Abstract
Male Breast Cancer (MBC) is a rare and aggressive disease that is associated with genetic factors. Mutations in BRCA1 and BRCA2 account for 10% of all MBC cases suggesting that other genetic factors are involved. The aim of the present study is to screen whole BRCA1 and BRCA2 exons using the Ampliseq BRCA panel in Tunisian MBC patients with family history. Furthermore, we performed exome sequencing using the TruSight One sequencing panel on an early onset BRCA negative patient. We showed that among the 6 MBC patients, only one (MBC-F1) harbored a novel frameshift mutation in exon 2 of the BRCA2 gene (c.17-20delAAGA, p.Lys6Xfs) resulting in a short BRCA2 protein of only 6 amino-acids. We selected 9 rare variants after applying several filter steps on the exome sequencing data. Among these variants, and based on their role in breast carcinogenesis, we retained 6 candidate genes (MSH5, DCC, ERBB3, NOTCH3, DIAPH1, and DNAH11). Further studies are needed to confirm the association of the selected genes with family MBC.
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References
Speirs V, Shaaban AM (2009) The rising incidence of male breast cancer. Breast Cancer Res Treat 115(2):429–430. https://doi.org/10.1007/s10549-008-0053-y
Siegel RL, Miller KD, Jemal A (2020) Cancer statistics. CA: Cancer J Clin 70(1):7–30. https://doi.org/10.3322/caac.21590
Ruddy KJ, Winer EP (2013) Male breast cancer: risk factors, biology, diagnosis, treatment, and survivorship. Ann Oncol 24(6):1434–1443. https://doi.org/10.1093/annonc/mdt025
Ottini L, Palli D, Rizzo S, Federico M, Bazan V, Russo A (2010) Male breast cancer. Crit Rev Oncol/Hematol 73(2):141–155. https://doi.org/10.1016/j.critrevonc.2009.04.003
Deb S, Lakhani SR, Ottini L, Fox SB (2016) The cancer genetics and pathology of male breast cancer. Histopathology 68(1):110–118. https://doi.org/10.1111/his.12862
Rizzolo P, Silvestri V, Tommasi S, Pinto R, Danza K et al (2013) Male breast cancer: genetics, epigenetics, and ethical aspects. Ann Oncol 8:viii75–viii82. https://doi.org/10.1093/annonc/mdt316
Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE et al (2002) Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20(6):1480–1490. https://doi.org/10.1200/jco.2002.20.6.1480
Zheng G, Yu H, Hemminki A, Försti A, Sundquist K, Hemminki K (2017) Familial associations of female breast cancer with other cancers. Int J Cancer 141(11):2253–2259. https://doi.org/10.1002/ijc.30927
Wasielewski M, den Bakker MA, van den Ouweland A, Meijer-van Gelder ME, Portengen H, Klijn JG (1100delC) CHEK2 1100delC and male breast cancer in the Netherlands. Breast Cancer Res Treat 116(2):397–400. https://doi.org/10.1007/s10549-008-0162-7
Hallamies S, Pelttari LM, Poikonen-Saksela P, Jekunen A et al (2017) CHEK2 c.1100delC mutation is associated with an increased risk for male breast cancer in Finnish patient population. BMC Cancer 17(1):620. https://doi.org/10.1186/s12885-017-3631-8
Silvestri V, Zelli V, Valentini V, Rizzolo P, Navazio AS et al (2017) Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene. Cancer 123(2):210–218. https://doi.org/10.1002/cncr.30337
Scarpitta R, Zanna I, Aretini P, Gambino G, Scatena C et al (2019) Germline investigation in male breast cancer of DNA repair genes by next-generation sequencing. Breast Cancer Res Treat 178(3):557–564. https://doi.org/10.1007/s10549-019-05429-z
Missaoui N, Jaidene L, Abdelkrim SB, Abdelkader AB, Beizig N et al (2011) Breast cancer in Tunisia: clinical and pathological findings. Asian Pac J Cancer Prev 12(1):169–172
Rizzolo P, Zelli V, Silvestri V, Valentini V, Zanna I et al (2019) Insight into genetic susceptibility to male breast cancer by multigene panel testing: results from a multicenter study in Italy. Int J Cancer 145(2):390–400. https://doi.org/10.1002/ijc.32106
Pritzlaff M, Summerour P, McFarland R, Li S, Reineke P et al (2017) Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results. Breast Cancer Res Treat 161(3):575–586. https://doi.org/10.1007/s10549-016-4085-4
Riahi A, El Ghourabi M, Fourati A, Chaabouni-Bouhamed H (2017) Family history predictors of BRCA1/BRCA2 mutation status among Tunisian breast/ovarian cancer families. Breast Cancer 24(2):238–244. https://doi.org/10.1007/s12282-016-0693-4
Chahed K, Kabbage M, Hamrita B, Guillier CL, Trimeche M et al (2008) Detection of protein alterations in male breast cancer using two-dimensional gel electrophoresis and mass spectrometry: the involvement of several pathways in tumorigenesis. Clin Chim Acta 388:106–114. https://doi.org/10.1016/j.cca.2007.10.018
Abdeljaoued S, Bettaieb L, Nasri M, Adouni O, Goucha A et al (2018) Forkhead box M1 (FOXM1) expression predicts disease free survival and may mediate resistance to chemotherapy and hormonotherapy in male breast cancer. Breast Dis 37(3):109–114
Manai M, Abdeljaoued S, Goucha A, Adouni O, Bettaieb I et al (2019) MARCKS protein overexpression is associated with poor prognosis in male breast cancer. Cancer Biomark 26(4):513–522. https://doi.org/10.3233/cbm-190637
Silvestri V, Rizzolo P, Zelli V, Valentini V, Zanna I et al (2018) A possible role of FANCM mutations in male breast cancer susceptibility: results from a multicenter study in Italy. Breast 38:92–97. https://doi.org/10.1016/j.breast.2017.12.013
Bowden AR, Tischkowitz M (2019) Clinical implications of germline mutations in breast cancer genes: RECQL. Breast Cancer Res Treat 174(3):553–560. https://doi.org/10.1007/s10549-018-05096-6
Nguyen-Dumont T, Myszka A, Karpinski P, Sasiadek MM, Akopyan H et al (2018) FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine. BMC Med Genet 19(1):12. https://doi.org/10.1186/s12881-018-0524-x
Fostira F, Saloustros E, Apostolou P, Vagena A, Kalfakakou D et al (2018) Germline deleterious mutations in genes other than BRCA2 are infrequent in male breast cancer. Breast Cancer Res Treat 169(1):105–113. https://doi.org/10.1007/s10549-018-4661-x
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13(11):2498–2504. https://doi.org/10.1101/gr.1239303
Doncheva NT, Morris JH, Gorodkin J, Jensen LJ (2019) Cytoscape StringApp: network analysis and visualization of proteomics data. J Proteome Res 18(2):623–632. https://doi.org/10.1021/acs.jproteome.8b00702
Karray-Chouayekh S, Trifa F, Khabir A, Sellami-Boudawara T, Frikha M et al (2012) Negative/low HER2 expression alone or combined with E-cadherin positivity is predictive of better prognosis in patients with breast carcinoma. Histol Histopathol 27(3):377–385. https://doi.org/10.14670/hh-27.377
Cipollini G, Tommasi S, Paradiso A, Aretini P, Bonatti F et al (2004) Genetic alterations in hereditary breast cancer. Ann Oncol 15(Suppl 1):I7–i13. https://doi.org/10.1093/annonc/mdh651
Hamdi Y, Boujemaa M, Ben Rekaya M, Ben Hamda C, Mighri N et al (2018) Family specific genetic predisposition to breast cancer: results from Tunisian whole exome sequenced breast cancer cases. J Trans Med 16(1):158. https://doi.org/10.1186/s12967-018-1504-9
Riahi A, Radmanesh H, Schurmann P, Bogdanova N, Geffers R et al (2018) Exome sequencing and case-control analyses identify RCC1 as a candidate breast cancer susceptibility gene. Int J Cancer 142(12):2512–2517. https://doi.org/10.1002/ijc.31273
O’Hayre M, Degese MS, Gutkind JS (2014) Novel insights into G protein and G protein-coupled receptor signaling in cancer. Curr Opt Cell Biol 27:126–135. https://doi.org/10.1016/j.ceb.2014.01.005
Nieto Gutierrez A, McDonald PH (2018) GPCRs: Emerging anti-cancer drug targets. Cell Signal 41:65–74. https://doi.org/10.1016/j.cellsig.2017.09.005
Liu J, Han P, Li M, Yan W, Liu J et al (2015) The histidine-rich calcium binding protein (HRC) promotes tumor metastasis in hepatocellular carcinoma and is upregulated by SATB1. Oncotarget 6(9):6811–6824. https://doi.org/10.18632/oncotarget.3049
Butler SL, Dong H, Cardona D, Jia M, Zheng R et al (2008) The antigen for Hep Par 1 antibody is the urea cycle enzyme carbamoyl phosphate synthetase 1. Lab Invest 88(1):78–88. https://doi.org/10.1038/labinvest.3700699
Liu H, Dong H, Robertson K, Liu C (2011) DNA methylation suppresses expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) in human hepatocellular carcinoma. Am Pathol 178(2):652–661. https://doi.org/10.1016/j.ajpath.2010.10.023
Lee YY, Li CF, Lin CY, Chen G, Lee SW et al (2014) Overexpression of CPS1 is an independent negative prognosticator in rectal cancers receiving concurrent chemoradiotherapy. Tumour Biol 35(11):11097–11105. https://doi.org/10.1007/s13277-014-2425-8
Sato T, Kashima K, Gamachi A, Daa T, Nakayama I et al (2002) Immunohistochemical localization of pyruvate carboxylase and carbamyl-phosphate synthetase I in normal and neoplastic human pancreatic tissues. Pancreas 25(2):130–135. https://doi.org/10.1097/00006676-200208000-00003
Clark N, Wu X, Her C (2013) MutS homologues hMSH4 and hMSH5: genetic variations, functions, and implications in human diseases. Curr Genomics 14(2):81–90. https://doi.org/10.2174/1389202911314020002
Kiavue N, Cabel L, Melaabi S, Bataillon G, Callens C et al (2020) ERBB3 mutations in cancer: biological aspects, prevalence and therapeutics. Oncogene 39(3):487–502. https://doi.org/10.1038/s41388-019-1001-5
Mishra R, Alanazi S, Yuan L, Solomon T, Thaker TM et al (2018) Activating HER3 mutations in breast cancer. Oncotarget 9(45):27773–27788. https://doi.org/10.18632/oncotarget.25576
Bartolini F, Gundersen GG (2010) Formins and microtubules. Biochem Biophys Acta 1803(2):164–173. https://doi.org/10.1016/j.bbamcr.2009.07.006
Lizárraga F, Poincloux R, Romao M, Montagnac G, Le Dez G et al (2009) Diaphanous-related formins are required for invadopodia formation and invasion of breast tumor cells. Cancer Res 69(7):2792–2800. https://doi.org/10.1158/0008-5472.can-08-3709
Verma S, Bakshi D, Sharma V, Sharma I, Shah R et al (2020) Genetic variants of DNAH11 and LRFN2 genes and their association with ovarian and breast cancer. Int J Gynaecol Obstet 148(1):118–122. https://doi.org/10.1002/ijgo.12997
Leontovich AA, Jalalirad M, Salisbury JL, Mills L, Haddox C et al (2018) NOTCH3 expression is linked to breast cancer seeding and distant metastasis. Breast Cancer Res 20(1):105. https://doi.org/10.1186/s13058-018-1020-0
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The authors thank the patients involved in the study.
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This work was supported by a grant of the CIC- Habib Bourguiba Hospital Sfax-Tunisia, (Centre d’Investigation Clinique) and the Tunisian Ministry of Higher Education and Research.
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Written informed consents were obtained from all participants. Ethical approval according to the Declaration of Helsinki Principles was obtained from the biomedical ethics committee of University Hospital Habib Bourguiba of Sfax -Tunisia.
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Informed consent was obtained from all patients included in the study. This study is approved by Ethic committee of University Hospitals of Sfax-Tunisia.
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Ben Kridis-Rejeb, W., Ben Ayed-Guerfali, D., Ammous-Boukhris, N. et al. Identification of novel candidate genes by exome sequencing in Tunisian familial male breast cancer patients. Mol Biol Rep 47, 6507–6516 (2020). https://doi.org/10.1007/s11033-020-05703-0
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DOI: https://doi.org/10.1007/s11033-020-05703-0