Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk

Kramer, Iris; Hooning, Maartje J.; Mavaddat, Nasim; Hauptmann, Michael; Keeman, Renske; Steyerberg, Ewout W.; Giardiello, Daniele; Antoniou, Antonis C.; Pharoah, Paul D.P.; Canisius, Sander; Abu-Ful, Zumuruda; Andrulis, Irene L.; Anton‐Culver, Hoda; Aronson, Kristan J.; Augustinsson, Annelie; Becher, Heiko; Beckmann, Matthias W.; Behrens, Sabine; Benı́tez, Javier; Bermisheva, Marina; Bogdanova, Natalia; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Brauch, Hiltrud; Bremer, Michael; Brucker, Sara Y.; Burwinkel, Barbara; Castelao, Jose E.; Chan, Tsun Leung; Chang‐Claude, Jenny; Chanock, Stephen J.; Chenevix-Trench, Georgia; Choi, Ji-Yeob; Clarke, Christine L.; Collée, J. Margriet; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Dörk, Thilo; dos‐Santos‐Silva, Isabel; Dunning, Alison M.; Dwek, Miriam; Eccles, Diana; Evans, D. Gareth; Fasching, Peter A.; Flyger, Henrik; Gago‐Dominguez, Manuela; García‐Closas, Montserrat; García-Sáenz, José Á.; Giles, Graham G.; Goldgar, David E.; González‐Neira, Anna; Haiman, Christopher A.; Håkansson, Niclas; Hamann, Ute; Hartman, Mikael; Heemskerk-Gerritsen, Bernadette A M; Hollestelle, Antoinette; Hopper, John L.; Hou, Ming‐Feng; Howell, Anthony; Investigators, Abctb; Investigators, kConFab; Ito, Hidemi; Jakimovska, Milena; Jakubowska, Anna; Janni, Wolfgang; John, Esther M.; Jung, Audrey; Kang, Daehee; Kets, C. Marleen; Khusnutdinova, Elza; Ko, Yon‐Dschun; Kristensen, Vessela N.; Kurian, Allison W.; Kwong, Ava; Lambrechts, Diether; Marchand, Loı̈c Le; Li, Jingmei; Lindblom, Annika; Lubiński, Jan; Mannermaa, Arto; Manoochehri, Mehdi; Margolin, Sara; Matsuo, Keitaro; Mavroudis, Dimitriοs; Meindl, Alfons; Milne, Roger L.; Mulligan, Anna Marie; Muranen, Taru; Neuhausen, Susan L.; Nevanlinna, Heli; Newman, William G.; Olshan, Andrew F.; Olson, Janet E.; Olsson, Håkan; Park‐Simon, Tjoung‐Won; Peto, Julian; Petridis, Christos; Plaseska‐Karanfilska, Dijana; Presneau, Nadège; Pylkäs, Katri; Radice, Paolo; Rennert, Gad; Romero, Atocha; Roylance, Rebecca; Saloustros, Emmanouil; Sawyer, Elinor J.; Schmutzler, Rita K.; Schwentner, Lukas; Scott, Rodney J.; See, Mee-Hoong; Shah, Mitul; Shen, Chen‐Yang; Shu, Xiao‐Ou; Siesling, Sabine; Slager, Susan L.; Sohn, Christof; Southey, Melissa C.; Spinelli, John J.; Stone, Jennifer; Tapper, William; Tengström, Maria; Teo, Soo Hwang; Terry, Mary Beth; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Troester, Melissa A.; Vachon, Celine M.; Ongeval, Chantal Van; Veen, Elke M. van; Winqvist, Robert; Wolk, Alicja; Wang, Zheng; Ziogas, Argyrios; Easton, Douglas F.; Hall, Per; Schmidt, Marjanka K.

doi:10.1016/j.ajhg.2020.09.001

Cited by 46 publications

(41 citation statements)

References 25 publications

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“…Contralateral breast cancer (CBC) is less common than unilateral breast cancer (UBC) and it has been supposed to have mainly a genetic cause (Mack et al 2002 ). Indeed, women carrying mutations in BRCA1 , BRCA2 and CHECK genes have a higher risk of developing CBC and the estimation of the risk is higher in carriers of germinal mutations, confirming the strong genetic contribution (Robson et al 2017 ; Kramer et al 2020 ). Based on these evidence, the finding of altered E2F1 CNVs in patients with CBC suggests that this structural variant, likely inherited, as well as it occurs in inherited germline mutations of BRCA genes, may contribute to an increased risk of CBC.…”

Section: Discussionmentioning

confidence: 82%

E2F1 copy number variations in germline and breast cancer: a retrospective study of 222 Italian women

Rocca

Benna

Goldin

et al. 2021

Mol Med

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Background Breast cancer is the most common neoplasia among women in developed countries. The risk factors of breast cancer can be distinguished in modifiable and unmodifiable factors and, among the latter, genetic factors play a key role. Copy number variations (CNVs) are genetic variants that are classified as rare when present in less than 1% of the healthy population. Since rare CNVs are often cause of diseases, over the last years, their contribution in carcinogenesis has become a relevant matter of study. E2F1 is a transcriptional factor that plays an important role in regulating cell cycle and apoptosis. Its double and conflicting role is the reason why it acts both as oncogene and as tumour suppressor, depending on cell context. Since anomalies in expression or in number of copies of E2F1 have been related to several cancers, we aimed to study number of germline copies of E2F1 in women with breast cancer in order to better elucidate their contribution as predisposing factor to this tumour. Methods We performed, hence, a retrospective study on 222 Italian women with breast cancer recruited from October 2002 to December 2007. TaqMan CNV assay and Real-Time PCR were carried out to analyse, respectively, E2F1 CNV and E2F1 expression in the subjects of the study. Chi square test or Fisher’s exact test and Student's t‐test were used to calculate the frequency of CNVs and differences in continuous variables between groups, respectively. Results Intriguingly, we found that 10/222 (4.5%) women with breast cancer had more copies than controls (0/200, 0%), furthermore, the number of copies positively correlated with E2F1 gene expression in breast cancer tissue, suggesting that the constitutive gain of the gene could translate into an increased risk of genomic instability. Additionally, we found that altered E2F1 copies were present prevalently in the patients with contralateral breast cancer (20%) and all of them had a positive family history, both typically associated with hereditary cancer. Conclusions Our findings suggest that copy number variations of E2F1 might be a susceptibility factor for breast cancer, however, further studies on large cohorts are to be performed in order to better delineate the phenotype linked to the gain of E2F1 copies.

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Section: Discussionmentioning

confidence: 82%

E2F1 copy number variations in germline and breast cancer: a retrospective study of 222 Italian women

Rocca

Benna

Goldin

et al. 2021

Mol Med

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“… 26 CIMBA includes 81 individual studies of which the majority of the participants were ascertained through cancer genetics clinics. 26 Although studies in CIMBA include individuals of non-European ancestry, our analyses were, due to power considerations (small numbers available for analyses and expected lower estimates for the PRS 313 in Asian ancestry based on results of women in the general breast cancer population 19 ), restricted to women of European ancestry with available array genotyping data (31,195 women of 67 studies).…”

Section: Methodsmentioning

confidence: 99%

“… 11 Details about the quality control procedures and correlation between the arrays have been described previously. 19 , 24 , 28 – 31 European ancestry was determined using genetic data and multidimensional scaling. More detailed information about the genotyping and PRS calculation is provided in the Supplementary methods .…”

Section: Methodsmentioning

confidence: 99%

“… 14 – 16 A limited number of studies have shown that variants associated with the risk of a first primary breast cancer are also associated with the risk of contralateral breast cancer. 17 – 19 Furthermore, the PRS derived from the general population has also been shown to be associated with breast cancer risk in BRCA1/2 heterozygotes. 20 – 24 …”

Section: Introductionmentioning

confidence: 99%

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The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Lakeman

Broek

Vos

et al. 2021

Genetics in Medicine

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Purpose To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

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“…Considering that collectively SNP account for a greater proportion of the familial risk of breast cancer, on a breast cancer population basis, it is those with women with a higher-risk PRS profile who are more likely to contribute to the population of contralateral breast cancers. For an SNP profile based on 313 variants, the contralateral lifetime breast cancer risk ranges from 12 to 20%, depending on the initial risk percentile [107].…”

Section: Detection Of Mutations In Known Breast Cancer Genesmentioning

confidence: 99%

From BRCA1 to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

2021

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Background: There has been huge progress over the last 30 years in identifying the familial component of breast cancer. Summary: Currently around 20% is explained by the high-risk genes BRCA1 and BRCA2, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes ATM and CHEK2. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. Key-Messages: There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as CDH1 and TP53, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.

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Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk

Abstract: This is a repository copy of Breast cancer polygenic risk score and contralateral breast cancer risk.

Cited by 46 publications

References 25 publications

E2F1 copy number variations in germline and breast cancer: a retrospective study of 222 Italian women

E2F1 copy number variations in germline and breast cancer: a retrospective study of 222 Italian women

The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

From <b><i>BRCA1</i></b> to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

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