Universität zu Köln

Neidhardt, Guido, Hauke, Jan, Ramser, Juliane, Gross, Eva, Gehrig, Andrea, Mueller, Clemens R., Kahlert, Anne-Karin, Hackmann, Karl, Honisch, Ellen, Niederacher, Dieter, Heilmann-Heimbach, Stefanie ORCID: 0000-0003-1057-465X, Franke, Andre ORCID: 0000-0003-1530-5811, Lieb, Wolfgang, Thiele, Holger, Altmueller, Janine, Nuernberg, Peter, Klaschik, Kristina, Ernst, Corinna, Ditsch, Nina, Jessen, Frank, Ramirez, Alfredo ORCID: 0000-0003-4991-763X, Wappenschmidt, Barbara, Engel, Christoph ORCID: 0000-0002-7247-282X, Rhiem, Kerstin, Meindl, Alfons, Schmutzler, Rita K. and Hahnen, Eric (2017). Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer. JAMA Oncol., 3 (9). S. 1245 - 1249. CHICAGO: AMER MEDICAL ASSOC. ISSN 2374-2445

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Abstract

IMPORTANCE Germline mutations in established moderately or highly penetrant risk genes for breast cancer (BC) and/or ovarian cancer (OC), including BRCA1 and BRCA2, explain fewer than half of all familial BC and/or OC cases. Based on the genotyping of 2 loss-of-function (LoF) variants c.5101C>T (p.GIn1701Ter [rs147021911]) and c.5791C>T (p.Arg1931Ter [rs144567652]), the FANCM gene has been suggested as a novel BC predisposition gene, while the analysis of the entire coding region of the FANCM gene in familial index cases and geographically matched controls is pending. OBJECTIVES To assess the mutational spectrum within the FANCM gene, and to determine a potential association of LoF germline mutations within the FANCM gene with BC and/or OC risk. DESIGN, SETTING, AND PARTICIPANTS For the purpose of identification and characterization of novel BC and/or OC predisposition genes, a total of 2047 well-characterized familial BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for LoF mutations within the FANCM gene by next-generation sequencing. All patients previously tested negative for pathogenic BRCA1 and BRCA2 mutations. All data collection occurred between June 1, 2013, and April 30, 2016. Data analysis was performed from May 1, 2016, to July 1, 2016. MAIN OUTCOMES AND MEASURES FANCM LoF mutation frequencies in patients with BC and/or OC were compared with the FANCM LoF mutation frequencies in geographically matched controls by univariate logistic regression. Positive associations were stratified by age at onset and cancer family history. RESULTS In this case-control study, 2047 well-characterized familial female BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for truncating FANCM alterations. Heterozygous LoF mutations within the FANCM gene were significantly associated with familial BC risk, with an overall odds ratio (OR) of 2.05 (95% CI, 0.94-4.54; P = .049) and a mutation frequency of 1.03% in index cases. In familial patients whose BC onset was before age 51 years, an elevated OR of 2.44 (95% CI, 1.08-5.59; P = .02) was observed. A more pronounced association was identified for patients with a triple-negative BC tumor phenotype (OR, 3.75; 95% CI, 1.00-12.85; P = .02). No significant association was detected for unselected OC cases (OR, 1.74; 95% CI, 0.57-5.08; P = .27). CONCLUSIONS AND RELEVANCE Based on the significant associations of heterozygous LoF mutations with early-onset or triple-negative BC, FANCM should be included in diagnostic gene panel testing for individual risk assessment. Larger studies are required to determine age-dependent disease risks for BC and to assess a potential role of FANCM mutations in OC pathogenesis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Neidhardt, Guido UNSPECIFIED UNSPECIFIED UNSPECIFIED Hauke, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Ramser, Juliane UNSPECIFIED UNSPECIFIED UNSPECIFIED Gross, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Gehrig, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Clemens R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kahlert, Anne-Karin UNSPECIFIED UNSPECIFIED UNSPECIFIED Hackmann, Karl UNSPECIFIED UNSPECIFIED UNSPECIFIED Honisch, Ellen UNSPECIFIED UNSPECIFIED UNSPECIFIED Niederacher, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Heilmann-Heimbach, Stefanie UNSPECIFIED orcid.org/0000-0003-1057-465X UNSPECIFIED Franke, Andre UNSPECIFIED orcid.org/0000-0003-1530-5811 UNSPECIFIED Lieb, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Klaschik, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Ernst, Corinna UNSPECIFIED UNSPECIFIED UNSPECIFIED Ditsch, Nina UNSPECIFIED UNSPECIFIED UNSPECIFIED Jessen, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Ramirez, Alfredo UNSPECIFIED orcid.org/0000-0003-4991-763X UNSPECIFIED Wappenschmidt, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Engel, Christoph UNSPECIFIED orcid.org/0000-0002-7247-282X UNSPECIFIED Rhiem, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Meindl, Alfons UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmutzler, Rita K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hahnen, Eric UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-219844
DOI:	10.1001/jamaoncol.2016.5592
Journal or Publication Title:	JAMA Oncol.
Volume:	3
Number:	9
Page Range:	S. 1245 - 1249
Date:	2017
Publisher:	AMER MEDICAL ASSOC
Place of Publication:	CHICAGO
ISSN:	2374-2445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SUSCEPTIBILITY GENE; RISK Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21984