Dataset Information

FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women.

ABSTRACT: Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.

SUBMITTER: Figlioli G

PROVIDER: S-EPMC10172381 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women.

Figlioli Gisella G Billaud Amandine A Ahearn Thomas U TU Antonenkova Natalia N NN Becher Heiko H Beckmann Matthias W MW Behrens Sabine S Benitez Javier J Bermisheva Marina M Blok Marinus J MJ Bogdanova Natalia V NV Bonanni Bernardo B Burwinkel Barbara B Camp Nicola J NJ Campbell Archie A Castelao Jose E JE Cessna Melissa H MH Chanock Stephen J SJ Czene Kamila K Devilee Peter P Dörk Thilo T Engel Christoph C Eriksson Mikael M Fasching Peter A PA Figueroa Jonine D JD Gabrielson Marike M Gago-Dominguez Manuela M García-Closas Montserrat M González-Neira Anna A Grassmann Felix F Guénel Pascal P Gündert Melanie M Hadjisavvas Andreas A Hahnen Eric E Hall Per P Hamann Ute U Harrington Patricia A PA He Wei W Hillemanns Peter P Hollestelle Antoinette A Hooning Maartje J MJ Hoppe Reiner R Howell Anthony A Humphreys Keith K Jager Agnes A Jakubowska Anna A Khusnutdinova Elza K EK Ko Yon-Dschun YD Kristensen Vessela N VN Lindblom Annika A Lissowska Jolanta J Lubiński Jan J Mannermaa Arto A Manoukian Siranoush S Margolin Sara S Mavroudis Dimitrios D Newman William G WG Obi Nadia N Panayiotidis Mihalis I MI Rashid Muhammad U MU Rhenius Valerie V Rookus Matti A MA Saloustros Emmanouil E Sawyer Elinor J EJ Schmutzler Rita K RK Shah Mitul M Sironen Reijo R Southey Melissa C MC Suvanto Maija M Tollenaar Rob A E M RAEM Tomlinson Ian I Truong Thérèse T van der Kolk Lizet E LE van Veen Elke M EM Wappenschmidt Barbara B Yang Xiaohong R XR Bolla Manjeet K MK Dennis Joe J Dunning Alison M AM Easton Douglas F DF Lush Michael M Michailidou Kyriaki K Pharoah Paul D P PDP Wang Qin Q Adank Muriel A MA Schmidt Marjanka K MK Andrulis Irene L IL Chang-Claude Jenny J Nevanlinna Heli H Chenevix-Trench Georgia G Evans D Gareth DG Milne Roger L RL Radice Paolo P Peterlongo Paolo P

European journal of human genetics : EJHG 20230127 5

Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-nega ...[more]

PMID: 36707629

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Project description:BackgroundLysyl oxidase (LOX) is an extracellular enzyme essential for the covalent crosslinking of extracellular matrix proteins and may also have additional functions. LOX expression can be both up- and downregulated in cancer and is associated both with tumour suppression and metastasis progression. The G473A polymorphism (rs1800449) results in the Arg158Gln amino acid substitution in the LOX propeptide, compromises its tumour suppressive activity, and was associated with an increased breast cancer risk in a Chinese Han population. In the first hospital-based case-control study in European women, we aimed at investigating the association of LOX expression and the G473A polymorphism with breast cancer risk and survival in unselected and estrogen receptor (ER) negative patients.Methodology/principal findingsThe G473A polymorphism was genotyped in 386 breast cancer patients and 243 female controls. Moreover, LOX mRNA expression was quantified in the tumors of 105 patients by qRT-PCR. We found that the minor A-allele of this polymorphism is associated with a later age at breast cancer onset, a trend towards a decreased disease-free and metastasis-free survival, but not with an increased breast cancer risk. LOX mRNA expression was significantly elevated in tumours of patients older than 55 years, postmenopausal patients, estrogen receptor positive tumours, and p53 negative tumours, but was unaffected by G473A genotype in tumours and breast cancer cell lines. High LOX expression was associated with a poor disease-free and metastasis-free survival in ER negative but not ER positive patients. LOX expression was an independent prognostic parameter in multivariate analysis, whereas G473A genotype was not. A small, distinct subgroup of the ER negative patients was identified which exhibited a considerably elevated LOX expression and a very poor disease-free (p = 0.001) and metastasis-free survival (p = 0.0003).Conclusions/significanceThis newly identified ER negative/LOX high subgroup may be a suitable collective for future individualized breast cancer diagnosis and therapy.

Project description:ObjectivesThough menstrual and reproductive factors have been associated with the risk of breast cancer in many populations, very few studies have been conducted among Vietnamese women. This study aimed to assess the association between menstrual and reproductive factors and the risk of breast cancer in Vietnamese women.MethodsA retrospective case-control study of 490 breast cancer cases and 468 controls was conducted in Northern Vietnam. Unconditional logistic regression models adjusting for confounders were used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for the associations of menstrual and reproductive factors with the risk of breast cancer; overall and by cancer subtype.ResultsAmong breast cancer patients, the luminal B subtype was the most frequent (48.6%), followed by HER2-overexpressing (24.5%), luminal A (16.7%), and triple-negative breast cancer (TNBC; 10.2%). Among menopausal women, menopausal age at 50 years or older (OR = 1.71, 95% CI: 1.15-2.57 vs. <50 y) was associated with an increased risk of breast cancer. Earlier age at menarche (<13 y) was associated with a significantly increased risk of breast cancer (OR = 2.66, 95% CI: 1.08-7.51) among premenopausal women only and the luminal A subtype of breast cancer (OR = 3.06, 95% CI: 1.04-8.16). Having more than two children was associated with a reduced risk of premenopausal (OR = .42, 95%CI: .21-.83), luminal B (OR = .43, 95% CI: .24-.79), and TNBC (OR = .34, 95% CI: .14-.89). Later menopause was positively associated with the risk of breast cancer with HER2 overexpression (OR = 2.19, 95% CI: 1.14-4.23).ConclusionAssociations of menstrual and reproductive factors with breast cancer among Vietnamese women, particularly for among premenopausal women and for the luminal A subtype, are generally consistent with those reported from other countries. These findings suggest that changes in menstrual and reproductive patterns among young Vietnamese women may contribute to the recent rising incidence of breast cancer in Vietnam.

Dataset Information

FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women.

Publications

FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women.

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