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Page 2 of 11 Zhang et al. J Cancer Metastasis Treat 2020;6:21 I http://dx.doi.org/10.20517/2394-4722.2020.40

INTRODUCTION
The majority of human cancers arise in response to exposure to environmental factors and carcinogenic
agents that may lead to somatic mutations. Signatures of these mutational processes are often evident
[1]
in the sequences of cancer genomes . Genetic and epigenetic factors also play an important role in
determining which exposed individuals will develop tumors. Most tumor susceptibility models in humans
and experimental animals have focused on the inherited abnormality of a single gene such as germline
mutations of Rb or p53. These particular single locus lesions are predisposed to tumor formation because
they harbor strong “altered function” alleles. However, it is estimated that such strong germline alleles
may only account for approximately 2%-14% of human cancers which implies that another paradigm is
[2]
required to explain the other 86%-98% . The individuals in whom these latter cancers arise must either
lack a germline genetic component, or tumor development in these individuals represents an inherited trait
that may depend on several genes or epigenetic modifiers, in concert with environmental stressors, thus
presenting cancer as a complex genetic trait.

Genome wide association studies of cancer development provide a systematic approach to identifying
[3]
genes that may influence cancer risk . Genome-wide linkage studies in genetically uniform strains of
mice can provide a window into the more complex genetics associated with human cancers and may
be used to model certain patient subpopulations. Thus in 1993, we chose to look at the inheritance
of mouse plasmacytoma (PCT) susceptibility alleles associated with genetic variants segregating in
[4]
immunocompetent backcross mice between BALB/c and DBA/2 strains of mice .

EXPERIMENTAL SYSTEM: IDENTIFICATION OF MOUSE TUMOR SUSCEPTIBILITY PATHWAYS
TO TARGET
Human multiple myeloma (MM) is a clonal proliferative of neoplastic plasma cells in the bone
marrow. Mouse plasma cell tumors model certain aspects of these antibody producing neoplasms.
Plasmacytomagenesis in BALB/cAn mice is a complex genetic trait with 40%-60% penetrance in non-
[5]
specific pathogen free mice . Through our genome-wide mapping studies utilizing genetic crosses with
DBA/2 mice (0% tumor incidence), together with the development and use of a series of C.D2 congenic
strains, coupled with representational difference analysis and positional cloning, we determined that
Cdkn2a (p16), Mtor, and Mndal contribute to PCT susceptibility and resistance [Figures 1 and 2] [4-11] . Pctr1-
2 are localized in non-contiguous, non-overlapping segments of mouse Chr 4, and Pctm, a modifier of
PCT, on Chr 1. The two Pctr loci on Chr 4 are susceptibility loci in BALB mice while in DBA mice, they are
resistance loci as evidenced by backcross and congenic strain analyses. The genes identified for Pctr1 and
Pctr2 are, Cdkn2a (p16) and Mtor, respectively. The BALB alleles of both p16 and Mtor encode efficiency
and hypomorphic alleles whose functional activities are much less active than the respective DBA alleles. In
contrast to Pctr1 and Pctr2, the Pctm locus on Chr 1 encodes a resistance allele in BALB and a susceptibility
allele in DBA. In fact, the candidate, Mndal, for the Pctm locus is deleted in DBA mice, but is present and
[12]
functionally active in BALB mice .
Compound allelic variation in both coding and promoter sequences, found in Cdkn2a [p16 exon 2: G232A
in ANK repeat domain, RREB cis regulatory element (CRE)] and Mtor (exon 11: R628C in HEAT repeat
domain; MZF1 CRE) [6,11,16,17] , contribute to the complex genetics associated with PCT susceptibility in
[4,9]
BALB/c mice . Hypomorphic activity of the promoter and coding regions of the BALB alleles of both
p16 and Mtor is associated with tumorigenesis after exposure to pristane, suggesting that both Cdkn2a
(p16) and Mtor can act as tumor suppressors in PCT development in response to stress and in an allele-
dependent manner [11,15-17] .

BALB/c mice are susceptible because they harbor several tumor susceptibility loci that act in concert to
produce the susceptible phenotype [Figure 2]. We hypothesize the combination of these relatively subtle