Purpose: Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether... Show morePurpose: Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in gBRCA carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship.Experimental Design: Thirty-eight gBRCA carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gyneco-logic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the gBRCA-wild-type allele (gBRCA/LOHpos) were defined "gBRCA-associated," those without LOH (gBRCA/LOHneg) were defined "sporadic."Results: LOH could be assessed for 40 ECs (30 gBRCA1, 10 gBRCA2), of which 60% were gBRCA/LOHpos. gBRCA/LOHpos ECs were more frequently of nonendometrioid (58%, P = 0.001) and grade 3 histology (79%, P < 0.001). All but two were in the TP53-mutated TCGA-subgroup (91.7%, P < 0.001). In contrast, gBRCA/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: POLE-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and TP53-mutated (6.3%).Conclusions: We provide novel evidence in favor of EC being part of the gBRCA-associated HBOC-syndrome. gBRCA-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of gBRCA carriers. Show less
Boonen, R.A.C.M.; Rodrigue, A.; Stoepker, C.; Wiegant, W.W.; Vroling, B.; Sharma, M.; ... ; Attikum, H. van 2019
Heterozygous carriers of germ-line loss-of-function variants in the DNA repair gene PALB2 are at a highly increased lifetime risk for developing breast cancer. While truncating variants in PALB2... Show moreHeterozygous carriers of germ-line loss-of-function variants in the DNA repair gene PALB2 are at a highly increased lifetime risk for developing breast cancer. While truncating variants in PALB2 are known to increase cancer risk, the interpretation of missense variants of uncertain significance (VUS) is in its infancy. Here we describe the development of a relatively fast and easy cDNA-based system for the semi high-throughput functional analysis of 48 VUS in human PALB2. By assessing the ability of PALB2 VUS to rescue the DNA repair and checkpoint defects in Palb2 knockout mouse embryonic stem (mES) cells, we identify various VUS in PALB2 that impair its function. Three VUS in the coiled-coil domain of PALB2 abrogate the interaction with BRCA1, whereas several VUS in the WD40 domain dramatically reduce protein stability. Thus, our functional assays identify damaging VUS in PALB2 that may increase cancer risk. Show less
Figlioli, G.; Bogliolo, M.; Catucci, I.; Caleca, L.; Lasheras, S.V.; Pujol, R.; ... ; Marsh, D. 2019
Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PAM, ATM, and CHEK2 are associated with breast cancer risk... Show moreBreast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PAM, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and pArg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM(-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors. Show less
Background In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM... Show moreBackground In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over BC surveillance has been reported yet. Methods In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specific mortality rates, separately for BRCA1 and BRCA2 mutation carriers. Results During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20-0.90) for overall mortality and 0.06 (95% CI 0.01-0.46) for BC-specific mortality. BC-specific survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15-1.36). BC-specific survival at age 65 was 98% for surveillance and 100% for BRRM. Conclusion BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specific survival as surveillance. Our findings support a more individualized counseling based on BRCA mutation type. Show less
Bredart, A.; Anota, A.; Dick, J.; Cano, A.; Pauw, A. de; Kop, J.L.; ... ; Dolbeault, S. 2019
Background We performed a comprehensive assessment of the psychometrics of the "Psychosocial Aspects in Hereditary Cancer" (PAHC) questionnaire in French, German and Spanish. Methods Women... Show moreBackground We performed a comprehensive assessment of the psychometrics of the "Psychosocial Aspects in Hereditary Cancer" (PAHC) questionnaire in French, German and Spanish. Methods Women consecutively approached in Cancer Genetic Clinics completed the PAHC, distress and satisfaction questionnaires at pre-testing (T1) and after test result disclosure (T2). In addition to standard psychometric attributes, we assessed the PAHC ability to respond to change (i.e. improvement or deterioration from T1 to T2) in perceived difficulties and computed minimal important differences (MID) in PAHC scores as compared with self-reported needs for additional counselling. Results Of 738 eligible counselees, 214 (90%) in France (Paris), 301 (92%) in Germany (Cologne) and 133 (77%) in Spain (Barcelona) completed the PAHC. A six-factor revised PAHC model yielded acceptable CFA goodness-of-fit indexes and good all scales internal consistencies. PAHC scales demonstrated expected conceptual differences with distress and satisfaction with counselling. Different levels of psychosocial difficulties were evidenced between counselees' subgroups and over time (p-values < .05). MID estimates ranged from 8 to 15 for improvement and 9 to 21 for deterioration. Conclusion The PAHC French, German and Spanish versions are reliable and valid for evaluating the psychosocial difficulties of women at high BC risk attending genetic clinics. Show less
Background The currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that... Show moreBackground The currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based polygenic risk score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families.Methods 101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm breast cancer lifetime risk with the effect of the sPRS.Results The mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95% CI 1.03 to 1.28, p=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7% and 19.8 % of the women according to breast screening guidelines from the USA (National Comprehensive Cancer Network), UK (National Institute for Health and Care Excellence and the Netherlands (Netherlands Comprehensive Cancer Organisation), respectively.Conclusion Our results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families. Show less
Bredart, A.; Kop, J.L.; Dick, J.; Cano, A.; Pauw, A. de; Anota, A.; ... ; Dolbeault, S. 2019
Objectives and setting Advances in multigene panel testing for cancer susceptibility has increased the complexity of counselling, requiring particular attention to counselees' psychosocial needs.... Show moreObjectives and setting Advances in multigene panel testing for cancer susceptibility has increased the complexity of counselling, requiring particular attention to counselees' psychosocial needs. Changes in psychosocial problems before and after genetic testing were prospectively compared between genetic test results in women tested for breast or ovarian cancer genetic susceptibility in French, German and Spanish clinics.Participants and measures Among 752 counselees consecutively approached, 646 (86%) were assessed after the initial genetic consultation (T1), including 510 (68%) affected with breast cancer, of which 460 (61%) were assessed again after receiving the test result (T2), using questionnaires addressing genetic-specific psychosocial problems (Psychosocial Aspects of Hereditary Cancer (PAHC)-six scales). Sociodemographic and clinical data were also collected.Results Seventy-nine (17.2%), 19 (4.1%), 259 (56.3%), 44 (9.6%) and 59 (12.8%) women received a BRCA1/2, another high/moderate-risk pathogenic variant (PV), negative uninformative, true negative (TN) or variant of uncertain significance result (VUS), respectively. On multiple regression analyses, compared with women receiving another result, those with a VUS decreased more in psychosocial problems related to hereditary predisposition (eg, coping with the test result) (beta=-0.11, p<0.05) and familial/social issues (eg, risk communication) (beta=-0.13, p<0.05), almost independently from their problems before testing. Women with a PV presented no change in hereditary predisposition problems and, so as women with a TN result, a non-significant increase in familial/social issues. Other PAHC scales (ie, emotions, familial cancer, personal cancer and children-related issues) were not affected by genetic testing.Conclusions In women tested for breast or ovarian cancer genetic risk in European genetics clinics, psychosocial problems were mostly unaffected by genetic testing. Apart from women receiving a VUS result, those with another test result presented unchanged needs in counselling in particular about hereditary predisposition and familial/social issues. Show less
Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast... Show moreFanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95% CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants. Show less
Background PALB2 monoallelic loss-of-function germ-line variants confer a breast cancer risk comparable to the average BRCA2 pathogenic variant. Recommendations for risk reduction strategies in... Show moreBackground PALB2 monoallelic loss-of-function germ-line variants confer a breast cancer risk comparable to the average BRCA2 pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify loss-of-function variants in PALB2-without incurring overprediction-is thus of paramount clinical relevance. Towards this aim, we have performed a comprehensive characterisation of alternative splicing in PALB2, analysing its relevance for the classification of truncating and splice site variants according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. Methods Alternative splicing was characterised in RNAs extracted from blood, breast and fimbriae/ovary-related human specimens (n=112). RNAseq, RT-PCR/CE and CloneSeq experiments were performed by five contributing laboratories. Centralised revision/curation was performed to assure high-quality annotations. Additional splicing analyses were performed in PALB2 c.212-1G>A, c.1684+1G>A, c.2748+2T>G, c.3113+5G>A, c.3350+1G>A, c.3350+4A>C and c.3350+5G>A carriers. The impact of the findings on PVS1 status was evaluated for truncating and splice site variant. Results We identified 88 naturally occurring alternative splicing events (81 newly described), including 4 in-frame events predicted relevant to evaluate PVS1 status of splice site variants. We did not identify tissue-specific alternate gene transcripts in breast or ovarian-related samples, supporting the clinical relevance of blood-based splicing studies. Conclusions PVS1 is not necessarily warranted for splice site variants targeting four PALB2 acceptor sites (exons 2, 5, 7 and 10). As a result, rare variants at these splice sites cannot be assumed pathogenic/likely pathogenic without further evidences. Our study puts a warning in up to five PALB2 genetic variants that are currently reported as pathogenic/likely pathogenic in ClinVar. Show less
Lakeman, I.M.M.; Hilbers, F.S.; Rodriguez-Girondo, M.; Lee, A.; Vreeswijk, M.P.G.; Hollestelle, A.; ... ; Devilee, P. 2019
Background The currently known breast cancer associated Single Nucleotide Polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that... Show moreBackground The currently known breast cancer associated Single Nucleotide Polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based Polygenic Risk Score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families. Methods 101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the BOADICEA breast cancer lifetime risk with the effect of the sPRS. Results The mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95%CI=1.03-1.28, P=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7%, and 19.8% of the women according to breast screening guidelines from the United States of America (NCCN), United Kingdom (NICE), and the Netherlands (IKNL), respectively. Conclusion Our results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families. Show less
Lakeman, I.M.M.; Schmidt, M.K.; Asperen, C.J. van; Devilee, P. 2019
Purpose of ReviewBreast cancer is the most common cancer among females in developed countries. Strategies such as early detection by breast cancer screening can reduce the burden of disease but... Show morePurpose of ReviewBreast cancer is the most common cancer among females in developed countries. Strategies such as early detection by breast cancer screening can reduce the burden of disease but have disadvantages including overdiagnosis and increased cost. Stratification of women according to the risk of developing breast cancer, based on genetic and lifestyle risk factors, could improve risk-reduction and screening strategies by targeting those most likely to benefit.Recent FindingsBreast cancer risk is partly determined by genetic factors including rare pathogenic variants in susceptibility genes and common low-risk variants. Other risk factors include alcohol use, smoking, reproductive factors, hormonal factors, family history, mammographic density, BMI, and body height. Ideally, all risk factors are combined into an individual breast cancer lifetime risk score, but this requires knowledge about their interactions as well as accurate effect sizes. A few risk models seem to be sufficiently developed to inform clinical risk management to minimise cancer risk of those at increased risk and avoid overtreatment of those at decreased risk.SummaryIn this review, we briefly summarise the breast cancer susceptibility factors and discuss avenues towards combining all these factors to create individual risk scores. Show less
Lakeman, I.M.M.; Schmidt, M.K.; Asperen, C.J. van; Devilee, P. 2019
Purpose of review - Breast cancer is the most common cancer among females in developed countries. Strategies such as early detection by breast cancer screening can reduce the burden of disease but... Show morePurpose of review - Breast cancer is the most common cancer among females in developed countries. Strategies such as early detection by breast cancer screening can reduce the burden of disease but have disadvantages including overdiagnosis and increased cost. Stratification of women according to the risk of developing breast cancer, based on genetic and lifestyle risk factors, could improve risk−reduction and screening strategies by targeting those most likely to benefit. Recent findings - Breast cancer risk is partly determined by genetic factors including rare pathogenic variants in susceptibility genes and common low risk variants. Other risk factors include alcohol use, smoking, reproductive factors, hormonal factors, family history, mammographic density, BMI and body height. Ideally, all risk factors are combined into an individual breast cancer lifetime risk score, but this requires knowledge about their interactions as well as accurate effect-sizes. A few risk models seem to be sufficiently developed to inform clinical risk management to minimize cancer risk of those at increased risk and avoid overtreatment of those at decreased risk. Summary - In this review we briefly summarise the breast cancer susceptibility factors and discuss avenues towards combining all these factors to create individual risk scores. Show less
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues,... Show moreGenome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer. Show less
BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.METHODS: Meta-analyses included summary... Show moreBACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using similar to 10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).RESULTS: We did not find any variant associated with breast cancer-specific mortality at P<5 x 10(-8). For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 x 10(-7), hazard ratio [HR] = 0.88, 95% confidence interval [ CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7: rs67918676 (BFDP = 11%, P = 1.38 x 10(-7), HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP <15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients. Show less
Opstal-van Winden, A.W.J.; Haan, H.G. de; Hauptmann, M.; Schmidt, M.K.; Broeks, A.; Russell, N.S.; ... ; Leeuwen, F.E. van 2019
Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined... Show moreFemale Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for generadiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients. Show less
Antoniou, A.; Anton-Culver, H.; Borowsky, A.; Broeders, M.; Brooks, J.; Chiarelli, A.; ... ; Ziv, E. 2019
Quantifying the genetic correlation between cancers can provide important insights into themechanisms driving cancer etiology. Using genome-wide association study summary sta-tistics across six... Show moreQuantifying the genetic correlation between cancers can provide important insights into themechanisms driving cancer etiology. Using genome-wide association study summary sta-tistics across six cancer types based on a total of 296,215 cases and 301,319 controls ofEuropean ancestry, here we estimate the pair-wise genetic correlations between breast,colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 otherdiseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5 ),breast and lung cancer (rg = 0.18, p =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15,p = 1.1 × 10−4 ). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functionalenrichment analysis revealed a significant excess contribution of conserved and regulatoryregions to cancer heritability. Our comprehensive analysis of cross-cancer heritability sug-gests that solid tumors arising across tissues share in part a common germline genetic basis. Show less
Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for... Show moreStratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs. Show less
