High Incidence of Familial Breast Cancer Segregates with Constitutional t(11;22)(q23;q11) Ilse Wieland, Petra Muschke, Marianne Volleth, Albrecht Ro ¨pke, Antje-Friederike Pelz, Markus Stumm, { and Peter Wieacker * Institut fˇr Humangenetik,Otto-von-Guericke-UniversitÌt, Magdeburg,Germany In a family with a high incidence of postmenopausal breast cancer and a case of glioblastoma, the constitutional translocation t(11;22)(q23;q11.2) was shown to segregate with the malignancies. The breakpoints in this family coincided with the common breakpoints in t(11;22) as shown by a translocation-specific PCR assay. Loss of heterozygosity analysis of breast tumor tissue revealed deletion of the normal chromosome 22, but retention of der(22) in the tumor cells, suggesting a predisposing effect of the der(22) for breast and brain tumor development in this family. V V C 2006 Wiley-Liss, Inc. INTRODUCTION Breast cancer is the most commonly occurring malignancy in women. Epidemiological studies have shown that 12% of women with breast cancer have one affected family member and 1% have two or more affected relatives (Collaborative group on hor- monal factors in breast cancer, 2001). Hereditary breast cancers [OMIM 114480] are often multifocal or bilateral. In the high-penetrance traits, germline mutations in cancer susceptibility genes such as BRCA1, BRCA2, TP53, PTEN, or ATM confer high individual risk for developing breast cancer (de Jong et al., 2002). The most common cause for fam- ilial premenopausal breast cancer are germline mu- tations in BRCA1 and BRCA2 that are responsible for 80–90% of hereditary breast cancer. Germline mutations in the TP53 and PTEN genes have been identified in cancer susceptibility syndromes, and mutations in other genes are responsible for syn- dromes with increased breast cancer risk. However, mutations in these genes appear to account for only 5–10% of all breast cancers (Collaborative group on hormonal factors in breast cancer, 2001). In the rela- tively common low-penetrance traits, reduced- penetrance cancer susceptibility genes act together with endogenous and lifestyle risk factors and are likely to account for the majority of breast cancer (de Jong et al., 2002; Dumitrescu and Cotarla, 2005). Recently, an inherited constitutional translo- cation t(11;12)(q24;q23) was shown to be associated with breast cancer at incomplete penetrance in a family with early-onset breast cancer and glioblas- toma (Martin et al., 2003). Previously, a significant association between postmenopausal breast cancer and a constitutional translocation t(11;22)(q23;q11) was observed in a series of patients [OMIM 600048] (Lindblom et al., 1994; Jobanputra et al., 2005), but not in others (Zackai and Emanuel, 1980; Kurahashi et al., 2000). The t(11;22)(q23;q11) is the most com- mon constitutional reciprocal translocation in human (Iselius et al., 1983). Carriers of balanced t(11;22) are phenotypically normal, but may seek genetic counseling because of reproductive problems (Kura- hashi and Emanuel, 2001a). They are at risk of hav- ing unbalanced progeny with the supernummaryÀ der(22)t(11;22) syndrome (Zackai and Emauel, 1980). Incidental occurrence of breast cancer has been observed in these families (Lindblom et al., 1994; Jobanputra et al., 2005). Herein, we describe a family with a high incidence of postmenopausal breast cancer and a case of glioblastoma in a male patient. Family members showed segregation of the constitutional balanced t(11;22) with the malignan- cies, suggesting an association between t(11;22) and breast and possibly brain cancer predisposition. PATIENTS Family History A 39-year-old woman (IV6) was referred to us for genetic counseling and testing because of a family history of breast cancer (Fig. 1). At that time, she suffered from fibrocystic mastopathy. Her mother The first two authors contributed equally to this work. { Present address: Praxis fu ¨ r Ultraschall und Humangenetik, Kur- fu ¨rstendamm 199, 10719 Berlin, Germany. *Correspondence to: P. Wieacker, Institut fu ¨ r Humangenetik, Otto-von-Guericke-Universita ¨t, Leipziger Str. 44, 39120 Magde- burg, Germany. E-mail: peter.wieacker@medizin.uni-magdeburg.de Received 22 March 2006; Accepted 6 June 2006 DOI 10.1002/gcc.20358 Published online 14 July 2006 in Wiley InterScience (www.interscience.wiley.com). V V C 2006 Wiley-Liss, Inc. GENES, CHROMOSOMES & CANCER 45:945–949 (2006)