About 10 years have elapsed since the first whole-genome scanning studies in the mouse to identify loci that affect susceptibility or resistance to tumorigenesis. In that time, >100 cancer modifiers have been mapped, and four strong candidate genes have been identified. Cancer modifier loci affect almost all types of mouse tumorigenesis, with some loci acting on the entire tumorigenic process, whereas others act on specific stages, e.g., tumor initiation or tumor growth/progression. Present evidence indicates that the effects of cancer modifier loci are tissue-specific and restricted to tumor cells. However, a subset of such loci may be involved in different types of tumors, and several chromosomal regions show significant clustering of cancer modifier loci. Human homologues of mouse cancer modifier loci most likely exist and play a role in the risk of sporadic cancer, although present experimental evidence for this possibility is sparse. Mouse cancer modifier loci might serve as the basis for understanding the genetic and biochemical mechanisms of polygenic inheritance of cancer predisposition/resistance. Identification of homologous cancer modifier loci in humans might, in turn, provide a step toward the development of diagnostic, preventive, and therapeutic strategies that target these loci.

In the late 1930s, several inbred strains of mice were characterized for their genetic susceptibility to spontaneous tumor development and to chemical carcinogen-induced tumorigenesis. Strains genetically susceptible or resistant to particular tumors were identified (1), and analysis of the F1 hybrids of resistant and susceptible strain crosses provided evidence for the existence of cancer modifier loci with allele-specific effects on cancer development, e.g., stimulation or inhibition of tumor development and/or tumor size/progression. Cancer modifier loci may comprise a “null” allele, with no effects on tumor phenotypes, and a “susceptibility” or “resistance” allele, which affect tumor phenotype in a dominant, codominant, or recessive way.

Before the advent of genetic markers, the number of loci affecting certain cancer susceptibilities was predicted based on analysis of phenotypic variance of F2 or backcross populations. For example, in 1942 Heston (2) predicted that four genetic factors were involved in susceptibility/resistance to lung tumorigenesis in F2, and backcrosses between the A (A/J) and L (C57L/J) mouse strains. In 1964, analysis of the tumor distribution and variance in backcrosses by Bloom and Falconer (3) led to the prediction of a “recessive major gene” that distinguishes between the C57BL and A strains with respect to lung tumor susceptibility. Some loci affecting cancer phenotypes were roughly mapped to certain chromosomal regions using biochemical, immunological, or coat color markers (4, 5).

The discovery of genetic markers, in particular simple sequence length polymorphisms or microsatellites, greatly facilitated efforts to distinguish the strain derivation of alleles at loci dispersed over the whole mouse genome (6). This technical advance, in turn, enabled genetic linkage experiments aimed at whole-genome scanning for cancer modifier loci. Essentially, these experiments are based on the cross of two parental strains that differ in their susceptibility to a particular tumor, followed by backcrossing or intercrossing to produce the segregation of strain-specific alleles, including those affecting the phenotype of interest. Phenotypic and extensive genotypic analyses of the backcross or intercross populations enable the chromosomal mapping of cancer modifier loci (Fig. 1).

Beginning in 1993, cancer modifier loci were mapped in specific chromosomal regions (10–20 cM intervals), defined by a peak linkage and flanking markers. Among the loci affecting strain variability in predisposition to carcinogenesis, the Hcs3 loci (7), the Pas1 (8), and loci affecting plasmacytomagenesis (9) were the first to be mapped by a whole-genome scanning approach. The Mom1 locus was the first locus mapped as a modifier of a specific cancer-inducing mutation, i.e., a modifier of the germ-line Apc gene mutation, which induces intestinal tumorigenesis (10). The hepatocellular cancer model provided the first conclusive demonstration of the polygenic nature of inherited cancer predisposition in mice (7, 11). Since then, cancer modifier loci affecting almost all types of tumors have been mapped in the mouse (Table 1). Cancer modifier loci do not represent a peculiar characteristic of the mouse, because >12 such loci have thus far been mapped in the much less studied rat models (12, 13, 14).

Cancer modifier loci affecting specific stages of the tumorigenesis process have been mapped in the experimental models where the tumor-initiation and tumor-promotion/progression phenotypes are clearly defined. For example, in lung tumorigenesis, the Pas1 and Par1 loci affect both tumor multiplicity and size, whereas Par2 and Par4 act specifically on tumor multiplicity, and Papg1 and Sluc affect only tumor size (8, 15, 16, 17). Hcs loci affect the clonal expansion of hepatocellular tumor cells rather than susceptibility to tumor initiation (7, 11). Mom1 affects multiplicity and size of Min-induced intestinal tumors (18). A subset of skin tumor modifier loci affects survival of tumor-bearing mice (19). Thus, cancer modifier loci may affect either single or multiple stages of carcinogenesis.

Cancer modifier loci mapped in standard crosses are characterized by phenotypic effects (main effects) that are most often additive or dominant. A subgroup of cancer modifier loci shows “interaction deviation” or epistasis (20, 21). These loci were first mapped in RC mouse strains, which derive from crosses between two inbred strains and carry ∼12.5% of a strain genome on the genetic background of the other strain (22). In these RC strains, the main effects of epistatic loci are undetectable, but because of reciprocal interaction, they produce detectable effects on tumor phenotypes (23). Epistasis between loci displaying a main effect has since been detected (12, 24), suggesting that epistasis may be common in polygenic inheritance of susceptibility/resistance to cancer.

Epistatic loci might encode proteins with amino acid variants that cause minor biochemical variations in protein functions. Specific interactions defining linked pathways could explain the phenotypic effects (25). Threshold-dependent activation of gene expression would also lead to epistatic effects and may favor the generation of networks of compensatory mutations (26). The possibility that epistatic loci are involved in the same biochemical pathways suggests the potential value of designing pathways-oriented population studies in humans.

Positional cloning of cancer modifier loci requires shortening of the map linkage region to a manageable size (<1 cM), which might be achieved by the generation of congenic mouse strains or by linkage disequilibrium analysis (27, 28). To date, four cancer modifier genes have been identified, either by positional cloning and/or candidate gene analysis.

Pla2g2a.

Pla2g2a, the first cancer modifier gene identified, was proposed as a candidate gene for the modifier of the Min (Mom1) locus, based on the strain distribution pattern of an insertion polymorphism in the coding region that results in a frameshift mutation causing a premature stop codon and protein truncation (29). Subsequent analysis of a transgenic mouse expressing the wild-type Pla2g2a gene instead of the nonfunctional proved the functional involvement of this gene in intestinal tumorigenesis induced by Min (30). However, the Mom1 locus is most likely complex, with more than one gene responsible for its function (31). Pla2g2a is a member of the phospholipase A2 family, which catalyzes the hydrolysis of membrane glycerophospholipids to generate free fatty acids. Expression levels of Pla2g2a are enhanced under various inflammatory conditions (32).

Pthlh.

The Pthlh gene is a candidate gene for a skin carcinogenesis susceptibility locus mapping to distal Chromosome 6 (33). Pthlh shows a Thr166Pro amino acid polymorphism in inbred mouse strains. The PthlhPro and PthlhThr alleles are linked with high and low genetic susceptibility to two-stage skin carcinogenesis of outbred Car-S (susceptible) and Car-R (resistant) mice, respectively (33). The PthlhPro allele also induced a change in the morphology in vitro of a transfected human squamous cell carcinoma cell line and stimulated in vivo tumor growth of the transfected line in nude mice (33). PTHrP acts as a local messenger in a variety of tissues and cell types, and is involved in apoptosis as well as in the stimulation of cell growth (reviewed in Ref. 34).

Cdkn2a.

Cdkn2a is a candidate for Pctr1, a locus affecting plasmacytoma susceptibility (35). A coding polymorphism in Cdkn2a distinguishes the BALB/c susceptibility allele from that carried by the resistant DBA/2 strain. The protein variant produced by the BALB/c Cdkn2a allele displays decreased biochemical activity and is less active than its DBA/2 counterpart in inducing growth arrest of mouse plasmacytoma cell lines and in preventing ras-induced transformation of NIH 3T3 cells (36). Cdkn2a has also been proposed as a candidate for the Papg1 locus affecting lung tumor progression (37). Cdkn2a is a cyclin-dependent kinase inhibitor (38).

Ptprj.

The gene encoding the protein tyrosine phosphatase, receptor type, J (Ptprj) is a candidate for the mouse locus Scc1 (39). The candidacy was based on the mapping of Ptprj to the restricted Scc1 region (in recombinant mice) and on the presence of five amino acid variations in the Ptprj coding sequence in mouse strains carrying the Scc1 cancer resistance versus susceptibility alleles (40). Functional characterization of the two Ptprj alleles in intestinal tumorigenesis awaits additional studies.

Few studies to date have addressed the site of action of cancer modifier genes, i.e., whether cancer modifier genes act directly within the tumor cells or instead in a cell-autonomous way, to determine the host response to the tumor. This issue likely bears on the mechanism of action of cancer modifier genes and on the targeting of these gene products. Indeed, secreted proteins encoded by cancer modifier genes and leading to a systemic effect might provide useful tumor markers, or aid in designing drugs that inhibit the susceptibility variant or in exploiting the resistance variant to inhibit tumor growth/progression. On the other hand, experiments using chimeric mice generated by aggregation of embryos derived from genetically susceptible and resistant strains indicate that at least for hepatocarcinogenesis, intestinal tumorigenesis, and plasmacytomagenesis, most of the tumors in these mice derive from the susceptible strain (41, 42, 43, 44, 45). Thus, the cancer modifier loci in these models appear to act in the target cells, with no apparent systemic effects.

There is no apparent correlation between susceptibility to carcinogenesis in different organs of mouse strains, suggesting that genetic susceptibility and resistance to cancer are organ- and tissue-specific (1, 46).

The genome of some inbred strains causes dominant resistance to different tumor types in the F1 progeny generated by crossing the given strain with one that is cancer-susceptible. However, the available data indicate that inhibition of the different cancers is under the control of unlinked loci. For example, Mus spretus mice carry the Par1 locus (Chromosome 11), which inhibits lung tumorigenesis (15), Skts loci (Chromosomes 1, 4, 5, 7, 9, 12, and 16), which inhibit skin papilloma multiplicity (19), and the Tlry1 locus (Chromosome 19), which inhibits lymphomagenesis (47). In separate F1 crosses, the genome of the BALB/c strain inhibits lung and liver tumor, and melanoma development because of independent loci (16, 46, 48).4

New models of outbred Car-R and Car-S mouse lines have been generated by phenotypic selection for these propensities to two-stage skin carcinogenesis, starting from a cross of eight inbred strains (49). The Car mouse interline difference in susceptibility is >100-fold (50). Tumor susceptibility and resistance in the Car lines were initially considered skin tissue-specific, because there was no interline difference in sarcoma induction after s.c. injection of chemical carcinogens (51). However, we showed recently that Car-R mice carry cancer-resistance loci that inhibit susceptibility to both skin and lung tumorigenesis (52), providing evidence that a subset of cancer modifier loci affects cancer of different organs (lung and skin) and of different histotypes (adenoma/adenocarcinoma and squamous cell papillomas/carcinomas).

In humans, most inherited major germ-line defects appear to confer predisposition to one major tumor type, with several others exhibiting a minor increased incidence in families. For example, carriers of the BRCA1 mutations are at high risk of breast and ovarian cancer, and may have an increased risk of colon, pancreas, and stomach cancers (53). BRCA2 mutation carriers show a high risk of breast cancer and an increased risk of pancreatic cancer (54). Compared with the general population, carriers of the mutations causing hereditary-nonpolyposis-colorectal-cancer syndrome show, in addition to colorectal cancer, an increased incidence of endometrial, ovarian, gastric, biliary tract, and kidney cancers (55). On the other hand, Li-Fraumeni syndrome is characterized by a wide spectrum of neoplasms in children and young adults (56). Thus, both specificity and pleiotropy, i.e., single-gene allelism that influences two or more types of tumorigenesis, in genetic susceptibility to cancer in humans have been described.

The literature to date reveals a total of 114 cancer modifier loci that have been mapped in mice (Table 1). These loci affect different types of tumorigenesis and are interspersed long over the whole mouse genome. Of these loci, 39 (9 Scc and 30 Sluc) have been detected in RC strains and show pairwise interaction.

Some chromosomal regions show a cluster of such loci. Clustering of different cancer modifier loci in the same short chromosomal region might reflect the presence of several cancer modifier loci that independently provide susceptibility or resistance to different types of cancer. Accordingly, even a region as short as 0.1 cM might contain several genes that affect independent phenotypes. Alternatively, at least some cancer modifier genes might display pleiotropy. Pleiotropic effects of noncancer QTLs have been reported in Drosophila and in mice, and there is no reason a priori to exclude pleiotropic involvement in cancer modifier loci (57, 58).

To test whether some chromosomal regions contain a particularly high “density” of the cancer modifier loci in Table 1, we counted the number of loci mapping in 10-cM intervals of each chromosome. The 10-cM interval was chosen because, in most cases, the cancer modifier loci map within ∼10 cM, which includes and flanks the peak lod score value.

Computer-assisted analysis (Excel macro) of the observed distribution curve for the 114 loci in the mouse genome (1600 cM) revealed several 10-cM regions containing more than one cancer modifier locus (Table 2; Fig. 2).

The occurrence of these clusters appears to contrast with the hypothesis that the 114 mouse cancer modifier loci are randomly scattered in the mouse genome. Actually, the hypothesis predicts 0.7 loci per 10-cM region, with a 0.0341 probability of 3 or more loci in a given 10-cM region (versus an observed frequency of 0.0625) and 0.0058 probability of 4 loci or more loci (versus an observed frequency of 0.0250).

Chromosome 4 showed the greatest number of high-density regions for cancer modifiers, with an interval from 38 to 48 cM (peak at 43) including 5 loci that affect four tumor types: lymphoma (Lyr), lung (Pas9, Papg1), plasmacytoma (Pctr1), and liver (Hcr1; Table 2). The Papg1 locus is characterized by a wide linkage region spanning ∼30 cM with two separate peaks, one at 43–50 cM (Papg1a) and one at ∼56 cM (Papg1b; Ref. 16). Papg1 and Pas9 loci have been mapped in crosses including the BALB/c strain, which carries the susceptibility allele, and it is likely that Papg1a and Pas9 represent the same locus. The susceptibility allele of loci affecting three tumor types is derived from the BALB/c strain (16, 35, 59, 60, 61), suggesting a role for the same gene. Accordingly, the BALB/c variant of the Cdkn2a gene has been proposed as a candidate gene for plasmacytoma and lung tumor susceptibility (36, 37). It remains to be determined whether Cdkn2a is also a candidate gene for the closely mapping Lyr locus, which affects lymphoma development. The Hcr1 locus, affecting hepatocarcinogenesis, has been mapped in a cross including the DBA/2 and the C57BL/6J strains. Both of these strains carry the same Cdkn2a variant (36), thus excluding Cdkn2a candidacy for Hcr1.

Genetic linkage experiments combining crosses and tumor phenotypes are needed to determine whether the clustered loci affects the different tumor phenotypes.

All of the human homologous regions of the mouse regions that contain clusters of cancer modifiers are the sites of genes either associated with somatic chromosomal imbalances (gain or loss) in tumors (reviewed in Ref. 62), or responsible for inherited predisposition to familial cancer, as in the case of 9p21 (CDKN2A) for melanoma (63), 1p36 for prostate cancer (64), and 3p22 for ovarian cancer (65), or affect risk of sporadic cancer or cancer progression, as in the case of 1p32 (l-myc locus; Ref. 66) and 7q32 (67). Thus, these still very preliminary data suggest that human homologues of mouse cancer modifier loci can affect cancer risk and prognosis.

Indirect evidence for the existence of cancer modifier genes in humans derives from epidemiological studies reporting segregation of disease severity in families with cancer that cannot be explained by the type of germ-line mutations (68). Moreover, several epidemiological studies report an increased risk of the same type of cancer in first-degree relatives of cancer patients, i.e., a family risk ratio >1.0, consistent with a polygenic model of inherited predisposition to cancer (69, 70).

However, there is still debate on the interpretation of these studies. Lichtenstein et al. (71) concluded recently from their large twin study that, “Inherited genetic factors make a minor contribution to susceptibility to most types of neoplasms. This finding indicates that the environment has the principal role in causing sporadic cancer.” However, reanalysis of the same study and of the largest family studies led Risch (72) to conclude that “… genes contribute high attributable risks for most cancer sites.” Some authors propose polygenic models of inherited predisposition to cancer (73, 74), whereas others propose models based on rare dominant alleles or additive gene effects (72), or on common alleles of low penetrance (75, 76).

Although all of these models agree in part with epidemiological evidence, no combination of genetic polymorphisms that convincingly defines an additive or polygenic inheritance of predisposition to sporadic cancer has yet been described in humans. This statement is particularly true if cancer modifier genes are strictly defined as those affecting tumor development, growth, and progression. Despite many reports indicating a higher or lower risk of cancer associated with metabolic polymorphisms, several meta-analyses showed that the relative risks associated with most of the metabolic polymorphisms are low (77, 78, 79). The exceptions include NAT2 polymorphism and bladder cancer risk, where mechanistic and epidemiological evidence is strong (80).

Regarding human homologues of cloned candidate mouse cancer modifier loci, studies in familial adenomatous polyposis families and in sporadic colorectal cancer patients indicated a possible association with marker polymorphisms located in the human Mom1 homologous region (81). However, no significant association was found between human PLA2G2A variants and risk of colorectal tumors (82). An association between an intronic PTHLH gene polymorphism and survival of lung adenocarcinoma patients has been reported (83). However, those results have not been confirmed in other studies, nor have additional PTHLH polymorphisms been reported. Inactivating mutations of CDKN2A have been associated with familial melanoma, pancreatic, and breast cancer (84, 85), and some CDKN2A gene polymorphisms showed an association with risk of sporadic melanoma (86, 87, 88). A multiple myeloma has been reported in a CDKN2A germ-line mutation carrier, suggesting that germ-line mutations of CDKN2A may predispose individuals to the human counterpart of murine plasmacytoma, in which Cdkn2a is a cancer modifier gene (9, 89). Genetic polymorphisms in the human chromosomal region homologous to the mouse region containing the Pas1 locus have been associated with lung adenocarcinoma risk and prognosis in independent studies, suggesting that a human homologue of the mouse Pas1 locus may exist and play a role in genetic predisposition to lung cancer (83, 90, 91).

The very limited studies available thus far suggest that cancer modifier genes do exist in humans and may play an important role in cancer risk and prognosis. Their identification would most likely be facilitated by analysis of human homologues of mouse cancer modifier genes, although it is possible that some mouse alleles are not carried in humans and vice versa; the human population is much more genetically complex than the relatively few mouse inbred strains used thus far for mapping cancer modifier loci. One approach to identifying human cancer modifier loci might involve screening for polymorphisms in genes causing familial cancer syndromes. Such syndromes are not observed as natural variations in tumor incidence/susceptibility in mouse inbred strains and are often difficult to reproduce in mouse knockout models. Missense variants in genes causing cancer syndromes might modify the risk of the corresponding sporadic cancer in the general population. Accordingly, a slight increase in the risk of sporadic breast cancer has been attributed to a common variant of the BRCA2 gene (92), and germ-line amino acid polymorphisms of the APC gene have been reported to affect colorectal adenoma risk in the general population (93).

Overall, it seems highly unlikely that the enormous genetic variability underlying susceptibility and resistance to tumorigenesis in mice evolved only in rodents and not in all mammals, including humans. In fact, QTLs affecting several noncancer phenotypes have been mapped in cattle, pigs, and in humans (94), and it seems reasonable to expect that cancer modifier QTLs are present in humans.

Identification of mouse cancer modifier genes provides a step toward understanding the genetic and biochemical mechanisms of inherited resistance/susceptibility to cancer. Even in cases where the human homologous gene does not display allelism and cancer modifier effects, the gene function might enable identification of pathways relevant in early diagnosis, chemoprevention, and therapy of cancer. For example, even if Pla2g2a alleles do not prove to modulate the risk of human colon cancer significantly, the involvement of Pla2g2a in inflammatory response and prostaglandin pathways has pointed to the use of anti-inflammatory drugs for chemoprevention and therapy of colon cancer (32, 95).

Eventually, new diagnostic markers might be devised to identify groups of individuals at higher risk of sporadic cancer as compared with the general population. This is now possible for members of families with monogenic cancer syndromes, which represent a minority of cancer cases. Identification of individuals at high risk of cancer raises the possibility of chemoprevention. For example, familial adenomatous polyposis carriers benefit from long-term use of nonsteroidal anti-inflammatory drugs (95).

New therapeutic strategies for cancer based on the biochemical effects of cancer modifier genes can also be envisioned. Cancer susceptibility alleles may be blocked by small molecule inhibitors with allele-specific antagonistic effects, and new drugs that induce or mimic dominant cancer resistance alleles may be developed. Importantly, the natural tumor resistance gene product of an organism would not be expected to cause the adverse side effects often associated with the cancer therapeutic drugs now available. Priority should be given to cancer modifier loci that affect different types of tumorigenesis, because these genes might well affect cancer development in other organs and in other species. Surely, many important findings are yet to come!

Database links for this article include (a)Human-Mouse Homology Map;5 (b) Mouse Genome Database;6 (c) Mouse Genome Resources;7 (d) Mouse Genome Server;8 (e) Mouse Phenome Database;9 (f) Online CGH Tumor Database;10 and (g) The Jackson Laboratory.11

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

Support by the European Commission (Association Contracts CT1999-00006 and QLK4-1999-01084) and Associazione and Fondazione Italiana Ricerca Cancro (AIRC and FIRC, Italy).

3

The abbreviations used are: Hcs, hepatocellular cancer susceptibility; RC, recombinant congenic; Pas1, pulmonary adenoma susceptibility 1; Pthlh, parathyroid hormone-like peptide; Scc1, susceptibility to colon cancer 1; Car-R, carcinogenesis-resistant; Car-S, carcinogenesis-susceptible; QTL, quantitative trait loci.

4

Unpublished observations.

5

Internet address: http://www.ncbi.nlm.nih.gov/Homology/.

6

Internet address: http://www.informatics.jax.org/.

7

Internet address: http://www.ncbi.nlm.nih.gov/genome/guide/mouse/.

8

Internet address: http://www.ensembl.org/Mus_musculus/.

9

Internet address: http://aretha.jax.org/pub-cgi/phenome/mpdcgi?rtn = docs/home.

10

Internet address: http://amba.charite.de/∼ksch/cghdatabase/index.htm.

11

Internet address: http://www.jax.org/.

Fig. 1.
Fig. 1. Polygenic inheritance of susceptibility and resistance to cancer in mouse models. Crossing of a genetically susceptible (strain H) and a resistant (strain L) mouse inbred strain results in an intercross progeny of mixed cancer-susceptible and -resistant mice (F2), depending on the allelic assortment of cancer modifier loci. In this example, inheritance of the “A” and “B” alleles at two unlinked cancer modifier loci confers high susceptibility, whereas “a” and “b” alleles confer resistance. Intermediate susceptibility results from heterozygosity and allele-dosage at the two cancer modifier loci.
View largeDownload slide

Polygenic inheritance of susceptibility and resistance to cancer in mouse models. Crossing of a genetically susceptible (strain H) and a resistant (strain L) mouse inbred strain results in an intercross progeny of mixed cancer-susceptible and -resistant mice (F2), depending on the allelic assortment of cancer modifier loci. In this example, inheritance of the “A” and “B” alleles at two unlinked cancer modifier loci confers high susceptibility, whereas “a” and “b” alleles confer resistance. Intermediate susceptibility results from heterozygosity and allele-dosage at the two cancer modifier loci.

Fig. 1.
Fig. 1. Polygenic inheritance of susceptibility and resistance to cancer in mouse models. Crossing of a genetically susceptible (strain H) and a resistant (strain L) mouse inbred strain results in an intercross progeny of mixed cancer-susceptible and -resistant mice (F2), depending on the allelic assortment of cancer modifier loci. In this example, inheritance of the “A” and “B” alleles at two unlinked cancer modifier loci confers high susceptibility, whereas “a” and “b” alleles confer resistance. Intermediate susceptibility results from heterozygosity and allele-dosage at the two cancer modifier loci.
View largeDownload slide

Polygenic inheritance of susceptibility and resistance to cancer in mouse models. Crossing of a genetically susceptible (strain H) and a resistant (strain L) mouse inbred strain results in an intercross progeny of mixed cancer-susceptible and -resistant mice (F2), depending on the allelic assortment of cancer modifier loci. In this example, inheritance of the “A” and “B” alleles at two unlinked cancer modifier loci confers high susceptibility, whereas “a” and “b” alleles confer resistance. Intermediate susceptibility results from heterozygosity and allele-dosage at the two cancer modifier loci.

Close modal
Fig. 2.
Fig. 2. Clustering of cancer modifier loci in 10-cM intervals on mouse Chromosomes 1 and 4. Peak regions of 6 loci clustering was observed at 59 cM on Chromosome 4, of 5 loci clustering at 83 cM on Chromosome 1 and at 43 cM on Chromosome 4, and of 4 loci clustering at 67 cM on Chromosome 4. Loci density was assessed using a computer macro written for the Excel program. Briefly, the number of loci mapping in 10-cM intervals of each chromosome was counted, starting from the first 10-cM interval distal to the centromere; the 10-cM interval 2 cM distal to the first was considered, and loci mapping into this second, third, and so forth, interval were counted until the last interval ending at the telomere. In this way, a smooth curve of loci density per 10-cM intervals was generated.
View largeDownload slide

Clustering of cancer modifier loci in 10-cM intervals on mouse Chromosomes 1 and 4. Peak regions of 6 loci clustering was observed at 59 cM on Chromosome 4, of 5 loci clustering at 83 cM on Chromosome 1 and at 43 cM on Chromosome 4, and of 4 loci clustering at 67 cM on Chromosome 4. Loci density was assessed using a computer macro written for the Excel program. Briefly, the number of loci mapping in 10-cM intervals of each chromosome was counted, starting from the first 10-cM interval distal to the centromere; the 10-cM interval 2 cM distal to the first was considered, and loci mapping into this second, third, and so forth, interval were counted until the last interval ending at the telomere. In this way, a smooth curve of loci density per 10-cM intervals was generated.

Fig. 2.
Fig. 2. Clustering of cancer modifier loci in 10-cM intervals on mouse Chromosomes 1 and 4. Peak regions of 6 loci clustering was observed at 59 cM on Chromosome 4, of 5 loci clustering at 83 cM on Chromosome 1 and at 43 cM on Chromosome 4, and of 4 loci clustering at 67 cM on Chromosome 4. Loci density was assessed using a computer macro written for the Excel program. Briefly, the number of loci mapping in 10-cM intervals of each chromosome was counted, starting from the first 10-cM interval distal to the centromere; the 10-cM interval 2 cM distal to the first was considered, and loci mapping into this second, third, and so forth, interval were counted until the last interval ending at the telomere. In this way, a smooth curve of loci density per 10-cM intervals was generated.
View largeDownload slide

Clustering of cancer modifier loci in 10-cM intervals on mouse Chromosomes 1 and 4. Peak regions of 6 loci clustering was observed at 59 cM on Chromosome 4, of 5 loci clustering at 83 cM on Chromosome 1 and at 43 cM on Chromosome 4, and of 4 loci clustering at 67 cM on Chromosome 4. Loci density was assessed using a computer macro written for the Excel program. Briefly, the number of loci mapping in 10-cM intervals of each chromosome was counted, starting from the first 10-cM interval distal to the centromere; the 10-cM interval 2 cM distal to the first was considered, and loci mapping into this second, third, and so forth, interval were counted until the last interval ending at the telomere. In this way, a smooth curve of loci density per 10-cM intervals was generated.

Close modal
Table 1

Mapped mouse cancer modifier loci according to chromosomal location and type of tumor affected

LocusChromosomePosition (cM)aTissueReference
Sluc15 1 19.5 Lung  (23)  
Melm1 1 65 Melanoma  (48)  
Tli1 1 68 Lymphoma  (96)  
Skts8 1 79 Skin  (19)  
Pas8 1 81.6 Lung  (60)  
Hcf2 1 81.6 Liver  (97)  
Hcs7 1 84 Liver  (98)  
Sluc5 1 87.9 Lung  (23)  
Melm2 1 100 Melanoma  (48)  
Scc3 1 101.5 Intestine  (99)  
Sluc16 2 5 Lung  (23)  
Scc2 2 28 Intestine (39,99) 
Pas6 2 41 Lung  (23)  
Sluc2 2 41 Lung  (23)  
Scc1 2 49.5 Intestine (39,99,100) 
Bts1 2 83 Bladder  (101)  
Hcs4 2 99 Liver  (11)  
Sluc17 2 107 Lung  (23)  
Scc7 3 79.7 Intestine  (102)  
Ccs2 3 87.6 Intestine  (103)  
Sluc18 4 12.1 Lung  (23)  
Mmtg1 4 31 Mammary  (104)  
Lyr 4 38 Lymphoma  (59)  
Papg1a;Pas9 4 42.5 Lung (16,60) 
Pctr1 4 43 Plasmacytoma  (35)  
Hcr1 4 47 Liver  (61)  
Thyls 4 55 Lymphoma  (105)  
Mmtg2 4 56 Mammary  (104)  
Skts7 4 56 Skin  (19)  
Papg1b 4 56.5 Lung  (16)  
Tlag2 4 56.5 Lymphoma  (106)  
Sluc21 4 62.3 Lung  (23)  
Sluc6 4 67 Lung  (23)  
Mom1 4 68 Intestine  (29)  
Gct1 4 71 Ovary  (107)  
Pctr2 4 77.5 Plasmacytoma (35,108) 
Skts3 5 24 Skin  (19)  
Hcs5 5 49 Liver  (11)  
Skts4 5 64 Skin  (109)  
Par4 6 3.3 Lung  (16)  
Sluc7 6 6 Lung  (23)  
Bts2 6 7 Bladder  (101)  
Skts11 6 36.5 Skin  (19)  
Ots1 6 40 Ovary  (110)  
Sluc3 6 53 Lung  (23)  
Pas1 6 72.2 Lung  (28)  
Skts12 6 74 Skin  (19)  
Mmtg3 7 3.4 Mammary  (104)  
Sluc30 7 4 Lung  (23)  
Hcs1 7 24 Liver  (7)  
Skts2 7 27 Skin  (111)  
Skts1 7 44 Skin (111,112) 
Tlag1 7 47 Lymphoma  (113)  
Sluc19 7 63.5 Lung  (23)  
Tlsm1 7 66 Lymphoma  (114)  
Sluc8 7 72 Lung  (23)  
Scc8 8 9.5 Intestine  (102)  
Sluc20 8 10 Lung  (23)  
Hcs2 8 56 Liver  (7)  
Sluc9 8 59 Lung  (23)  
Pas4 9 12 Lung  (60)  
Sluc10 9 17 Lung  (23)  
Skts6 9 49 Skin  (19)  
Apmt2 9 55 Mammary  (115)  
Sluc11 9 55 Lung  (23)  
Psl1 9 61 Skin  (116)  
Sluc29 10 4 Lung  (23)  
Pasl1 10 21 Lung  (117)  
Hcr2 10 35 Liver  (61)  
Sluc22 10 61 Lung  (23)  
Scc9 10 63 Intestine  (102)  
Scc6 11 4.5 Intestine  (102)  
Melm3 11 17 Melanoma  (48)  
Pas5 11 40 Lung  (23)  
Sluc4 11 40 Lung  (23)  
Par1 11 57 Lung (15,118) 
Skts5 12 17 Skin  (19)  
Gct2 12 22 Ovary  (107)  
Par3 12 37 Lung  (118)  
Ccs1 12 38 Intestine  (119)  
Hcs3 12 59 Liver  (7)  
Sluc12 12 59 Lung  (23)  
Sluc23 13 32 Lung  (23)  
Pas10 13 36 Lung  (60)  
Pgct1 13 37 Germ cell  (120)  
Sluc13 14 12.5 Lung  (23)  
Sluc24 15 6.7 Lung  (23)  
Apmt1 15 25 Mammary  (115)  
Sluc25 15 32 Lung  (23)  
Gct3 15 39.1 Ovary  (107)  
Sluc26 15 48.9 Lung  (23)  
Ritls 16 9.6 Lymphoma  (121)  
Skts9 16 14 Skin  (19)  
Sluc27 16 54 Lung  (23)  
Hcf1 17 18.64 Liver  (97)  
Msmr1 17 22 Lymphoma  (122)  
Pas12 17 22.8 Lung  (117)  
Skts10 17 32 Skin  (19)  
Scc4 17 47.4 Intestine  (99)  
Sluc14 18 20 Lung  (23)  
Scc5 18 25 Intestine  (99)  
Msmr2 18 32 Lymphoma  (122)  
Pas7 18 40 Lung  (60)  
Par2 18 45.5 Lung (16,60,123124125) 
Mom2 18 50 Intestine  (126)  
Sluc28 18 50 Lung  (23)  
Mtes1 19 4 Mammary  (127)  
Tlyr1 19 20 Lymphoma  (47)  
Pas3 19 26 Lung  (128)  
Hcs6 19 38 Liver  (11)  
Mp53D2 19 41 Lymphoma  (129)  
Pas13 19 47 Lung  (117)  
Sluc1 19 47 Lung  (23)  
Gct4 X 37 Ovary  (107)  
LocusChromosomePosition (cM)aTissueReference
Sluc15 1 19.5 Lung  (23)  
Melm1 1 65 Melanoma  (48)  
Tli1 1 68 Lymphoma  (96)  
Skts8 1 79 Skin  (19)  
Pas8 1 81.6 Lung  (60)  
Hcf2 1 81.6 Liver  (97)  
Hcs7 1 84 Liver  (98)  
Sluc5 1 87.9 Lung  (23)  
Melm2 1 100 Melanoma  (48)  
Scc3 1 101.5 Intestine  (99)  
Sluc16 2 5 Lung  (23)  
Scc2 2 28 Intestine (39,99) 
Pas6 2 41 Lung  (23)  
Sluc2 2 41 Lung  (23)  
Scc1 2 49.5 Intestine (39,99,100) 
Bts1 2 83 Bladder  (101)  
Hcs4 2 99 Liver  (11)  
Sluc17 2 107 Lung  (23)  
Scc7 3 79.7 Intestine  (102)  
Ccs2 3 87.6 Intestine  (103)  
Sluc18 4 12.1 Lung  (23)  
Mmtg1 4 31 Mammary  (104)  
Lyr 4 38 Lymphoma  (59)  
Papg1a;Pas9 4 42.5 Lung (16,60) 
Pctr1 4 43 Plasmacytoma  (35)  
Hcr1 4 47 Liver  (61)  
Thyls 4 55 Lymphoma  (105)  
Mmtg2 4 56 Mammary  (104)  
Skts7 4 56 Skin  (19)  
Papg1b 4 56.5 Lung  (16)  
Tlag2 4 56.5 Lymphoma  (106)  
Sluc21 4 62.3 Lung  (23)  
Sluc6 4 67 Lung  (23)  
Mom1 4 68 Intestine  (29)  
Gct1 4 71 Ovary  (107)  
Pctr2 4 77.5 Plasmacytoma (35,108) 
Skts3 5 24 Skin  (19)  
Hcs5 5 49 Liver  (11)  
Skts4 5 64 Skin  (109)  
Par4 6 3.3 Lung  (16)  
Sluc7 6 6 Lung  (23)  
Bts2 6 7 Bladder  (101)  
Skts11 6 36.5 Skin  (19)  
Ots1 6 40 Ovary  (110)  
Sluc3 6 53 Lung  (23)  
Pas1 6 72.2 Lung  (28)  
Skts12 6 74 Skin  (19)  
Mmtg3 7 3.4 Mammary  (104)  
Sluc30 7 4 Lung  (23)  
Hcs1 7 24 Liver  (7)  
Skts2 7 27 Skin  (111)  
Skts1 7 44 Skin (111,112) 
Tlag1 7 47 Lymphoma  (113)  
Sluc19 7 63.5 Lung  (23)  
Tlsm1 7 66 Lymphoma  (114)  
Sluc8 7 72 Lung  (23)  
Scc8 8 9.5 Intestine  (102)  
Sluc20 8 10 Lung  (23)  
Hcs2 8 56 Liver  (7)  
Sluc9 8 59 Lung  (23)  
Pas4 9 12 Lung  (60)  
Sluc10 9 17 Lung  (23)  
Skts6 9 49 Skin  (19)  
Apmt2 9 55 Mammary  (115)  
Sluc11 9 55 Lung  (23)  
Psl1 9 61 Skin  (116)  
Sluc29 10 4 Lung  (23)  
Pasl1 10 21 Lung  (117)  
Hcr2 10 35 Liver  (61)  
Sluc22 10 61 Lung  (23)  
Scc9 10 63 Intestine  (102)  
Scc6 11 4.5 Intestine  (102)  
Melm3 11 17 Melanoma  (48)  
Pas5 11 40 Lung  (23)  
Sluc4 11 40 Lung  (23)  
Par1 11 57 Lung (15,118) 
Skts5 12 17 Skin  (19)  
Gct2 12 22 Ovary  (107)  
Par3 12 37 Lung  (118)  
Ccs1 12 38 Intestine  (119)  
Hcs3 12 59 Liver  (7)  
Sluc12 12 59 Lung  (23)  
Sluc23 13 32 Lung  (23)  
Pas10 13 36 Lung  (60)  
Pgct1 13 37 Germ cell  (120)  
Sluc13 14 12.5 Lung  (23)  
Sluc24 15 6.7 Lung  (23)  
Apmt1 15 25 Mammary  (115)  
Sluc25 15 32 Lung  (23)  
Gct3 15 39.1 Ovary  (107)  
Sluc26 15 48.9 Lung  (23)  
Ritls 16 9.6 Lymphoma  (121)  
Skts9 16 14 Skin  (19)  
Sluc27 16 54 Lung  (23)  
Hcf1 17 18.64 Liver  (97)  
Msmr1 17 22 Lymphoma  (122)  
Pas12 17 22.8 Lung  (117)  
Skts10 17 32 Skin  (19)  
Scc4 17 47.4 Intestine  (99)  
Sluc14 18 20 Lung  (23)  
Scc5 18 25 Intestine  (99)  
Msmr2 18 32 Lymphoma  (122)  
Pas7 18 40 Lung  (60)  
Par2 18 45.5 Lung (16,60,123124125) 
Mom2 18 50 Intestine  (126)  
Sluc28 18 50 Lung  (23)  
Mtes1 19 4 Mammary  (127)  
Tlyr1 19 20 Lymphoma  (47)  
Pas3 19 26 Lung  (128)  
Hcs6 19 38 Liver  (11)  
Mp53D2 19 41 Lymphoma  (129)  
Pas13 19 47 Lung  (117)  
Sluc1 19 47 Lung  (23)  
Gct4 X 37 Ovary  (107)  
a

Based on the reported LOD score peak values and on the MGD attribution (www.informatics.jax.org).

View Large
Table 2

Clustering of ≥3 mouse cancer modifier loci in 10-cM chromosomal regions and human homologous regions

ChromosomePeak of the clustering region (cM)No. of clustering lociTumor types affectedHuman homologous region
1 83 5 Liver, lung, skin 1q23-q31 
4 43 5 Liver, lung, lymphoma, plasmacytoma 9p21 
4 59 6 Lung, lymphoma, mammary, skin 1p32-p36 
4 67 4 Intestine, lung, ovary 1p33-p36 
6 7 3 Bladder, lung 7q21-q32 
9 53,59 3 Lung, mammary, skin 3q22-q25 
    3p21-p22 
13 35 3 Germ cells, lung 5q31-q35 
    9q21-q22 
17 19 3 Liver, lung, lymphoma 6p21-22 
18 47 3 Intestine, lung 18q21 
19 43 3 Liver, lung, lymphoma 10q22-q24 
ChromosomePeak of the clustering region (cM)No. of clustering lociTumor types affectedHuman homologous region
1 83 5 Liver, lung, skin 1q23-q31 
4 43 5 Liver, lung, lymphoma, plasmacytoma 9p21 
4 59 6 Lung, lymphoma, mammary, skin 1p32-p36 
4 67 4 Intestine, lung, ovary 1p33-p36 
6 7 3 Bladder, lung 7q21-q32 
9 53,59 3 Lung, mammary, skin 3q22-q25 
    3p21-p22 
13 35 3 Germ cells, lung 5q31-q35 
    9q21-q22 
17 19 3 Liver, lung, lymphoma 6p21-22 
18 47 3 Intestine, lung 18q21 
19 43 3 Liver, lung, lymphoma 10q22-q24 
View Large

I thank Kari Hemminki and Marco A. Pierotti for comments and suggestions, and Silvano Milani for help on statistical aspects.

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2003