Faculty of Medicine

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Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival
(Wiley, 2023-08)
Morra, Anna
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Schreurs, Maartje A C
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Andrulis, Irene L
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Anton-Culver, Hoda
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Augustinsson, Annelie
Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers.
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Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival
(Research Square Platform LLC, 2023-02-13)
Morra, Anna
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Schreurs, Maartje A C
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Andrulis, Irene L
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Anton-Culver, Hoda
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Augustinsson, Annelie
Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09-1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words).
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CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers
(Springer Science and Business Media LLC, 2021-02)
Johnson, Nichola
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Maguire, Sarah
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Morra, Anna
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Kapoor, Pooja Middha
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Tomczyk, Katarzyna
Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.
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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
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Zhang, Haoyu
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Michailidou, Kyriaki
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Milne, Roger L
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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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Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment
(Springer Science and Business Media LLC, 2021-08-18)
Morra, Anna
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Escala-Garcia, Maria
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Beesley, Jonathan
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Keeman, Renske
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Canisius, Sander
Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.
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Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment
(Springer Science and Business Media LLC, 2021)
Morra, Anna
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Escala-Garcia, Maria
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Beesley, Jonathan
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Keeman, Renske
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Canisius, Sander
Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.
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CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers
(Springer Nature and Cancer Research UK, 2021-01-26)
Johnson, Nichola
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Maguire, Sarah
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Morra, Anna
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Kapoor, Pooja Middha
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Tomczyk, Katarzyna
Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the <jats:italic>CYP3A</jats:italic> locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, <jats:italic>P</jats:italic> = 3.1 × 10<jats:sup>–18</jats:sup>); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, <jats:italic>P</jats:italic> = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10. Conclusions The CYP3A7*1C</jats:italic> allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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Two truncating variants in FANCC and breast cancer risk
(Springer Science and Business Media LLC, 2019-08-29)
Dörk, Thilo
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Peterlongo, Paolo
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Mannermaa, Arto
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Bolla, Manjeet K
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Wang, Qin
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 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.
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Common breast cancer risk loci predispose to distinct tumor subtypes
(Cold Spring Harbor Laboratory, 2019-08-15)
Ahearn, Thomas U.
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Zhang, Haoyu
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Michailidou, Kyriaki
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Milne, Roger L.
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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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