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Common variants in breast cancer risk loci predispose to distinct tumor subtypes
(Springer Science and Business Media LLC, 2022-01-04)
Ahearn, Thomas U
;
Zhang, Haoyu
;
Michailidou, Kyriaki
;
Milne, Roger L
;
Bolla, Manjeet K
Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.
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Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
(Springer Science and Business Media LLC, 2020)
Fachal, Laura
;
Aschard, Hugues
;
Beesley, Jonathan
;
Barnes, Daniel R
;
Allen, Jamie
Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
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The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases
(MDPI AG, 2020)
Figlioli, Gisella
;
Kvist, Anders
;
Tham, Emma
;
Soukupova, Jana
;
Kleiblova, Petra
Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.
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Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
(Springer Science and Business Media LLC, 2020-01)
Fachal, Laura
;
Aschard, Hugues
;
Beesley, Jonathan
;
Barnes, Daniel R
;
Allen, Jamie
Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
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Common breast cancer risk loci predispose to distinct tumor subtypes
(Cold Spring Harbor Laboratory, 2019-08-15)
Ahearn, Thomas U.
;
Zhang, Haoyu
;
Michailidou, Kyriaki
;
Milne, Roger L.
;
Bolla, Manjeet K.
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Genome-wide association studies have identified over 170 common breast cancer susceptibility variants, many of them with differential associations by estrogen receptor (ER). How these variants are related to other tumor features is unclear.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Analyses included 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 178 genotyped or imputed single nucleotide polymorphisms (SNPs). We used two-stage polytomous logistic regression models to evaluate SNPs in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Nearly half of the SNPs (85 of 178) were associated with at least one tumor feature (false discovery rate <5%). Case-case comparisons identified ER and grade as the most common heterogeneity sources, followed by PR and HER2. Case-control comparisons among these 85 SNPs with intrinsic-like subtypes identified 65 SNPs strongly or exclusively associated at P<0.05 with luminal-like subtypes, 5 SNPs associated with all subtypes at differing strengths, and 15 SNPs primarily associated with non-luminal tumors, especially triple-negative (TN) disease. The I157T <jats:italic>CHEK2</jats:italic> variant (rs17879961) was associated in opposite directions with luminal A-like (odds ratio (OR; 95% confidence interval (CI))=1.44 (1.31 to 1.59); P=9.26×10<jats:sup>−14</jats:sup>) and TN (OR (95% CI)=0.61 (0.47 to 0.80); P=2.55×10<jats:sup>−4</jats:sup>).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>About half of the breast cancer susceptibility loci discovered in overall and ER-specific risk analyses have differential associations with clinical tumor features. These findings provide insights into the genetic predisposition of breast cancer subtypes and can inform subtype-specific risk prediction.</jats:p></jats:sec>
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BRCA1 and BRCA2 germline variants in breast cancer patients from the Republic of Macedonia
(Springer Science and Business Media LLC, 2018-04)
Jakimovska, Milena
;
Maleva Kostovska, Ivana
;
Popovska-Jankovic, Katerina
;
Kubelka-Sabit, Katerina
;
Karadjozov, Mitko
We aimed to establish the spectrum of BRCA1/2 mutations among the breast cancer (BC) patients from the Republic of Macedonia.
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The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases
(MDPI AG, 2020)
Figlioli, Gisella
;
Kvist, Anders
;
Tham, Emma
;
Soukupova, Jana
;
Kleiblova, Petra
Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

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