Metadata supporting data files of the related manuscript: The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
Creators: name: The Breast Cancer Association Consortium (BCAC)
name: The Consortium Of Investigators Of Modifiers Of BRCA1/2 (CIMBA)
Publisher: name: figshare
Year: 2019
Subjects: subject: Cancer
subject: Genetics
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: 60408 Genomics
subject: Medicine
subject: Molecular Biology
subject: 111201 Cancer Cell Biology
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine
subject: 111203 Cancer Genetics
subject: 111204 Cancer Therapy (excl. Chemotherapy and Radiation Therapy)

description: In this study, the authors tested the three recurrent protein-truncating variants <i>FANCM</i>:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk. <i>In vitro </i>experiments were also carried out whereby these three variants were studied functionally by measuring survival and chromosome fragility in <i>FANCM</i> − / − patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib.<br><b>Data access</b>: A subset of the genotype data analysed in this study (that originated from the Oncoarray Consortium project) is publicly available from the dbGaP repository. A subset of the genotype data generated as part of the BCAC studies (and analysed in the present study) can be accessed at <b>https://identifiers.org/dbgap:phs001265.v1.p1</b>. A subset of the genotype data generated as part of the CIMBA studies (and analysed in the present study) can be accessed at <b>https://identifiers.org/dbgap:phs001321.v1.p1</b>. The remaining genotype data analysed in the present study (and generated in the BCAC and CIMBA studies listed in supplementary Tables 4 and 5 of the related article respectively) are not publicly available due to restraints imposed by the ethics committees of individual studies but can be accessed from the corresponding author on reasonable request; Dr. Paolo Peterlongo, Genome Diagnostics Program, IFOM, The FIRC Institute for Molecular Oncology, Via Adamello 16 - 20139 Milano (Italy), email address: <b>paolo.peterlongo@ifom.eu. </b>Datasets <b>survivals DEB e OLAPARIB.pzfx </b>(supporting figure 1 and supplementary tables 2 and 3 in the published article) and <b>chromatidics breaks distribution.xlsx </b>(supporting figure 1 in the published article) generated during this study can be accessed from the corresponding author on reasonable request as described above.<br><b>Participant consent:</b> All participating studies were approved by their ethics review boards and followed national guidelines for informed consent. However, due to the retrospective nature of the majority of the studies, not all participant individuals have provided written informed consent to take part in the present analysis. The Milan Breast Cancer Study Group (MBCSG) was approved by ethics committee from Istituto Nazionale dei Tumori di Milano and Istituto Europeo di Oncologia, in Milan.<br><b>Study aims and methodology: </b>Previous studies identified several protein-truncating variants in the <i>FANCM</i> gene, which encodes for a DNA translocase, that were described as moderate breast cancer risk factors with a greater risk of triple negative breast cancer (TNBC). This study aimed to investigate the effect of <i>FANCM</i> further, by testing three recurrent truncating variants <i>FANCM</i>:p.Arg658*, p.Gln1701*, and p.Arg1931*, within the OncoArray Consortium, a collaboration of consortia established to discover germline genetic variants predisposing to different human cancers (e.g., breast, colon, lung, ovary, endometrium and prostate cancers). These three variants were tested for association with breast cancer risk in 67 112 breast cancer cases, 53 766 controls and 26 662 carriers of pathogenic variants of <i>BRCA1</i> or <i>BRCA2</i>. The individuals included in this study were women of genetically confirmed European ancestry who were originally ascertained in 73 case-control studies from 19 countries participating in the Breast Cancer Association Consortium (BCAC) or in 59 studies enrolling <i>BRCA1</i> or <i>BRCA2 </i>pathogenic variants carrier from 30 countries participating in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). The CIMBA studies contributed 15 679 carriers of a pathogenic <i>BRCA1</i> variant and 10 983 carriers of a pathogenic <i>BRCA2</i> variant to this analysis. The BCAC studies contributed 67 112 invasive breast cancer cases and 53 766 controls. Genotyping of <i>FANCM</i>:p.Arg658*, p.Gln1701* and p.Arg1931* truncating variants was conducted using a custom-designed Illumina genotyping array (the “OncoArray”, Illumina, Inc. San Diego, CA, USA) at six independent laboratories.Additionally, the authors studied the functional effect of these three variants after their lentiviral transduction into a <i>FANCM</i>−/− patient-derived cell line, EGF280, in which they measured survival and chromosome fragility after exposure to diepoxybutane (DEB) or the poly (ADP-ribose) polymerase inhibitor (PARPi) olaparib.Statistical analyses of the genotype data, western blot and mRNA experiments are described in detail in the published article.<br><b>Dataset description:</b><b>Data supporting table 1:</b> Data <b>SNP Genotypes from Illumina array and variables datasets</b> include single variant and burden analyses of <i>FANCM</i>:p.Arg658*, p.Gln1701* and p.Arg1931 cases and controls, a subset of which can be accessed from the dbGaP repository at <b>https://identifiers.org/dbgap:phs001265.v1.p1</b>. <br><b>Data supporting figure 1:</b> The datasets <b>survivals DEB e OLAPARIB.pzfx </b>and <b> chromatidics breaks distribution.xlsx </b>are in .pzfx (Graphpad) and .xlsx file formats respectively and consist of results of functional studies of the <i>FANCM</i>:p.Arg658*, p.Gln1701* and p.Arg1931* truncating variants using the patient derived <i>FANCM</i>−/− EGF280 cell line. These data include western blot analysis showing the expression of FANCM in EGF280 cells after lentiviral transduction with the three <i>FANCM</i> variants, expression of the FANCM protein in EGF280+p.Arg658* cells, data on diepoxybutane (DEB) sensitivity on cell survival, chromosome fragility data in <i>FANCM</i>−/− patient-derived immortalized fibroblasts treated with diepoxybutane and data of the analysis of cellular sensitivity to olaparib.<br><b>Data supporting supplementary table 1:</b> The <b>SNP Genotypes from Illumina array and variables</b> dataset consist of <i>FANCM</i>:p.Arg658*, p.Gln1701* and p.Arg1931 truncating variants in carriers of pathogenic <i>BRCA1</i> or <i>BRCA2</i> variants. A subset of these genotype data from the CIMBA studies can be accessed from dbGaP at <b>https://identifiers.org/dbgap:phs001321.v1.p1</b>.<br><b>Data supporting supplementary table 2</b>: Dataset <b>survivals DEB e OLAPARIB.pzfx</b> is in a. pzfx (Graphpad) file format and reports on the sensitivity of different EGF280 cell lines to diepoxybutane (DEB) treatment.<br><b>Data supporting supplementary table 3</b>: Dataset <b>survivals DEB e OLAPARIB.pzfx</b> is in a. pzfx (Graphpad) file format and reports on the sensitivity of different EGF280 cell lines to olaparib treatment.<br><b>Supplementary tables 4 and 5</b> provide descriptions of the BCAC and CIMBA studies respectively, included in the present analysis. A subset of the genotype data generated in the BCAC studies can be accessed from dbGaP at <b>https://identifiers.org/dbgap:phs001265.v1.p1</b>. A subset of the genotype data generated in the CIMBA studies can be accessed from dbGaP at <b>https://identifiers.org/dbgap:phs001321.v1.p1</b>.<br><br>