Women with Saethre-Chotzen Syndrome Are at Increased Risk of Breast Cancer Pelle Sahlin, 1,2 * Per Windh, 1 Claes Lauritzen, 1 Monica Emanuelsson, 3 Henrik Gro¨ nberg, 4 and Go¨ ran Stenman 2 * 1 Department of Plastic Surgery, The Sahlgrenska Academy at G˛teborg University, Sahlgrenska University Hospital, G˛teborg, Sweden 2 Lundberg Laboratory for Cancer Research,Department of Pathology,The Sahlgrenska Academy at G˛teborg University, Sahlgrenska University Hospital,G˛teborg, Sweden 3 Oncology Center,UmeÔ University Hospital,UmeÔ, Sweden 4 Department of Medical Epidemiology and Biostatistics,Karolinska Institute, Stockholm, Sweden The Saethre-Chotzen syndrome is an autosomal, dominantly inherited craniosynostosis caused by mutations in the basic helix-loop-helix transcription factor gene TWIST1. This syndrome has hitherto not been associated with an increased risk of cancer. However, recent studies, using a murine breast tumor model, have shown that Twist may act as a key regulator of metastasis and that the gene is overexpressed in subsets of sporadic human breast cancers. Here, we report a novel associa- tion between the Saethre-Chotzen syndrome and breast cancer. In 15 Swedish Saethre-Chotzen families, 15 of 29 (52%) women carriers over the age of 25 had developed breast cancer. At least four patients developed breast cancer before 40 years of age, and five between 40 and 50 years of age. The observed cases with breast cancer (n ¼ 15) are significantly higher than expected (n 5 0.89), which gives a standardized incidence ratio (SIR) of 16.80 (95% CI 1.54–32.06). Our finding of a high frequency of breast cancer in women with the Saethre-Chotzen syndrome identifies breast cancer as an important and previously unrecognized symptom characteristic of this syndrome. The results strongly suggest that women carriers of this syndrome would benefit from genetic counseling and enrolment in surveillance programs including yearly mammography. Our results also indicate that the TWIST1 gene may be a novel breast cancer susceptibility gene. Additional studies are, how- ever, necessary to reveal the mechanism by which TWIST1 may predispose to early onset breast cancer in Saethre-Chotzen patients. V VC 2007 Wiley-Liss, Inc. INTRODUCTION The Saethre-Chotzen syndrome (acrocephalo- syndactyly type III, ACS III; MIM no. 101400) is an autosomal dominantly inherited form of cranio- synostosis (premature closure of one or more cranial sutures) originally characterized by brachycephaly, partial cutaneous syndactyly of the second interdi- gital space and blepharoptosis (Bartsocas et al., 1970; Kreiborg et al., 1972; Pantke et al., 1975; Friedman et al., 1977). It is one of the most com- mon craniosynostosis syndromes in humans with an incidence of 1 in 25,000 to 1 in 50,000 newborns. The syndrome has a high degree of penetrance and shows a variable expressivity (Pantke et al., 1975; Reardon and Winter, 1994). We have previously, based on detailed analyses of a large cohort of patients with the Saethre-Chot- zen syndrome (48 patients from 20 families), iden- tified the six most frequently occurring symptoms, designated cardinal symptoms, associated with this syndrome (Sahlin et al., 1994). These include coro- nal synostosis (91%), S-shaped blepharoptosis (90%), low set ears with typical apical cartilage deformity (78%), cutaneous syndactyly of dig II–III (76%), typical nasal deformity (60%), and low frontolateral hair line (62%). On the basis of this study, we have suggested two sets of criteria either of which is required for the diagnosis of Saethre-Chotzen syn- drome, i.e., three cardinal symptoms or one cardial symptom and one or more individual in the same family with the syndrome. The Saethre-Chotzen syndrome is caused by mutations in the basic helix-loop-helix (bHLH) transcription factor gene TWIST1 (located at 7p21.1) (El Ghouzzi et al., 1997; Howard et al., 1997; Rose et al., 1997). The mutations preferentially occur within the DNA-binding, helix I, and loop domains, *Correspondence to: Dr. Go¨ran Stenman, Lundberg Laboratory for Cancer Research, Department of Pathology, The Sahlgrenska Academy at Go¨teborg University, Sahlgrenska University Hospital, SE-413 45 Go¨teborg, Sweden. E-mail: goran.stenman@llcr.med.gu.se or Dr. Pelle Sahlin, Department of Plastic Surgery, Sahlgrenska University Hospital, SE-413 45 Go¨teborg, Sweden. E-mail: per.sahlin@vgregion.se Supported by: The Swedish Cancer Society and The IngaBritt and Arne Lundberg Research Foundation. Received 4 April 2006; Accepted 2 March 2007 DOI 10.1002/gcc.20449 Published online 16 April 2007 in Wiley InterScience (www.interscience.wiley.com). V VC 2007 Wiley-Liss, Inc. GENES, CHROMOSOMES & CANCER 46:656–660 (2007)