A polygenic model of inherited predisposition to cancer

0892.6638/96/001 0-0865/$01 .50. © FASEB 865

TOMMASO A. DRAGANI,1 FEDERICO CANZIAN,2 AND MARCO A. PIERO1I!

Division of Experimental Oncology A, Istituto Nazionale Tumori, Milan, Italy

ABSTRACT Polygenic inheritance of predisposi-tion to cancer is demonstrated in experimental ani-mals for different tumor types. Genetic susceptibilityto hepatocarcinogenesis, lung tumorigenesis, skin

and intestine carcinogenesis, and plasmacytom-agenesis is determined by inheritance of multiplecancer predisposition and resistance alleles, whosechromosomal locations have been found by geneticlinkage analysis. In some of these experimental mod-els, genetic heterogeneity has also been reported. Inhumans, increased risk of lung cancer associated withmultiple genes coding for drug metabolizing en-zymes, increased risk of cancer in relatives of cancerpatients, and genetic heterogeneity are compatiblewith polygemc inheritance of cancer predisposition.Polygenic inheritance based on the combination ofmultiple alleles that give predisposition and resis-tance to cancer would predict a very high risk ofcancer in carrier individuals and a marginal increasein the relative risk of cancer in the progeny of thecancer patients. Therefore, predisposition to cancermay be genetically determined even in the absenceof fanulial clustering of cases.-Dragani, T. A.,Canzian, F., Pierotti, M. A. A polygenic model ofinherited predisposition to cancer. FASEB J. 10,865-870 (1996)

Key Words: disease models animal/disease susceplibilily/linkagegenelics/m ice, inbred si rains/models

IN THE LAST FEW YEARS THE genetics of cancer predispo-sition has experienced great progress. A number of genes,whose germ-line mutations cause a highly penetrant fa-milial predisposition to cancer have been mapped on thehuman genome, and some have been cloned and identi-fied (1-3). The frequency of alleles that confer an inher-ited predisposition to cancer is variable in humans, beingabout 1:100,000 in the case of retinoblastoma (RB1),31-2:10,000 in neurofibromatosis (NFl), 1:10,000 in fa-milial adenomatous polyposis (APC), 1:1,000 in familialbreast cancer (BRCA1), and an estimated -1:1,000 inthe case of hereditary nonpolyposis colorectal cancer(HNPCC) (3-6). Therefore, patients with the cancer pre-disposition phenotype determined by germ-line mutations

of these particular genes are rare.On the other hand, environmental and dietary factors

are indicated as major etiologic factors in the develop-ment of sporadic tumors, which represent the vast major-ity of tumors (7). However, although the roles of the

environment and diet are clearly demonstrated, the possi-ble role of complex genetic factors cannot be excluded.Indeed, epidemiological evidence indicates that in manycases of sporadic cancers, first degree relatives of cancer

patients show an excess risk of cancer (two- to fourfold)when compared with the general population (8-13). This

evidence may suggest the existence of a polygenic inheri-tance of predisposition to particular types of cancer.

Here we present a review on the polygenic inheritanceof predisposition to cancer in experimental animals, andwe discuss the possible relevance of such a polygenic in-heritance in human cancer.

EXPERIMENTAL MODELS

Most inbred strains of laboratory mice derive from thewild Mus musculus musculus and Mus musculus domesti-

cus mice, trapped at the beginning of the century. Simi-larly, inbred rat strains were derived from the wild Rattus

norvegicus, trapped in different countries. Although someintermixing between strains has occurred, the inbred ro-

dent strains differ genetically from each other and repre-sent good animal models of human diseases (14-16).Therefore, the distribution and frequency of different al-

leles, including those related to cancer predisposition,may be sufficiently represented in laboratory strains com-

pared with the wild groups from which they were derived.The listing of 430 inbred strains of mice reports that

38 (8.8%) strains have a high incidence (>10%) ofspontaneous tumors at particular sites (17, 18). Obvi-ously, this percentage represents a severe underestima-tion of reality, because most of the listed strains have notbeen investigated for their life span incidence of tumors.Mice that have a high incidence of spontaneous tumorsare also particularly susceptible to the induction of thesame tumor type by chemical carcinogens. In most cases,genetic susceptibility is organ specific and limited to asingle tumor histotype. Genetic predisposition to develop-ment of different tumor types is not limited to the mouseinbred strains, but is also observed in rat strains (18). In-

tTo whom correspondence and reprint requests should be addressed,

at: Istituto Nazionale Tumori, Via G. Venezian 1, 20133, Milan, Italy.

2Present address: University of Helsinki, Department of Medical Ge-

netics, Helsinki, Finland.

3Abbreviations: RB1, retinoblastoma; NFl, neurofibromatosis;BRCA1, familial breast cancer; HNPCC, hereditary nonpolyposis cal-orectal cancer; RR, relative risk.

866 Vol. 10 June 1996 The FASEB Journal DRAGANI El AL

deed, in rats, the genes determining susceptibility to liverand renal tumors have been mapped and identified(19-21) and a locus affecting resistance to mammary tu-

mors has been mapped (22).Therefore, it seems relatively easy to select inbred

strains genetically susceptible to particular types of tu-mors. This means that alleles that confer a predisposition

to defined types of cancer are relatively numerous andfrequent in wild rodent populations. These alleles can be

selected and their effects identified by the inbreedingprocess that creates a laboratory strain that is homozy-gous at every genetic locus. However, the effects of suchallelic combinations are difficult to prove in wild popula-tions. In fact, genetic variation in the feral individualswould not allow assessment of the inherited or acquiredcomponent of disease.

Hepatocarcinogenesis

Inherited predisposition to murine hepatocarcinogenesis

is controlled by multiple unlinked loci. We found that ineach of two different genetic linkage experiments per-

formed in different crosses, a combination of three sus-

ceplibility loci, named hepatocarcinogen sensitivity (Hcs),determined the liver cancer predisposition phenotype (23,

24). Two hepatocarcinogen resistance (Hcrl and Hcr2)loci have also recently been mapped (25). Genetic het-

erogeneity is apparent in this system (Table 1).

Lung tumorigenesis

We mapped a major locus (Pasi) associated with the in-herited predisposition to lung tumorigenesis in mice (26).Other groups have confirmed our observation and have

also found chromosomal location of minor susceptibilityloci (Pas2, Pas3, Pas4) (27, 28). Recently, we have ob-tained evidence for the existence of pulmonary adenomaresistance (Par) loci deriving from the Mus spretus andBALB/c strains (29, 30, and data not shown) (Table 1).

Intestine carcinogenesis

Another polygenic trait is the susceptibility to intestinaltumor development in mice. A mouse mutant (Mm) with a

high genetic predisposition to intestine tumor develop-ment was found to contain a mutant Apc gene, repre-senting an experimental model of the familial

adenomatous polyposis in humans (31). A modulator lo-cus (Momi) was reported to affect intestine tumor devel-opment in different crosses with the Mm mice (32). Acandidate Momi gene has recently been cloned (33).Other loci (Sccl and Ccsl) were reported to affect intes-tine carcinogenesis in mice (34, 35), indicating that ge-netic heterogeneity plays a role in this genetic system(Table 1).

Plasmacytomagenesis

Strains of mice genetically susceptible and resistant to

plasmacytomagenesis (plasmacytomas are tumors of ma-

ture B cells that can be induced in mice by i.p. admini-stration of paraffin oils or pristane) have been identified,and different loci associated with resistance to plasmacy-toma were found (36, 37) (Table 1).

Skin carcinogenesis

Genetic susceptibility and resistance to chemically in-duced skin cancer in mice are controlled by multiple loci(38) (Table 1). That genes conferring predisposition toskin tumor development are relatively frequent has alsobeen shown by Bangrazi et al. (39). Starting from eightdifferent inbred strains of mice and crossing them to cre-ate new genetic combinations, they selected two lines:one highly susceptible and the other highly resistant to

carcinogen-induced skin tumorigenesis (39).

HUMAN MODELS

Polygenic inheritance is difficult to demonstrate in hu-mans, and the chances of detecting the involved genesare hindered by a series of difficulties that include: ge-netic heterogeneity, epistasis or interaction betweengenes, low frequency of family cases compared with fre-quency of the disease in the general population, gene-en-vironment interaction, etc. Notwithstanding thedifficulties, recent progress in genetic research is leading

TABLE 1. Experimental mode is of polygenic inheritance of predisposition to canc er in mice

Model be) Chromosome(s) Reference

Hepatocarcinogenesis Hcsl, Hcs2, Hcs3

Hcs4, Hcs5, Hcs#{243}

Her), Hcr2

7, 8, 122, 5, 19

4, 10

2324

25

Lung tumorigenesis PasIPasi, Pas2, Pas3, Pas4Pasi, Pas3Par)

66, 17, 19, 9

6, 1911

2627

2830

Intestine carcinogenesis MmMm, Mom)Scc)

CesI

1818, 4

2

12

313234

35

Plasmacytomagenesis Pctl”, Pct2r2 1, 4 36, 37Skin carcinogenesis Sktsl, Skt.s2, Skts3 5, 7 38

POLYGENIC INHERITANCE OF CANCER PREDISPOSITION 867

to major achievements in the analysis of polygenic dis-eases such as diabetes, Alzheimer disease, and hyperten-sion (40-42).

Multiple susceptibility genes

Lung tumor represents the human tumor type for which ahigh risk is clearly determined by exposure to environ-mental chemical carcinogens (tobacco smoking, etc.).However, numerous polymorphisms at genes coding forenzymes involved with metabolism of exogenous com-

pounds, including carcinogens, have been associated withan increased risk (two- to fourfold) of lung cancer. Thecombination of two lung tumor associated polymorphismsresults in an additive risk of lung cancer (43-45). These

findings suggest genetic heterogeneity and polygenic in-heritance of lung cancer risk.

Genetic heterogeneity

Genetic heterogeneity means that mutations at differentgenes may confer high genetic predisposition to the sametumor type. An important role of genetic heterogeneityhas been reported for familial predisposition to mela-noma, HNPCC, and breast cancer (6, 46, 47). Multiple

regions linked to testicular cancer susceptibility geneshave been reported by sib-pair analysis, indicating ge-netic heterogeneity and possible polygenic inheritance of

susceptibility to testicular cancer (48).

An example modeL

The number of possible models for a multilocus system is

large, therefore precluding investigation of all the models(49). We wanted to test the hypothesis of a polygenic in-heritance of cancer susceptibility in humans, based onevidence in rodent systems. The model assumes that thetrait “predisposition to cancer” requires the combined ac-tion of several loci carrying mutations that increase by acertain level the risk of developing cancer. Considering a

risk of 1:1,000 (0.1%) for a particular type of cancer innoncarrier people as an example, we tested a model withthree loci, i.e., with the same number of loci that deter-mines predisposition to experimental hepatocarcinogene-sis. Each susceptibility allele would be dominant over the

nonsusceptibility allele, and individuals inheriting allthree cancer susceptibility alleles would have a -50%risk of developing that tumor type during their lifetime.Therefore, each cancer susceptibility allele would in-crease the risk of cancer 8-fold (increased risk of 8 x 8 x8 = 512-fold, with a probability of developing that can-cer of 0.1% x 512-fold = 51.2%). That risk may seemtoo high, but it is quite reasonable because in experimen-tal models, more than 70% of mice genetically suscepti-ble to cancer may develop spontaneous tumors duringtheir lifetime (17, 18, 50).

We tested, using computer simulation, the effects of theallelic combination at different allelic frequencies in thegeneral population, from relatively rare (0.005) to quite com-mon (0.3) frequencies. Indeed, a number of candidate sus-ceptibility genes (CYP2D6, GSTM1, NAT2) show a

TABLE 2. Polygenic model ofheredityofcancer predispositionbased on Ihree dominant cancer susceptibility aileles

% Carriers in”

Estimated number of cancer

Frequency of the disease allele(s)6 No. of cancer predisposition alleles General population Cancer patients cases/lO,000 peoplT

0.3 0 11.8 0.1 1

1 36.7 3.1 29

2 38.2 25.6 244

3 13.3 71.2 681

0.2 0

1

2

3

26.2

44.2

24.9

4.7

0.6

8.1

36.5

54.8

3

35

159

240

0.1 0

1

2

3

53.1

37.4

8.8

0.7

4.2

23.6

44.4

27.8

5

30

56

36

0.05 0

1

2

3

73.5

23.8

2.6

0.09

15.4

40.0

34.6

10.0

7

19

17

5

“For a particular type of cancer: percentage of carriers of cancer susceptibility alleles in the general population and in cancer patients, at different frequency ofcancer predisposition alleles in the general population. t’The three alleles are assumed to be present at the same frequency in the general population. ‘Thebasic risk 1 in noncamers is given by 1 person of 1,000 (0.1%) that will develop that particular type of cancer. Each disease allele increases the risk of cancer of8 folds (a total of 8X8X8512 folds at the combination of all the three disease alleles).

0-r, r

r, r

r, S

-0S. r

S. rr, r

s,r r,r

r,r r,r

r,r s,r

868 Vol. 10 June 1996 The FASEB Journal DRAGANI El AL.

relatively high (>0.2) frequency of the susceptibility allele(44, 45). Percentages of carriers of two and three cancersusceptibility loci are predicted to be higher in cancer pa-

tients than the general population. The ratio increases by

decreasing the frequency of the disease alleles in the generalpopulation, and it is as much as > 100-fold higher at allelic

frequencies < 0.05 (TabLe 2). Although carriers of threecancer susceptibility alleles have a very high risk of cancer(odds ratio = 512), the progeny of cancer patients will experi-ence only a marginal increase in the relative risk (RR) ofcancer (Fig. 1 and Fig. 2). Indeed, the RRs of the cancerpatients’ progeny will range from 2 to 5, varying slightly withthe frequencies of alleles predisposing to cancer in the gen-eral population (Fig. 2), in agreement with epidemiologicalevidence (see below). Although the risk of cancer increases

by inheritance of increasing number of susceptibility alleles,at the population level the contribution to the number ofcancer cases is a function of allele frequency. Indeed, if

susceptibility alleles are common (frequency 0.2-0.3), car-riers of multiple alleles will experience the highest numberof cancer cases (Table 2). Otherwise, at low allele frequency(0.1-0.05) a significant number of tumors will develop in

noncarriers and in single gene carriers (Table 2). Because

polygenic inheritance in our example model predicts thatany of several susceptibility alleles increases cancer risk as

a consequence, genetic heterogeneity represents an impor-tant and linked aspect of polygenic inheritance.

Cancer patients’ relatives

These predictions of the example of polygenic model ofinherited predisposition to cancer are in good agreementwith the results of epidemiological studies. In fact, forsome tumors, including colorectal, endometrial, liver,lung, prostate, stomach, and testicular cancer, the RR ofthat particular cancer for people with affected first degreerelatives is about 2 to 4 compared to those without a fam-

ily history of the disease (8-13, 48).

Other poLygenic models

Moreover, if we consider a polygenic model that includes,along with dominant cancer susceptibility alleles, domi-nant cancer resistance alleles and also recessive cancersusceptibility and resistance alleles, the pattern will bevery complicated. However, we still face a situation char-acterized by very high genetic susceptibility to cancer insome individuals inheriting the appropriate combinationof alleles that give a predisposition to cancer, and by otilya marginal increase in the RR of cancer in the progeny ofthese individuals. Therefore, in polygenic inheritance thephenotype is genetically controlled, but it does not run in

families.

FUTURE PERSPECTIVES

If a polygenic inheritance of predisposition to cancer is

operating in humans, what kind of perspective do wehave of identifying the genes involved and the individuals

Figure 1. Allele asssortment in polygenie inhei-itance: Why the pene-

trance of polygenic cancer predisposition is low. This rnixlel shows three

genes controlling tumor predisposition. Each gene has two alleles: r,

resistance; s, susceptibility; the “s’ allele is dominant over the “i’ allele.

Thc risk of cancer is I) high in individuals carrying three “susceptibility”

alleles (black symbols), 2 intermediate in individuals with two “suscep-

tibility” allele (gray symbols), and 3)Iow in individuals with one “susecp-

tihility” allele (while symbols). belt: The low possibility that all the “s”

alleles are passed to the progeny results in offsprings at low genetic risk

from high risk parents. Right: On the otla-r hand. parents at low genetic

risk for cancer may provide the appropriate combination of cancer sus-

ceptibility alleles and may generate children at high genetic risk. Other

polygenic models, characterized by recessive canter alleles. (lomninantcancer resistance alleles. etc., lead to the same con,Iusions: high risk of

cancer in people with the appropriate conilnr,atioii of cancer alleles, and

low risk of cancer in their parents, sibs, and progeny.

at genetic risk? In humans, the absence of familial aggre-

gation of cases does not allow linkage analysis on ex-tended pedigrees. However, sib-pair analysis seems to

have enough power of resolution to detect reliable link-ages (51), although it is always necessary to replicate thefindings on large numbers of pairs. A complementary ap-

proach is to pursue population-based association studies

that provide a strategy for detection of disease suscepti-

bility genes. In such studies, the frequency of a matker

allele is tested in patients and controls, matched carefullyin order to avoid population stratification (52). Significant

association exists if the marker is in linkage disequili-briurn with a susceptibility gene or if the marker itself

(e.g., gene mutation) is causally involved with disease(52, 53). Linkage disequilibrium mapping may be bestpursued in isolated populations, where linkage disequili-brium could extend over greater distances than in hetero-

geneously mixed populations (53). In the latterpopulations, the fatnily-based association studies avoid

the problem of population stratification, and have been

successfully applied to complex diseases such as diabetes

(54, 55).The cloning of candidate genes may be pursued in the

available experimental models of cancer susceptibilityand resistance in inbred strains of rodents. A large Ior-

tion of the mouse genome shows regions of hotnology andconserved syntenies with the human genome, and com-parative genetic maps between mice and humans have

been used to predict tIle location of human and murine

disease genes on the basis of their mapping in other spe-cies (16). If the genes responsible for susceptibility andresistance to a particular form of cancer in animals are

6.54

32

1

0-

Figure 2. Relative risk of cancer in the progeny of cancer patients

(compared to the general population) as a function of the frequency of

cancer predisposition alleles in the general population. Computer simu-

lation of a polygenic model of inherited predisposition to a particular type

of cancer based on three dominant cancer susceptibility alleles. The three

alleles are assumed to be present at the same frequency in the generalpopulation. For additional details, see text.

cloned, it would be relatively easy to find the humanhomologue and to look for the presence of mutationsand/or allelic variations in cancer patients. However, withour present technology, a large population screening formutations at numerous genes is very expensive. In anycase, even in well-characterized experimental models, thepositional cloning of each locus affecting tumor develop-ment is very difficult, due to the relatively large regions

of linkage (5-10 cM, with hundreds of genes present) andto the relatively small effects of each locus (see the hepa-tocarcinogenesis model in mice as an example).

A more feasible alternative would be possible if one ormore final biochemical products are produced by the inter-action of multiple alleles that give a predisposition to cancer.Therefore, if one or more proteins or biochemical functionsare expressed at altered levels in the target organs of mice

and humans genetically predisposed to cancer, it would bepossible to identify these altered biochemical functions. Ac-cordingly, mismatch repair deficiency has been reported inphenotypically normal cells of HNPCC patients (56). Recentdevelopments in mRNA and DNA subtraction techniquesmay also be helpful to identify and clone candidate genesthat could be tested as markers of genetic predisposition tocancer in different species, including humans.

0(0 VCCKliC IkILICOITAkI(’c (Ic t’AkI(CD oDcrIICDriCITIrlJ

0 0.1 0.2

Frequency of disease alleles

This work is dedicated to Prof. Giuseppe Della Porta, who initiated

us to science and continues to encourage and support us. This work was

partially funded by grants from Finalized Project CNR “ACRO,” and

from Associazione and Fondazione Italiana Ricerca Cancro (AIRC and

FIRC) of Italy.

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