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  • Online Resource  (4)
  • American Association for Cancer Research (AACR)  (4)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 17 ( 2016-09-01), p. 5103-5114
    Abstract: Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 2
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 25, No. 8 ( 2016-08-01), p. 1251-1258
    Abstract: Background:Paternal transmission of a BRCA mutation has been reported to increase the risk of breast cancer in offspring more than when the mutation is maternally inherited. As this effect might be caused by referral bias, the aim of this study was to assess the parent-of-origin effect of the BRCA1/2 mutation on the breast cancer lifetime risk, when adjusted for referral bias. Methods: A Dutch national cohort including 1,314 proven BRCA1/2 mutation carriers and covering 54,752 person years. Data were collected by family cancer clinics, via questionnaires and from the national Dutch Cancer Registry. The parent-of-origin effect was assessed using Cox regression analyses, both unadjusted and adjusted for referral bias. Referral bias was operationalized by number of relatives with cancer and by personal cancer history. Results: The mutation was of paternal origin in 330 (42%, P & lt; 0.001) BRCA1 and 222 (42%, P & lt; 0.001) BRCA2 carriers. Paternal origin increased the risk of prevalent breast cancer for BRCA1 [HR, 1.54; 95% confidence interval (CI), 1.19–2.00] and BRCA2 carriers (HR, 1.40; 95% CI, 0.95–2.06). Adjusted for referral bias by several family history factors, these HRs ranged from 1.41 to 1.83 in BRCA1 carriers and 1.27 to 1.62 in BRCA2 carriers. Adjusted for referral bias by personal history, these HRs were 0.66 (95% CI, 0.25–1.71) and 1.14 (95% CI, 0.42–3.15), respectively. Conclusion: A parent-of-origin effect is present after correction for referral bias by family history, but correction for the personal cancer history made the effect disappear. Impact: There is no conclusive evidence regarding incorporating a BRCA1/2 parent-of-origin effect in breast cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 25(8); 1251–8. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3627-3627
    Abstract: Women who carry the germline CHEK2 c.1100delC mutation have a 2.3-fold increased life-time risk to develop breast cancer (BC). Their BCs are mostly of the luminal/ER+ subtype and diagnosed at a younger age than BCs in sporadic patients. BC patients carrying a CHEK2 c.1100delC mutation are at an increased risk of developing a contralateral BC and have a worse survival compared to sporadic BC patients although resistance to either endocrine or chemotherapy does not appear to play a role herein. To unravel the biological mechanism by which CHEK2 c.1100delC exerts its tumorigenic potential, whole genome sequencing was performed of matching normal and primary BC (pBC) DNA from twenty female CHEK2 c.1100delC mutation carriers at Hartwig Medical Foundation (HMF). We compared the somatic pBC genomes of these twenty patients to 560 pBC genomes from the International Cancer Genome Consortium including 30 BRCA1 and 25 BRCA2 mutation carriers and 329 sporadic ER+ pBC patients. The validation cohort consisted of 517 metastatic BC (mBC) genomes from the Center for Personalized Cancer Treatment that were sequenced at HMF and included 24 mBC genomes from CHEK2 c.1100delC mutation carriers. We found that CHEK2 pBC and mBC genomes were dissimilar to pBC and mBC genomes of BRCA1 and BRCA2 mutation carriers and did not show evidence of a homologous recombination deficiency (HRD) phenotype. Instead, CHEK2 pBC and mBC genomes were very similar to genomes of sporadic ER+ pBC and mBC patients in terms of tumor mutational burden, single and double base substitution signatures as well as small insertion/deletion signatures. The size distribution of structural variants (SVs), however, was different for CHEK2 pBCs and mBCs compared with ER+ as well as BRCA1 and BRCA2 pBCs and mBCs. Importantly, the CHEK2 c.1100delC mutation was associated with an increased frequency of larger ( & gt; 1Mb) deletions, inversions and tandem duplications (TDs) with peaks at specific sizes. Although CHEK2 mBC genomes more frequently harbored chromothripsis compared with other mBC subtypes, this did not explain the CHEK2-specific SV size distribution pattern. Moreover, increased chromothripsis in CHEK2 mBC genomes was not associated with a higher frequency of somatic TP53 mutations. In fact, we did not observe any somatic TP53 mutations among CHEK2 pBC and mBC genomes. This mutual exclusiveness suggests CHEK2-driven tumorigenesis could act through the TP53 signaling pathway. To conclude, CHEK2 BC genomes do not harbor somatic TP53 mutations and display a unique SV size distribution profile. Moreover, the absence of an HRD phenotype among CHEK2 BC genomes suggests PARP inhibitors will not be effective for treatment of BC in CHEK2 c.1100delC mutation carriers. Increasing knowledge of the mechanisms of CHEK2-driven tumorigenesis may ultimately lead to the development of tailored strategies for treatment and prevention of BC for CHEK2 mutation carriers. Citation Format: Marcel Smid, Marjanka K. Schmidt, Wendy J. Prager - van der Smissen, Kirsten Ruigrok - Ritstier, Sten Cornelissen, Maartje A. Schreurs, J. Margriet Collee, Muriel A. Adank, Maartje J. Hooning, John W. Martens, Antoinette Hollestelle. The genomic landscape of breast cancers from CHEK2 c.1100delC mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3627.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P5-07-12-P5-07-12
    Abstract: Background: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model, and evaluate its applicability for clinical decision-making. Methods: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4,682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics, and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B). Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results: In the multivariable model, BRCA1/2 germline mutation status, family history and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years: 0.52–0.74; at 10 years: 0.53–0.72). Calibration in-the-large was -0.13 (95%PI: -1.62–1.37) and the calibration slope was 0.90 (95%PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent, however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision regarding contralateral preventive mastectomy, especially in the general breast cancer population, remains challenging. Citation Format: Daniele Giardiello, Ewout W Steyerberg, Michael Hauptmann, Muriel A Adank, Agnes Jager, Hester OA Oldenburg, Maartje J Hooning, Marjanka K Schmidt, Breast Cancer Association Consortium. Prediction and clinical utility of a contralateral breast cancer risk model [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-12.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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