Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy
Correction(s) for this article
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Erratum
- Volume 147Issue 2International Journal of Cancer
- pages: E2-E2
- First Published online: March 11, 2020
Piera Rizzolo
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
P.R. and V.Z. contributed equally to this work as co-first authorsSearch for more papers by this authorVeronica Zelli
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
P.R. and V.Z. contributed equally to this work as co-first authorsSearch for more papers by this authorValentina Silvestri
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Search for more papers by this authorVirginia Valentini
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Search for more papers by this authorInes Zanna
Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
Search for more papers by this authorSimonetta Bianchi
Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
Search for more papers by this authorGiovanna Masala
Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
Search for more papers by this authorAlessandro Mauro Spinelli
Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy
Search for more papers by this authorMaria Grazia Tibiletti
Department of Pathology, ASST Settelaghi and Centro di Ricerca per lo studio dei tumori eredo-familiari, Università dell'Insubria, Varese, Italy
Search for more papers by this authorAntonio Russo
Section of Medical Oncology, Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy
Search for more papers by this authorLiliana Varesco
IRCCS Ospedale Policlinico San Martino, Genoa, Italy
Search for more papers by this authorGiuseppe Giannini
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Search for more papers by this authorCarlo Capalbo
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Search for more papers by this authorDaniele Calistri
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy
Search for more papers by this authorLaura Cortesi
Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy
Search for more papers by this authorAlessandra Viel
Unit of Functional onco-genomics and genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
Search for more papers by this authorBernardo Bonanni
Division of Cancer Prevention and Genetics, European Institute of Oncology IEO, Milan, Italy
Search for more papers by this authorJacopo Azzollini
Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
Search for more papers by this authorSiranoush Manoukian
Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
Search for more papers by this authorMarco Montagna
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV—IRCCS, Padua, Italy
Search for more papers by this authorPaolo Peterlongo
Genome Diagnostics Program, IFOM—The FIRC Institute of Molecular Oncology, Milan, Italy
Search for more papers by this authorPaolo Radice
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy
Search for more papers by this authorDomenico Palli
Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
Search for more papers by this authorCorresponding Author
Laura Ottini
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Correspondence to: Laura Ottini, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 324, Rome 00161, Italy, Tel.: +39-06-4464129, E-mail: [email protected]Search for more papers by this authorPiera Rizzolo
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
P.R. and V.Z. contributed equally to this work as co-first authorsSearch for more papers by this authorVeronica Zelli
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
P.R. and V.Z. contributed equally to this work as co-first authorsSearch for more papers by this authorValentina Silvestri
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Search for more papers by this authorVirginia Valentini
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Search for more papers by this authorInes Zanna
Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
Search for more papers by this authorSimonetta Bianchi
Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
Search for more papers by this authorGiovanna Masala
Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
Search for more papers by this authorAlessandro Mauro Spinelli
Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy
Search for more papers by this authorMaria Grazia Tibiletti
Department of Pathology, ASST Settelaghi and Centro di Ricerca per lo studio dei tumori eredo-familiari, Università dell'Insubria, Varese, Italy
Search for more papers by this authorAntonio Russo
Section of Medical Oncology, Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy
Search for more papers by this authorLiliana Varesco
IRCCS Ospedale Policlinico San Martino, Genoa, Italy
Search for more papers by this authorGiuseppe Giannini
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Search for more papers by this authorCarlo Capalbo
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Search for more papers by this authorDaniele Calistri
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy
Search for more papers by this authorLaura Cortesi
Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy
Search for more papers by this authorAlessandra Viel
Unit of Functional onco-genomics and genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
Search for more papers by this authorBernardo Bonanni
Division of Cancer Prevention and Genetics, European Institute of Oncology IEO, Milan, Italy
Search for more papers by this authorJacopo Azzollini
Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
Search for more papers by this authorSiranoush Manoukian
Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
Search for more papers by this authorMarco Montagna
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV—IRCCS, Padua, Italy
Search for more papers by this authorPaolo Peterlongo
Genome Diagnostics Program, IFOM—The FIRC Institute of Molecular Oncology, Milan, Italy
Search for more papers by this authorPaolo Radice
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy
Search for more papers by this authorDomenico Palli
Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
Search for more papers by this authorCorresponding Author
Laura Ottini
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Correspondence to: Laura Ottini, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 324, Rome 00161, Italy, Tel.: +39-06-4464129, E-mail: [email protected]Search for more papers by this authorAbstract
Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non-BRCA1/2 MBC patients were examined in our study. Twenty-seven of the non-BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non-BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.
Abstract
What's new?
While multigene panel testing for breast cancer predisposition has been performed extensively in females, its use in male breast cancer (MBC) patients has been much more limited, despite a likely role for genetic predisposition in MBC. In this multicenter study in Italy, panel testing involving 50 cancer-associated genes identified germline pathogenic variants in about 5 percent of BRCA1/2-negative MBC patients. In non-BRCA1/2 MBC, the most frequently mutated genes were PALB2 and ATM, with PALB2 mutations having a major impact on MBC risk. By comparison, mutations in CHEK2 had little impact on MBC predisposition in the Italian population.
Supporting Information
| Filename | Description |
|---|---|
| ijc32106-sup-0001-FigureS1.pdfPDF document, 29.5 KB | Supplementary Figure 1 Distribution of VUS identified in 523 MBC cases. The number of VUS carriers is reported for each gene (cases with two or more VUS are counted in the totals for each gene). |
| ijc32106-sup-0002-TableS1.docWord document, 31 KB | Supplementary Table 1 Cancer susceptibility genes included in the custom 50 cancer-gene panel |
| ijc32106-sup-0003-TableS2.docWord document, 83.5 KB | Supplementary Table 2 Pathogenic variants identified in our study (No. 42) |
| ijc32106-sup-0004-TableS3.docWord document, 125.5 KB | Supplemetary Table 3. Variants of uncertain significance (VUS) identified in 523 MBC cases |
| ijc32106-sup-0005-TableS4.docWord document, 45.5 KB | Supplementary Table 4 Distribution of pathogenic variants and VUS identified in our study |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Ottini L. Male breast cancer: a rare disease that might uncover underlying pathways of breast cancer. Nat Rev Cancer 2014; 14: 643–4.
- 2Ly D, Forman D, Ferlay J, et al. An international comparison of male and female breast cancer incidence rates. Int J Cancer 2013; 132: 1918–26.
- 3 AIOM/AIRTUM. www.registrotumori.it.
- 4Korde LA, Zujewski JA, Kamin L, et al. Multidisciplinary meeting on male breast cancer: summary and research recommendations. J Clin Oncol 2010; 28: 2114–22.
- 5Rizzolo P, Silvestri V, Tommasi S, et al. Male breast cancer: genetics, epigenetics, and ethical aspects. Ann Oncol 2013; 24(Suppl 8): viii75–82.
- 6Giordano SH. Breast cancer in men. N Engl J Med 2018; 378: 2311–20.
- 7Pritzlaff M, Summerour P, McFarland R, et al. Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results. Breast Cancer Res Treat 2017; 161: 575–86.
- 8Fostira F, Saloustros E, Apostolou P, et al. Germline deleterious mutations in genes other than BRCA2 are infrequent in male breast cancer. Breast Cancer Res Treat 2018; 169: 105–13.
- 9Nielsen FC, van Overeem Hansen T, Sørensen CS. Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer 2016; 16: 599–612.
- 10Easton DF, Pharoah PD, Antoniou AC, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 2015; 372: 2243–57.
- 11Tung N, Battelli C, Allen B, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 2015; 121: 25–33.
- 12Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 2015; 33: 304–11.
- 13Couch FJ, Shimelis H, Hu C, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol 2017; 3: 1190–6.
- 14Kraus C, Hoyer J, Vasileiou G, et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer 2017; 140: 95–102.
- 15Slavin TP, Maxwell KN, Lilyquist J, et al. The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer 2017; 3: 44.
- 16Li J, Li H, Makunin I, et al. Panel sequencing of 264 candidate susceptibility genes and segregation analysis in a cohort of non-BRCA1, non-BRCA2 breast cancer families. Breast Cancer Res Treat 2017; 166: 937–49.
- 17Li J, Jing R, Wei H, et al. Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. Int J Cancer 2018; 144: 281–9. https://doi.org/10.1002/ijc.31601.
- 18Hauke J, Horvath J, Groß E, et al. Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German consortium for hereditary breast and ovarian cancer. Cancer Med 2018; 7: 1349–58.
- 19Rehm HL. Disease-targeted sequencing: a cornerstone in the clinic. Nat Rev Genet 2013; 14: 295–300.
- 20Cybulski C, Wokołorczyk D, Jakubowska A, et al. Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol 2011; 29: 3747–52.
- 21Silvestri V, Rizzolo P, Zelli V, et al. A possible role of FANCM mutations in male breast cancer susceptibility: results from a multicenter study in Italy. Breast 2018; 38: 92–7.
- 22Ottini L, Silvestri V, Rizzolo P, et al. Clinical and pathologic characteristics of BRCA-positive and BRCA-negative male breast cancer patients: results from a collaborative multicenter study in Italy. Breast Cancer Res Treat 2012; 134: 411–8.
- 23Richards S, Aziz N, Bale S, et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405–24.
- 24Rizzolo P, Silvestri V, Bucalo A, et al. Contribution of MUTYH variants to male breast cancer risk: results from a multicenter study in Italy. Front Oncol 2018; 8: 583. https://doi.org/10.3389/fonc.2018.00583.
- 25Gershoni-Baruch R, Patael Y, Dagan, Dagan E, et al. Association of the I1307K APC mutation with hereditary and sporadic breast/ovarian cancer: more questions than answers. Br J Cancer 2000; 83: 153–5.
- 26Rizzolo P, Silvestri V, Ottini L. Retesting BRCA1/BRCA2 mutation negative male breast cancer patients using next generation sequencing technologies. Breast Cancer Res Treat 2017; 162: 199–200.
- 27Silvestri V, Zelli V, Valentini V, et al. Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene. Cancer 2017; 123: 210–8.
- 28Antoniou AC, Casadei S, Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014; 371: 497–506.
- 29Meijers-Heijboer H, van den Ouweland A, Klijn J, et al. CHEK2-Breast Cancer Consortium.CHEK2-Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 2002; 31: 55–9.
- 30Wasielewski M, den Bakker MA, van den Ouweland A, et al. CHEK21100delC and male breast cancer in the Netherlands. Breast Cancer Res Treat 2009; 116: 397–400.
- 31Hallamies S, Pelttari LM, Poikonen-Saksela P, et al. CHEK2 c.1100delC mutation is associated with an increased risk for male breast cancer in Finnish patient population. BMC Cancer 2017; 17: 620.
- 32Caligo MA, Agata S, Aceto G, et al. The CHEK2 c.1100delC mutation plays an irrelevant role in breast cancer predisposition in Italy. Hum Mutat 2004; 24: 100–1.
- 33Falchetti M, Lupi R, Rizzolo P, et al. BRCA1/BRCA2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases. Breast Cancer Res Treat 2008; 110: 161–7.
- 34Usitalo E, Kallionpää RA, Kurki S, et al. Breast cancer in neurofibromatosis type 1: overrepresentation of unfavourable prognostic factors. Br J Cancer 2017; 116: 211–7.
- 35Ronchese F. Neurofibromatosis and adenocarcinoma of (male) breast. AMA Arch DermSyphilol 1953; 68: 359.
- 36Lakshmaiah KC, Kumar AN, Purohit S, et al. Neurofibromatosis type I with breast cancer: not only for women. Hered Cancer Clin Pract 2014; 12: 5.
- 37Tandon M, Panwar P, Garg P, et al. Neurofibromatosis with male breast cancer-risk factor or co-incidence? Report of two rare cases. Breast Dis 2015; 35: 29–32.
- 38Mann N, Ma T, Dalton A. Neurofibromatosis type 1 and male breast cancer: emerging risk factor? J Surg Case Rep 2017; 2017: rjw138.
- 39Mendes-Pereira AM, Sims D, Dexter T, et al. Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen. Proc Natl Acad Sci U S A 2012; 109: 2730–5.
- 40Brinton LA, Cook MB, McCormack V, et al. Anthropometric and hormonal risk factors for male breast cancer: male breast cancer pooling project results. J Natl Cancer Inst 2014; 106: djt465.
- 41Zhang B, Beeghly-Fadiel A, Long J, et al. Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol 2011; 12: 477–88.
- 42Aloraifi F, McDevitt T, Martiniano R, et al. Detection of novel germline mutations for breast cancer in non-BRCA1/2 families. FEBS J 2015; 282: 3424–37.
- 43McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 2006; 66: 8109–15.
- 44Wang X, Weaver DT. The ups and downs of DNA repair biomarkers for PARP inhibitor therapies. Am J Cancer Res 2011; 1: 301–27.
- 45Liang J, Lin C, Hu F, et al. APC polymorphisms and the risk of colorectal neoplasia: a huge review and meta-analysis. Am J Epidemiol 2013; 177: 1169–79.
- 46Bonache S, Esteban I, Moles-Fernández A, et al. Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. J Cancer Res Clin Oncol 2018; 144: 2495–513. https://doi.org/10.1007/s00432-018-2763-9.
- 47Vogt S, Jones N, Christian D, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 2009; 137: 1976–85.e1-10.
- 48Schon K, Tischkowitz M. Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat 2018; 167: 417–23.
- 49Ottini L, Rizzolo P, Zanna I, et al. BRCA1/BRCA2 mutation status and clinical-pathologic features of 108 male breast cancer cases from Tuscany: a population-based study in central Italy. Breast Cancer Res Treat 2009; 116: 577–86.
- 50National Comprehensive Cancer Network: NCCN guidelines genetic/familial high-risk assessment: Breast and ovarian, version 2, 2019. http://www.nccn.org.
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