Association Between Loss-of-Function Mutations Within the <i>FANCM</i> Gene and Early-Onset Familial Breast Cancer

Neidhardt, Guido; Hauke, Jan; Ramser, Juliane; Groß, Eva; Gehrig, Andrea; Müller, C. R.; Kahlert, Anne‐Karin; Hackmann, Karl; Honisch, Ellen; Niederacher, Dieter; Nöthen, Markus M.; Franke, André; Lieb, Wolfgang; Thiele, Holger; Altmüller, Janine; Nürnberg, Peter; Klaschik, Kristina; Ernst, Corinna; Ditsch, Nina; Jessen, Frank; Ramı́rez, Alfredo; Wappenschmidt, Barbara; Engel, Christoph; Rhiem, Kerstin; Meindl, Alfons; Schmutzler, Rita K.; Hahnen, Eric

doi:10.1001/jamaoncol.2016.5592

Cited by 76 publications

(75 citation statements)

References 8 publications

(23 reference statements)

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“…Notably, the TNBC phenotype appears to be closely associated with a hereditary cause of the disease [4]. This notion is based on i) the generally early age of onset which is similar to that observed for patients carrying germline mutations in breast cancer predisposition genes, ii) the high rate of TNBC cases with a positive family history of cancer, iii) the high prevalence of germline mutations, and, vice versa, iv) the association of a small subset of breast cancer predisposition genes (e.g., BRCA1 , BRCA2 , PALB2 , FANCM ) with the TNBC phenotype [12,13,14,15]. Most breast cancer predisposition genes, including BRCA1/2 , are critical genes in the process of homologous recombination (HR) repair of double-strand DNA breaks [13,16,17,18,19].…”

Section: Introductionsupporting

confidence: 55%

“…Many of the other genes involved in HR repair are now recognized to also contribute to hereditary breast and/or ovarian cancer risk, including ATM , BRIP1 , CHEK2 , NBN , PALB2 , RAD51C, and RAD51D , while only limited evidence is available for BARD1 , FANCM , MRE11A, and RAD50 [13,15,17,18,19,40]. Notably, only BRCA1 , BRCA2 , PALB2, and FANCM have so far been associated with the TNBC phenotype [12,13,14,15]: Approximately 66-70% of breast cancers arising in BRCA1 mutation carriers and up to 16-23% of breast cancers in BRCA2 carriers are triple-negative [35,41].…”

Section: Other Predisposition Genes Associated With Tnbc Phenotypementioning

confidence: 99%

“…Notably, only BRCA1 , BRCA2 , PALB2, and FANCM have so far been associated with the TNBC phenotype [12,13,14,15]: Approximately 66-70% of breast cancers arising in BRCA1 mutation carriers and up to 16-23% of breast cancers in BRCA2 carriers are triple-negative [35,41]. A recent analysis of patients positive for PALB2 germline mutations revealed 34% being triple-negative.…”

Section: Other Predisposition Genes Associated With Tnbc Phenotypementioning

confidence: 99%

“…A recent analysis of patients positive for PALB2 germline mutations revealed 34% being triple-negative. For FANCM, higher mutation frequencies were observed in TNBC cases versus breast cancer cases not selected for tumor phenotype [13,15]. Other breast cancer risk genes such as CHEK2 and probably ATM are unlikely to predispose for TNBC [42].…”

Section: Other Predisposition Genes Associated With Tnbc Phenotypementioning

confidence: 99%

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Germline Mutations in Triple-Negative Breast Cancer

et al. 2017

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Triple-negative breast cancer (TNBC) is associated with a poor prognosis and defines a subgroup of patients who do not benefit from endocrine or anti-HER2 therapy. Rather than being a biological entity, TNBC represents a heterogeneous disease, and further subtyping is necessary to establish targeted therapies. Germline mutational status may serve as a robust biomarker predicting therapy response, especially with respect to compounds challenging the DNA repair machinery. Patients with TNBC usually show an early onset of the disease, as well as a positive family history of breast and/or ovarian cancer in more than one third of all cases, which suggests that TNBC is closely associated with a hereditary disease cause. In unselected TNBC cases, the prevalence of pathogenic germline BRCA1/2 mutations is approximately twice as high as in breast cancer overall. Early age at diagnosis and positive family history are strong predictors for an increased BRCA1/2 mutation probability, which is up to 40% when both risk factors are considered. Apart from BRCA1/2, the rarely mutated breast cancer predisposition genes PALB2 and FANCM have been associated with TNBC. This review summarizes the role of germline mutational status in TNBC pathogenesis. Clinical trials addressing BRCA1/2 mutation carriers are discussed.

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Section: Introductionsupporting

confidence: 55%

Section: Other Predisposition Genes Associated With Tnbc Phenotypementioning

confidence: 99%

Section: Other Predisposition Genes Associated With Tnbc Phenotypementioning

confidence: 99%

Section: Other Predisposition Genes Associated With Tnbc Phenotypementioning

confidence: 99%

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Germline Mutations in Triple-Negative Breast Cancer

et al. 2017

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“…However, the sample size of such study is likely to be significantly less than ExAC. Despite these limitations, the ExAC data has been commonly used and validated as an effective control dataset for estimating cancer risk for both known and newly discovered cancer predisposition genes/loci …”

Section: Discussionmentioning

confidence: 99%

Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes

Zhu

Zhang

Chen

et al. 2019

Intl Journal of Cancer

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Despite the identification of several ovarian cancer (OC) predisposition genes, a large proportion of familial OC risk remains unexplained. We adopted a two‐stage design to identify new OC predisposition genes. We first carried out a large germline whole‐exome sequencing study on 158 patients from 140 families with significant OC history, but without evidence of genetic predisposition due to BRCA1/2. We then evaluated the potential candidate genes in a large case–control association study involving 381 OC cases in the Cancer Genome Atlas project and 27,173 population controls from the Exome Aggregation Consortium. Two new putative OC risk genes were identified, namely, ANKRD11, a putative tumor suppressor, and POLE, an enzyme involved in DNA repair and replication. These two genes likely confer moderate OC risk. We performed in vitro experiments and showed an ANKRD11 mutation identified in our patients markedly lowered the protein expression by compromising protein stability. Upon future validation and functional characterization, these genes may shed light on cancer etiology along with improving ascertainment power and preventive care of individuals at high risk of OC.

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Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer

et al. 2020

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IMPORTANCE The GeparOcto randomized clinical trial compared the efficacy of 2 neoadjuvant breast cancer (BC) treatment regimens: sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) vs weekly paclitaxel and nonpegylated liposomal doxorubicin (PM) in patients with different biological BC subtypes. Patients with triple-negative BC (TNBC) randomized to the PM arm received additional carboplatin (PMCb). Overall, no difference in pathologic complete response (pCR) rates was observed between study arms. It remained elusive whether the germline variant status of BRCA1/2 and further BC predisposition genes are associated with treatment outcome.OBJECTIVE To determine treatment outcome for BC according to germline variant status. DESIGN, SETTING, AND PARTICIPANTSThis retrospective biomarker study is a secondary analysis of the GeparOcto multicenter prospective randomized clinical trial conducted between December 2014 and June 2016. Genetic analyses assessing for variants in BRCA1/2 and 16 other BC predisposition genes in 914 of 945 women were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany, from August 2017 through December 2018.MAIN OUTCOMES AND MEASURES Proportion of patients who achieved pCR (ypT0/is ypN0 definition) after neoadjuvant treatment according to germline variant status. RESULTSIn the study sample of 914 women with different BC subtypes with a mean (range) age at BC diagnosis of 48 (21-76) years, overall higher pCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P = .01); variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Patients with TNBC with BRCA1/2 variants achieved highest pCR rates. In the TNBC subgroup, a positive BRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% without BRCA1/2 variant; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04). A positive BRCA1/2 variant status was also associated with elevated pCR rates in patients with ERBB2-negative, hormone receptor-positive BC (31.8% vs 11.9%; OR, 3.44; 95% CI, 1.22-9.72; P = .02). CONCLUSIONS AND RELEVANCEEffective chemotherapy for BRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a pCR rate of 64.7%, iddEPC may also be effective in these patients, though further prospective studies are needed. The elevated pCR rate in BRCA1/2-mutated ERBB2-negative, hormone receptor-positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start.

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Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer

Cited by 76 publications

References 8 publications

Germline Mutations in Triple-Negative Breast Cancer

Germline Mutations in Triple-Negative Breast Cancer

Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes

Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer

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