg/m2) attenuated the associations. While large body size at age 7 by itself was positively associated with increased risks of diabetes (1.34 [1.16-1.55]), PCOS (1.69 [1.13-2.51]) and hype...

Research paper thumbnail of Longitudinal fluctuation in mammographic percent density differentiates between interval and screen-detected breast cancer

International Journal of Cancer, 2016

Research paper thumbnail of Differences in mammographic density between Asian and Caucasian populations: a comparative analysis

Breast Cancer Research and Treatment, 2016

Mammographic density is a measurable and modifiable biomarker that is strongly and independently ... more Mammographic density is a measurable and modifiable biomarker that is strongly and independently associated with breast cancer risk. Paradoxically, although Asian women have lower risk of breast cancer, studies of minority Asian women in predominantly Caucasian populations have found that Asian women have higher percent density. In this cross-sectional study, we compared the distribution of mammographic density for a matched cohort of Asian women from Malaysia and Caucasian women from Sweden, and determined if variations in mammographic density could be attributed to population differences in breast cancer risk factors. Volumetric mammographic density was compared for 1501 Malaysian and 4501 Swedish healthy women, matched on age and body mass index. We used multivariable log-linear regression to determine the risk factors associated with mammographic density and mediation analysis to identify factors that account for differences in mammographic density between the two cohorts. Compared to Caucasian women, percent density was 2.0% higher among Asian women (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), and dense volume was 5.7 cm(3) higher among pre-menopausal Asian women (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Dense volume was 3.0 cm(3) lower among post-menopausal Asian women (p = 0.009) compared to post-menopausal Caucasian women, and this difference was attributed to population differences in height, weight, and parity (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Our analysis suggests that among post-menopausal women, population differences in mammographic density and risk to breast cancer may be accounted for by height, weight, and parity. Given that pre-menopausal Asian and Caucasian women have similar population risk to breast cancer but different dense volume, development of more appropriate biomarkers of risk in pre-menopausal women is required.

Research paper thumbnail of Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

American journal of human genetics, Jan 3, 2016

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated wit... more Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen receptor-positive (ER(+)) breast cancer (per-g allele OR ER(+) = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10(-30)). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER(-)) breast cancer (lead SNP rs6864776: per-a allele OR ER(-) = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10(-12)), and a single signal 3 SNP (rs200229088: per-t allele OR ER(+) = 1.12; 95% C...

Research paper thumbnail of PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Journal of medical genetics, Dec 5, 2016

The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associate... more The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT,…

Research paper thumbnail of Worse quality of life in young and recently diagnosed breast cancer survivors compared with female survivors of other cancers: A cross-sectional study

International journal of cancer, Jan 3, 2016

Literature focusing on health-related quality of life (HRQoL) by cancer site among women only is ... more Literature focusing on health-related quality of life (HRQoL) by cancer site among women only is scarce. This study examines HRQoL of breast cancer (BC) survivors compared with female survivors of other cancers, and to understand which subgroups of BC survivors were particularly at risk of reduced HRQoL. We placed emphasis on young (<50 years) and recently diagnosed (≤5 years) survivors, where the deficits in HRQoL were most pronounced. The cross-sectional study consisted of 2,224 BC survivors, 8,504 non-cancer controls and 2,205 other cancer survivors in the Karma study. We examined HRQoL differences using linear regression analyses in the whole cohort and in a subset of young and recently diagnosed BC survivors (n = 242) and female survivors of other cancers (n = 140) with comparable ages at diagnosis (43.6 vs 43.6, p = 0.917) and time since diagnosis (2.3 vs 2.8 years, p < 0.001). HRQoL was assessed using the EORTC QLQ-C30 questionnaire. While only cognitive functioning was...

Research paper thumbnail of No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Journal of medical genetics, May 26, 2016

BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementa... more BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. The rare truncating al...

Research paper thumbnail of Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium

Human genetics, Jan 30, 2015

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promot... more Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated wit...

Research paper thumbnail of In Search for the Genetic Basis of Quality of Life in Healthy Swedish Women-A GWAS Study Using the iCOGS Custom Genotyping Array

PloS one, 2015

Quality of life (QoL) is increasingly measured in both research and clinical practice. QoL-assess... more Quality of life (QoL) is increasingly measured in both research and clinical practice. QoL-assessments are built on a long, empirically-based, and stringent approach. There is ample evidence that QoL is, in part, heritable. We therefore performed a GWAS relating genetic variation to QoL in healthy females. In 5,142 healthy females, background characteristics (e.g. demographic, clinical, lifestyle and psychological factors) and QoL by means of the EORTC QLQ-C30 were measured. Moreover, women were genotyped using a custom array including ~210,000 single nucleotide polymorphisms (SNPs). Initially, SNPs were related to each QoL-domain, by means of partially adjusted (controlling for age and population stratification) and fully adjusted (controlling for age, population stratification, and background characteristics) regression analyses. Additionally, gene-based analyses were performed relating the combined effect of SNPs within each gene to QoL using the statistical software package VEGA...

Research paper thumbnail of Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization

Journal of the National Cancer Institute, 2015

Epidemiological studies have linked adult height with breast cancer risk in women. However, the m... more Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients. The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendeli...

Research paper thumbnail of Predictors of Discontinuation of Adjuvant Hormone Therapy in Patients With Breast Cancer

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015

To identify predictors of discontinuation of adjuvant hormone therapy in patients with breast can... more To identify predictors of discontinuation of adjuvant hormone therapy in patients with breast cancer. We conducted a record-linkage study based on data from Stockholm-Gotland Breast Cancer Register, Swedish Prescribed Drug Register, and self-reported questionnaire. Women diagnosed with breast cancer between 2005 and 2008 in Stockholm, Sweden, were prospectively followed for 5 years until 2013, starting from their first prescription of tamoxifen or aromatase inhibitors (N = 3,395). Family history of ovarian cancer (hazard ratio [HR], 1.55; 95% CI, 1.19 to 2.02); younger (< 40 years; HR, 1.39; 95% CI, 1.08 to 1.78) and older (≥ 65 years; HR, 1.15; 95% CI, 1.03 to 1.28) age; higher Charlson comorbidity index (≥ 2 v 0; HR, 1.35; 95% CI, 1.03 to 1.76); and use of analgesics (HR, 1.33; 95% CI, 1.16 to 1.52), hypnotics/sedatives (HR, 1.24; 95% CI, 1.07 to 1.43), GI drugs (HR, 1.25; 95% CI, 1.08 to 1.43), and hormone replacement therapy (HR, 1.27; 95% CI, 1.08 to 1.49) were identified as...

Research paper thumbnail of No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Gynecologic oncology, May 2, 2015

Clinical genetic testing is commercially available for rs61764370, an inherited variant residing ... more Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS…

Research paper thumbnail of Identification of novel genetic markers of breast cancer survival

Journal of the National Cancer Institute, 2015

Survival after a diagnosis of breast cancer varies considerably between patients, and some of thi... more Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to ...

Research paper thumbnail of Prediction of breast cancer risk based on profiling with common genetic variants

Journal of the National Cancer Institute, 2015

Data for multiple common susceptibility alleles for breast cancer may be combined to identify wom... more Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women ...

Research paper thumbnail of Background risk of breast cancer and the association between physical activity and mammographic density

Breast Cancer Research, 2015

Research paper thumbnail of Occupational exposures and risk of gastric cancer in a population-based case-control study

Cancer research, 1999

Gastric cancer trends seem to follow improvements in the environment of blue-collar workers, but ... more Gastric cancer trends seem to follow improvements in the environment of blue-collar workers, but the etiological role of occupational exposures in gastric carcinogenesis is scantily investigated. The risk of gastric adenocarcinoma in 10 common occupational industries, and particularly the long-term effects of asbestos, organic solvents, impregnating agents, insecticides, and herbicides, were evaluated in a population-based case-control study, including data on most established risk factors. The study base included all individuals of ages 40-79, born in Sweden and living in either of two areas (total population, 1.3 million) with differing gastric cancer incidences, from February 1989 through January 1995. We interviewed 567 cases classified to site (cardia/noncardia) and histological type, and 1,165 population-based controls, frequency-matched for age and sex. Metal workers had a 46% excess gastric cancer risk [adjusted odds ratio (OR), 1.46; 95% confidence interval (CI), 1.10-1.94]...

Research paper thumbnail of Cohort profile: The Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA)

International journal of epidemiology, Jan 9, 2017

Research paper thumbnail of Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

The American Journal of Human Genetics, 2018

Research paper thumbnail of Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort

International journal of cancer, Jan 2, 2018

Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not cl... more Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose of this study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi-Seq 2500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were co...

Research paper thumbnail of A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Nature genetics, Jan 18, 2018

The breast cancer risk variants identified in genome-wide association studies explain only a smal... more The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new ins...

Research paper thumbnail of Associations between childhood body size and seventeen adverse outcomes: analysis of 65,057 European women

Scientific reports, Jan 5, 2017

Large childhood body size has been consistently shown to be associated with decreased breast canc... more Large childhood body size has been consistently shown to be associated with decreased breast cancer risk. However, it is important to consider the effects of a large childhood body size on other adult diseases. It is not clear if the associations between childhood body size and adult diseases will persist if they later attain healthy weight. The associations between body size at age 7 and 17 adverse outcomes in adulthood were examined using Cox models in a Swedish study of 65,057 women. Large body size at age 7, when compared to small body size, was associated with decreased risk for breast cancer (HR [95% CI]: 0.81 [0.70-0.93]) and increased risks for anorexia (2.13 [1.63-2.77]) and bulimia (1.91 [1.35-2.70]). Neither adjusting for adult BMI nor restricting the dataset to lean adults (BMI < 25 kg/m2) attenuated the associations. While large body size at age 7 by itself was positively associated with increased risks of diabetes (1.34 [1.16-1.55]), PCOS (1.69 [1.13-2.51]) and hype...

Research paper thumbnail of Longitudinal fluctuation in mammographic percent density differentiates between interval and screen-detected breast cancer

International Journal of Cancer, 2016

Research paper thumbnail of Differences in mammographic density between Asian and Caucasian populations: a comparative analysis

Breast Cancer Research and Treatment, 2016

Mammographic density is a measurable and modifiable biomarker that is strongly and independently ... more Mammographic density is a measurable and modifiable biomarker that is strongly and independently associated with breast cancer risk. Paradoxically, although Asian women have lower risk of breast cancer, studies of minority Asian women in predominantly Caucasian populations have found that Asian women have higher percent density. In this cross-sectional study, we compared the distribution of mammographic density for a matched cohort of Asian women from Malaysia and Caucasian women from Sweden, and determined if variations in mammographic density could be attributed to population differences in breast cancer risk factors. Volumetric mammographic density was compared for 1501 Malaysian and 4501 Swedish healthy women, matched on age and body mass index. We used multivariable log-linear regression to determine the risk factors associated with mammographic density and mediation analysis to identify factors that account for differences in mammographic density between the two cohorts. Compared to Caucasian women, percent density was 2.0% higher among Asian women (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), and dense volume was 5.7 cm(3) higher among pre-menopausal Asian women (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Dense volume was 3.0 cm(3) lower among post-menopausal Asian women (p = 0.009) compared to post-menopausal Caucasian women, and this difference was attributed to population differences in height, weight, and parity (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Our analysis suggests that among post-menopausal women, population differences in mammographic density and risk to breast cancer may be accounted for by height, weight, and parity. Given that pre-menopausal Asian and Caucasian women have similar population risk to breast cancer but different dense volume, development of more appropriate biomarkers of risk in pre-menopausal women is required.

Research paper thumbnail of Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

American journal of human genetics, Jan 3, 2016

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated wit... more Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen receptor-positive (ER(+)) breast cancer (per-g allele OR ER(+) = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10(-30)). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER(-)) breast cancer (lead SNP rs6864776: per-a allele OR ER(-) = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10(-12)), and a single signal 3 SNP (rs200229088: per-t allele OR ER(+) = 1.12; 95% C...

Research paper thumbnail of PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Journal of medical genetics, Dec 5, 2016

The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associate... more The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT,…

Research paper thumbnail of Worse quality of life in young and recently diagnosed breast cancer survivors compared with female survivors of other cancers: A cross-sectional study

International journal of cancer, Jan 3, 2016

Literature focusing on health-related quality of life (HRQoL) by cancer site among women only is ... more Literature focusing on health-related quality of life (HRQoL) by cancer site among women only is scarce. This study examines HRQoL of breast cancer (BC) survivors compared with female survivors of other cancers, and to understand which subgroups of BC survivors were particularly at risk of reduced HRQoL. We placed emphasis on young (<50 years) and recently diagnosed (≤5 years) survivors, where the deficits in HRQoL were most pronounced. The cross-sectional study consisted of 2,224 BC survivors, 8,504 non-cancer controls and 2,205 other cancer survivors in the Karma study. We examined HRQoL differences using linear regression analyses in the whole cohort and in a subset of young and recently diagnosed BC survivors (n = 242) and female survivors of other cancers (n = 140) with comparable ages at diagnosis (43.6 vs 43.6, p = 0.917) and time since diagnosis (2.3 vs 2.8 years, p < 0.001). HRQoL was assessed using the EORTC QLQ-C30 questionnaire. While only cognitive functioning was...

Research paper thumbnail of No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Journal of medical genetics, May 26, 2016

BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementa... more BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. The rare truncating al...

Research paper thumbnail of Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium

Human genetics, Jan 30, 2015

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promot... more Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated wit...

Research paper thumbnail of In Search for the Genetic Basis of Quality of Life in Healthy Swedish Women-A GWAS Study Using the iCOGS Custom Genotyping Array

PloS one, 2015

Quality of life (QoL) is increasingly measured in both research and clinical practice. QoL-assess... more Quality of life (QoL) is increasingly measured in both research and clinical practice. QoL-assessments are built on a long, empirically-based, and stringent approach. There is ample evidence that QoL is, in part, heritable. We therefore performed a GWAS relating genetic variation to QoL in healthy females. In 5,142 healthy females, background characteristics (e.g. demographic, clinical, lifestyle and psychological factors) and QoL by means of the EORTC QLQ-C30 were measured. Moreover, women were genotyped using a custom array including ~210,000 single nucleotide polymorphisms (SNPs). Initially, SNPs were related to each QoL-domain, by means of partially adjusted (controlling for age and population stratification) and fully adjusted (controlling for age, population stratification, and background characteristics) regression analyses. Additionally, gene-based analyses were performed relating the combined effect of SNPs within each gene to QoL using the statistical software package VEGA...

Research paper thumbnail of Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization

Journal of the National Cancer Institute, 2015

Epidemiological studies have linked adult height with breast cancer risk in women. However, the m... more Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients. The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendeli...

Research paper thumbnail of Predictors of Discontinuation of Adjuvant Hormone Therapy in Patients With Breast Cancer

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015

To identify predictors of discontinuation of adjuvant hormone therapy in patients with breast can... more To identify predictors of discontinuation of adjuvant hormone therapy in patients with breast cancer. We conducted a record-linkage study based on data from Stockholm-Gotland Breast Cancer Register, Swedish Prescribed Drug Register, and self-reported questionnaire. Women diagnosed with breast cancer between 2005 and 2008 in Stockholm, Sweden, were prospectively followed for 5 years until 2013, starting from their first prescription of tamoxifen or aromatase inhibitors (N = 3,395). Family history of ovarian cancer (hazard ratio [HR], 1.55; 95% CI, 1.19 to 2.02); younger (< 40 years; HR, 1.39; 95% CI, 1.08 to 1.78) and older (≥ 65 years; HR, 1.15; 95% CI, 1.03 to 1.28) age; higher Charlson comorbidity index (≥ 2 v 0; HR, 1.35; 95% CI, 1.03 to 1.76); and use of analgesics (HR, 1.33; 95% CI, 1.16 to 1.52), hypnotics/sedatives (HR, 1.24; 95% CI, 1.07 to 1.43), GI drugs (HR, 1.25; 95% CI, 1.08 to 1.43), and hormone replacement therapy (HR, 1.27; 95% CI, 1.08 to 1.49) were identified as...

Research paper thumbnail of No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Gynecologic oncology, May 2, 2015

Clinical genetic testing is commercially available for rs61764370, an inherited variant residing ... more Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS…

Research paper thumbnail of Identification of novel genetic markers of breast cancer survival

Journal of the National Cancer Institute, 2015

Survival after a diagnosis of breast cancer varies considerably between patients, and some of thi... more Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to ...

Research paper thumbnail of Prediction of breast cancer risk based on profiling with common genetic variants

Journal of the National Cancer Institute, 2015

Data for multiple common susceptibility alleles for breast cancer may be combined to identify wom... more Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women ...

Research paper thumbnail of Background risk of breast cancer and the association between physical activity and mammographic density

Breast Cancer Research, 2015

Research paper thumbnail of Occupational exposures and risk of gastric cancer in a population-based case-control study

Cancer research, 1999

Gastric cancer trends seem to follow improvements in the environment of blue-collar workers, but ... more Gastric cancer trends seem to follow improvements in the environment of blue-collar workers, but the etiological role of occupational exposures in gastric carcinogenesis is scantily investigated. The risk of gastric adenocarcinoma in 10 common occupational industries, and particularly the long-term effects of asbestos, organic solvents, impregnating agents, insecticides, and herbicides, were evaluated in a population-based case-control study, including data on most established risk factors. The study base included all individuals of ages 40-79, born in Sweden and living in either of two areas (total population, 1.3 million) with differing gastric cancer incidences, from February 1989 through January 1995. We interviewed 567 cases classified to site (cardia/noncardia) and histological type, and 1,165 population-based controls, frequency-matched for age and sex. Metal workers had a 46% excess gastric cancer risk [adjusted odds ratio (OR), 1.46; 95% confidence interval (CI), 1.10-1.94]...