Five new mouse susceptibility to colon cancer loci, Scc11–Scc15 Claudia AL Ruivenkamp 1,1 , Tama´ s Csiko´ s 1 , Anita M Klous 1 , Tom van Wezel 1,2 , and Peter Demant* ,1,3 1 Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands Although several genes causing familial cancer syndromes have been identified, susceptibility to sporadic cancer remains unsolved. Animal experiments have demonstrated a large number of quantitative trait loci affecting cancer susceptibility. Previously, we described in mouse strain CcS-19/Dem five susceptibility to colon cancer (Scc) loci, Scc1–Scc5 controlling tumor numbers. In the present study, we performed an independent identical mouse cross using a distinct carcinogen, azoxymethane, to induce colon tumors. We confirmed all five originally described Scc loci and detected five additional new Scc loci; Scc11– Scc15. All these loci were detected in two-way interactions. Oncogene (2003) 22, 7258–7260. doi:10.1038/sj.onc.1207096 Keywords: susceptibility genes; colon cancer; genetic mapping; mouse genetics; AOM Colorectal cancer is the third leading cause of cancer in Europe and US. Familial colon cancer explains only a small percentage of all colorectal cancer cases. The majority of cases is represented by sporadic cancer without any obvious genetic linkage. This, however, does not mean that there is no hereditary determinant of susceptibility. Genetic predisposition to nonfamilial, sporadic cancer is a major factor in cancer susceptibility (Lichtenstein et al., 2000). Cancer susceptibility is controlled by many genes, acting either alone or through interactions with other genes. Nevertheless, the relevant genes do not have a strong effect and hence are difficult to detect (Ponder, 2001). Therefore, mouse models are helping to understand cancer as a complex genetic trait. Inbred strains of mice differ widely in their susceptibility to both spontaneous and chemically induced tumors, and have been used to map several susceptibility quantitative trait loci (QTLs) and their mutual interac- tions (Balmain, 2002; Mao and Balmain, 2003). To study QTLs influencing the development of colon tumors, we have used the CcS/Dem series of recombi- nant congenic (RC) strains, derived from the mouse inbred strains BALB/cHeA (BALB/c) and STS/A (STS). BALB/c is resistant to chemically induced colon adenomas, whereas STS is susceptible. Each individual CcS strain contains a different random subset of approximately 12.5% of genes derived from the susceptible strain STS and 87.5% of genes from the resistant strain BALB/c. In this way, the STS alleles of different loci are divided between 20 different CcS strains, reducing the genetic complexity (Demant, 1992). Treatment of BALB/c and CcS-strain mice with repeated injections of the carcinogen 1,2-dimethylhy- drazine (DMH) induces multiple colonic adenomas, that are benign, even if they are very large (Moen et al., 1991). Five loci affecting susceptibility to chemically induced colon cancer, Scc1–Scc5, were previously identified using 192 F 2 mice between susceptible RC strain CcS-19 and BALB/c. A strong candidate gene for Scc1 was identified recently as Ptprj (protein tyrosine phosphatase receptor type-J). The demonstration that its human homolog PTPRJ is involved in several cancer types opens a possibility to identify the cancer suscept- ibility genes in animals and subsequently in humans (Ruivenkamp et al., 2002). In contrast to our previous studies using the carcino- gen DMH alone or in combination with N-ethyl-N- nitrosourea (ENU) to induce colon tumors (Moen et al., 1992; Van Wezel et al., 1996), we used the direct metabolite of DMH, the carcinogen azoxymethan (AOM). Pilot studies using AOM showed the same difference in colon tumor susceptibility between the two parental strains, BALB/c and STS, and the RC strain CcS-19 as reported previously for DMH-induced tumors (Moen et al., 1992; Van Wezel et al., 1996). The number and size of the AOM-induced colon tumors, however, was markedly higher. In addition, we analysed the novel mouse cross with a more powerful statistical package that simultaneously assay possible main effects and pairwise interactions of microsatellite markers from all segregating segments (see legend to Table 1). The P-values given below for the novel loci and interactions indicate whole genome significance levels. Analysis of 314 AOM-treated (BALB/c  CcS-19)F 2 mice for the genetics of colon tumor number confirmed the five previously reported Scc loci and detected five Received 7 May 2003; revised 30 July 2003; accepted 7 August 2003 *Correspondence: P Demant; E-mail: peter.demant@roswellpark.org 1 Present address: Department of Human and Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands 2 Present address: Department of Pathology, Leiden University Medical Center, Leiden The Netherlands 3 Present address: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA Oncogene (2003) 22, 7258–7260 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc ONCOGENOMICS