17 research outputs found
Identifying the BRCA1 c.-107A > T variant in Dutch patients with a tumor BRCA1 promoter hypermethylation
An inherited single nucleotide variant (SNV) in the 5′UTR of the BRCA1 gene c.-107A > T was identified to be related to BRCA1 promoter hypermethylation and a hereditary breast and ovarian cancer phenotype in two UK families. We investigated whether this BRCA1 variant was also present in a Dutch cohort of breast and ovarian cancer patients with tumor BRCA1 promoter hypermethylation. We selected all breast and ovarian cancer cases that tested positive for tumor BRCA1 promoter hypermethylation at the Netherlands Cancer Institute and Sanger sequenced the specific mutation in the tumor DNA. In total, we identified 193 tumors with BRCA1 promoter hypermethylation in 178 unique patients. The wild-type allele was identified in 100% (193/193) of sequenced tumor samples. In a large cohort of 178 patients, none had tumors harboring the previously identified c.-107A > T SNV in BRCA1. We therefore can conclude that the germline SNV is not pervasive in patients with tumor BRCA1 promoter hypermethylation
Breast cancer risks associated with missense variants in breast cancer susceptibility genes
BACKGROUND: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk
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
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 decisionmaking.This work was supported by the Alpe d’HuZes/Dutch Cancer Society (KWF
Kankerbestrijding) project 6253 and Dutch Cancer Society (KWF Kankerbestrijding)
project UL2014-7473. CIMBA: The CIMBA data management and data analysis were
supported by Cancer Research–UK grants C12292/A20861, C12292/A11174. G.C.T.
and A.B.S. are NHMRC Research Fellows. iCOGS: the European Community’s Seventh
Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-
223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/
A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/
A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS
initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112–the GAME-ON
initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes
of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-
87521), and the Ministry of Economic Development, Innovation and Export Trade
(PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research
Foundation, and the Ovarian Cancer Research Fund. OncoArray: the PERSPECTIVE
and PERSPECTIVE I&I projects funded by the Government of Canada through
Genome Canada and the Canadian Institutes of Health Research, the Ministère de
l’Économie, de la Science et de l’Innovation du Québec through Genome Québec,
and the Quebec Breast Cancer Foundation; the NCI Genetic Associations and
Mechanisms in Oncology (GAME-ON) initiative and Discovery, Biology and Risk of
Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and
X01HG007492); and Cancer Research UK (C1287/A10118 and C1287/A16563). BCFR:
UM1 CA164920 from the National Cancer Institute. The content of this paper does
not necessarily reflect the views or policies of the National Cancer Institute or any of
the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does
mention of trade names, commercial products, or organizations imply endorsement
by the US Government or the BCFR. BFBOCC: Lithuania (BFBOCC-LT): Research
Council of Lithuania grant SEN-18/2015. BIDMC: Breast Cancer Research Foundation.
BMBSA: Cancer Association of South Africa (PI Elizabeth J. van Rensburg). BRI-COH: S.
L.N. is partially supported by the Morris and Horowitz Families Professorship. CNIO:
Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish
Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research
reported in this publication was supported by the National Cancer Institute of the
National Institutes of Health under grant number R25CA112486, and RC4CA153828
(PI: J. Weitzel) from the National Cancer Institute and the Office of the Director,
National Institutes of Health. The content is solely the responsibility of the authors
and does not necessarily represent the official views of the National Institutes of
Health. CONSIT TEAM: Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 number
16732) to P. Peterlongo. DEMOKRITOS: European Union (European Social Fund–ESF)
and Greek national funds through the Operational Program “Education and Lifelong
Learning” of the National Strategic Reference Framework (NSRF)–Research Funding
Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA.
Investing in knowledge society through the European Social Fund. DFKZ: German
Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and
C1287/A11990. D.G.E. and F.L. are supported by an NIHR grant to the Biomedical
Research Centre, Manchester. The Investigators at The Institute of Cancer Research
and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the
Biomedical Research Centre at The Institute of Cancer Research and The Royal
Marsden NHS Foundation Trust. R.E. and E.B. are supported by Cancer Research UK
Grant C5047/A8385. R.E. is also supported by NIHR support to the Biomedical
Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: A.K.G. was in part funded by the NCI (R01 CA214545), The
University of Kansas Cancer Center Support Grant (P30 CA168524), The Kansas
Institute for Precision Medicine (P20 GM130423), and the Kansas Bioscience Authority
Eminent Scholar Program. A.K.G. is the Chancellors Distinguished Chair in Biomedical
Sciences Professorship. FPGMX: A. Vega is supported by the Spanish Health Research
Foundation, Instituto de Salud Carlos III (ISCIII), partially supported by FEDER funds
through Research Activity Intensification Program (contract grant numbers: INT15/
00070, INT16/00154, INT17/00133), and through Centro de Investigación Biomédica
en Red de Enferemdades Raras CIBERER (ACCI 2016: ER17P1AC7112/2018);
Autonomous Government of Galicia (Consolidation and structuring program:
IN607B), and by the Fundación Mutua Madrileña. The German Consortium for
Hereditary Breast and Ovarian Cancer (GC-HBOC) is funded by the German Cancer
Aid (110837, 70111850, coordinator: Rita K. Schmutzler, Cologne) and the Ministry for
Innovation, Science and Research of the State of North Rhine-Westphalia (#323-
8.0302.16.02-132142). GEMO: initially funded by the French National Institute of
Cancer (INCa, PHRC Ile de France, grant AOR 01 082, 2001-2003, grant 2013-1-BCB-01-
ICH-1), the Association “Le cancer du sein, parlons-en!” Award (2004), the Association
for International Cancer Research (2008-2010), and the Foundation ARC pour la
recherche sur le cancer (grant PJA 20151203365). It also received support from the
Canadian Institute of Health Research for the “CIHR Team in Familial Risks of Breast
Cancer” program (2008–2013), and the European commission FP7, Project
«Collaborative Ovarian, breast and prostate Gene-environment Study (COGS),
Large-scale integrating project» (2009–2013). GEMO is currently supported by the
INCa grant SHS-E-SP 18-015. GEORGETOWN: The Survey, Recruitment, and Biospecimen
Collection Shared Resource at Georgetown University (NIH/NCI grant P30-
CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research,
and the Nina Hyde Center for Breast Cancer Research. G-FAST: Bruce Poppe is a
senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from
IWT. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301
CIBERONC from ISCIII (Spain), partially supported by European Regional Development
FEDER funds. HEBCS: Helsinki University Hospital Research Fund, the Finnish Cancer
Society and the Sigrid Juselius Foundation. The HEBON study is supported by the
Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink
Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46
and the Transcan grant JTC 2012 Cancer 12-054. HRBCP: Hong Kong Sanatorium and
Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation,
National Institute of Health1R 03CA130065, and North California Cancer Center.
HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745, NKFI_OTKA K-112228
and TUDFO/51757/2019-ITM. ICO: Contract grant sponsor: Supported by the Carlos III
National Health Institute funded by FEDER funds–a way to build Europe–(PI16/00563,
PI19/00553 and CIBERONC); the Government of Catalonia (Pla estratègic de recerca i
innovaciĂł en salut (PERIS) Project MedPerCan, 2017SGR1282 and 2017SGR496); and
CERCA program.IHCC: supported by grant PBZ_KBN_122/P05/2004 and the program
of the Minister of Science and Higher Education under the name “Regional Initiative
of Excellence” in 2019–2022 project number 002/RID/2018/19 amount of financing 12
000 000 PLN. ILUH: Icelandic Association “Walking for Breast Cancer Research” and by
the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of
Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program–grant
CRN-87521 and the Ministry of Economic Development, Innovation and Export
Trade–grant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and “5×1000” Istituto
Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The
National Breast Cancer Foundation, and previously by the National Health and
Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer
Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer
Foundation of Western Australia. KOHBRA: the Korea Health Technology R&D Project
through the Korea Health Industry Development Institute (KHIDI), and the National
R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea
(HI16C1127; 1020350; 1420190). KUMC: NIGMS P20 GM130423 (to A.K.G.). MAYO: NIH
grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research
Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer
Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast
Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade.
Marc Tischkowitz is supported by the funded by the European Union Seventh
Framework Program (2007Y2013)/European Research Council (Grant No. 310018).
MODSQUAD: MH CZ–DRO (MMCI, 00209805) and LM2018125, MEYS–NPS I–LO1413 to LF, and by Charles University in Prague project UNCE204024 (MZ). MSKCC: the
Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer
Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support
Grant/Core Grant (P30 CA008748). NAROD: 1R01 CA149429-01. NCI: the Intramural
Research Program of the US National Cancer Institute, NIH, and by support services
contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc,
Rockville, MD. NICCC: Clalit Health Services in Israel, the Israel Cancer Association and
the Breast Cancer Research Foundation (BCRF), NY. NNPIO: the Russian Foundation
for Basic Research (grants 17-00-00171, 18-515-45012 and 19-515-25001). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative
Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA
37517) and the Intramural Research Program, NCI. OSUCCG: Ohio State University
Comprehensive Cancer Center. PBCS: supported by the “Fondazione Pisa per la
Scienza, project nr. 127/2016. Maria A Caligo was supported by the grant: “n. 127/16
Caratterizzazione delle varianti missenso nei geni BRCA1/2 per la valutazione del
rischio di tumore al seno” by Fondazione Pisa, Pisa, Italy; SEABASS: Ministry of
Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/
06) and Cancer Research Initiatives Foundation. SMC: the Israeli Cancer Association.
SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of
Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996,
1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the
Entertainment Industry Fund National Women’s Cancer Research Alliance and the
Breast Cancer research Foundation. O.I.O. is an ACS Clinical Research Professor. UCLA:
Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research
Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive
Cancer Center. UKFOCR: Cancer Research h UK. UPENN: Breast Cancer Research
Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for
BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency,
Cancer Australia, National Breast Cancer Foundation. WCP: B.Y.K. is funded by the
American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and
the National Center for Advancing Translational Sciences (NCATS), grant
UL1TR000124.https://www.gimjournal.org/am2023Genetic
RAPID DETECTION OF BRCA1 MUTATIONS BY THE PROTEIN TRUNCATION TEST
More than 75% of the reported mutations in the hereditary breast and ovarian cancer gene, BRCA1, result in truncated proteins, We have used the protein truncation test (PTT) to screen for mutations in exon 11, which encodes 61% of BRCA1. In 45 patients from breast and/or ovarian cancer families we found six novel mutations: two single nucleotide insertions, three small deletions (1-5 bp) and a nonsense mutation identified two unrelated families, Furthermore, we were able to amplify the remaining coding region by RT-PCR using lymphocyte RNA. Combined with PTT, we detected aberrantly spliced products affecting exons 5 and 6 in one of two BRCA1-linked families examined. The protein truncation test promises to become a valuable technique in detecting BRCA1 mutations
Uncovering the Contribution of Moderate-Penetrance Susceptibility Genes to Breast Cancer by Whole-Exome Sequencing and Targeted Enrichment Sequencing of Candidate Genes in Women of European Ancestry
Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes