We previously mapped several quantitative trait loci (QTLs) controlling DMBA-induced mammary tumor development in female rats derived from a SPRD-Cu3 (susceptible strain) 3 WKY (resistant strain) cross. Two of these QTLs were assigned to chromosomes 5 and 18. In the present study, we generated and characterized congenic strains in which a segment of WKY chromosomes 5 or 18 was introduced in the SPRD-Cu3 genetic background, thereby physically demonstrating that each of these two chromosomes controls mammary tumor multiplicity. The chromosome 5 QTL (Mcstm1) accounts for 7 tumors per animal (versus a total of 11 tumors per SPRD-Cu3 rat). The chromosome 18 QTL (Mcstm2) accounts for 3 tumors per animal and is the first chemically-induced mammary cancer susceptibility locus assigned to this chromosome. In addition, the Mcstm1 region was shown to also controls tumor latency. These loci thus play a major role in chemically-induced mammary tumor development. QTLs controlling chemically-induced or estrogen-induced mammary tumor development have independently been identified on chromosomes 5 and 18, using susceptible strains others than SPRD-Cu3. Therefore the haplotype structure of the relevant chromosome regions was analyzed in the different strains. Some chromosome regions were found to be highly mosaic (haplotype blocks < 1 Mb), while one region showed an apparently conserved haplotype block of 7.5 Mb. This analysis points to limited regions that could harbor the causative genes and also indicates that at least Mcstm2 is a novel QTL. ' 2007 Wiley-Liss, Inc.Key words: rat; mammary cancer; cancer susceptibility; congenics; haplotype Breast cancer is a complex, multi-factorial disease affecting about 10% of women in industrials countries. One major risk factor for breast cancer is genetic predisposition (for reviews, see Refs. 1 and 2). Two major breast cancer susceptibility genes (BRCA1, BRCA2) have been identified, [3][4][5][6] and 5-10% of all breast cancers can be explained by the inheritance of mutations in one of these two genes.7 However, a great deal remains to be understood as regards the possible role of other genes involved in susceptibility to breast cancer.2,7-10 Some other susceptibility/ modifier genes have been identified and/or evaluated, mainly by means of association tests, 1,2,11 but it is reasonable to assume that several additional genes remain to be discovered. It is assumed that if 50% of this breast cancer modifier genes could be identified it would be possible to assign 80% of the total breast cancer risk to 50% of the population.10 Such a risk-prone population could then be chosen for increased surveillance. It thus seems justified to search for high-frequency, low-penetrance modifier alleles that either increase or decrease breast cancer risk and thereby help to delimitate the aforementioned at risk population. However, identifying genes that are not highly penetrant in human populations is a difficult task, 12 owing to the genetic and environmental heterogeneity of most of these populations.On...
