**1. Introduction**

18 Liver Tumors

[105] Akavia UD, Litvin O, Kim J, Sanchez-Garcia F, Kotliar D, Causton HC, Pochanard P,

cancer. *Cell* 2010, 143:1005-1017.

Mozes E, Garraway LA, Pe'er D: An integrated approach to uncover drivers of

Genes that affect a person's chance of developing hepatocellular carcinoma (HCC), as *BRCA1* and *BRCA2* affect a person's chance of developing breast or ovarian cancer, have been difficult to detect. The vast majority of liver cancers can be attributed to Hepatitis B or C virus infection, aflatoxin exposure, or alcoholic cirrhosis, alone or in combination (Montalto et al., 2002). This high background of predisposing environmental factors makes identifying less penetrant genetic contributors more difficult. Familial patterns of susceptibility to liver cancer independent of environmental factors have helped identify a few monogenic metabolic syndromes (*e.g.*, hemochromatosis; Dragani, 2010). However, the analysis of liver tumors points to a variety of other genes that affect liver tumor development. The patterns of chromosome gain and loss in liver cancers worldwide reveal several regions that are gained or lost in up to 86% of tumors, including gains of 1q, 6p, 8q, and 20q, and losses of 1p, 4q, 6q, 8p, 13q, 16q, and 17p (Lau and Guan, 2005; Chochi et al., 2009; Zhang et al., 2010). Chromosome analyses combined with genome-wide association studies have revealed candidate HCC modifier genes for some of these regions, such as *PAPSS1* on chromosome 4q and *HCAP1* on chromosome 17p (Wan et al., 2004; Shih et al., 2009).

Mice present an independent model of liver carcinogenesis for which external variables such as chemical exposure can be controlled and the genetics is manipulable. Different inbred strains of mice develop cancers at different frequencies. Because these differences are genetic, and the mice are homozygous due to inbreeding, causative genes can be identified through positional cloning.

Inbred mouse strains differ dramatically in their susceptibility to both spontaneous and carcinogen-induced HCC. Females of the C57BR/cdJ strain, for example, develop up to 50 fold more tumors after a single injection of N,N-diethylnitrosamine (DEN) than females of the related, relatively resistant C57BL/6J (B6) strain. We have recently mapped the predominant locus responsible for this difference to a 6 Mb region on Chromosome 17 (Peychal et al., 2009). This region corresponds to part of the chromosome 6p region amplified in the majority of late-stage HCC (Santos et al., 2007; Chochi et al., 2009).

The C3H/HeJ strain (C3H), highly susceptible to both spontaneous and carcinogen-induced HCC, develops up to 50-fold more liver tumors than the B6 strain after a single carcinogen treatment (Drinkwater and Ginsler, 1986). We previously reported mapping the predominant locus responsible for this susceptibility, *Hcs7*, to distal Chromosome 1 (Bilger et al., 2004). This chromosomal region corresponds in part to the 1q21-24 chromosomal region amplified in up to 86% of human liver cancers (Lau and Guan, 2005; Chochi et al., 2009; Zhang et al., 2010). C3H alleles on mouse Chromosome 1 confer a dominant 15-fold increased susceptibility to male mice and a semi-dominant 5-fold increased susceptibility to female mice carrying C3H alleles (Bilger et al., 2004).

Here we analyze the effect of C3H Chromosome 1 alleles on spontaneous hepatocarcinogenesis, on apoptosis and mitosis after DEN treatment, and on preneoplastic lesion growth. We have mapped the *Hcs7* modifier to a 3.3 Mb region and used expression and CGH arrays to identify the *Ifi202b* gene as a strong candidate for this locus.
