Strain difference in susceptibility to radiation lymphomagenesis
Development of tumors is controlled by multiple genes such as cellular oncogenes and tumor suppressors activated or inactivated by somatic mutations and/or epigenetic mechanisms. Tumor development is also controlled by heritable factors as well as environmental factors, i. e., diet, oxidative stress and sustained inflammation, as reviewed by a large number of recent reports [1-12]. Both heritable and environmental factors are important targets for clinical controls and prevention of cancers.
Heritable factors underlying cancer risks have been identified in familial cancer-prone pedigrees. In the pedigree members, tumors develop in a Mendelian dominant inheritance fashion. Breast cancer 1, early onset (
Several strains of mice with different susceptibility to lymphomagenesis so far reported might be useful in the study of tumor susceptibility. Using genetic crosses between BALB/cHeA (refer to as BALB/c, hereafter) and STS/A (refer to as STS) mice with different tumor susceptibility, and between the BALB/c and recombinant congenic CcS/Dem strains of mice with 12.5% STS and 87.5% BALB/c allele in the genome, we mapped three loci controlling susceptibility to radiation-induced apoptosis of thymocytes to chromosomes 16, 9 and 3 [18, 19], and two loci for susceptibility to lymphomagenesis to chromosome 4 . We identified the protein kinase, DNA activated, catalytic polypeptide (
In this chapter, we initially review recent advances in the research of tumor susceptibility, in particular, susceptibility to radiation lymphomagenesis in mice, and show that two loci controlling radiation lymphomagenesis map to chromosome 4. Then, we show that two types of allele loss, i. e., loss common to lymphoma and parental strain-specific loss, occur in radiation-induced lymphomas from various F1 hybrids between strains with different lymphoma susceptibility. We show that LOH on chromosome 4 in F1 hybrids between BALB/c and STS occurs in a strain-specific manner and exhibits a bias towards the STS allele loss. At the close, by exploiting congenic strains of mice containing different segments of chromosome 4 from the donor strain STS on the BALB/c background, we present a concordance between the allele loss region and a lymphoma susceptibility locus area on chromosome 4, where the BALB/c mouse harbors a hypomorphic allele of
2. Mouse strain difference in susceptibility to radiation-induced lymphomagenesis
In laboratory strains of mice irradiated by ionizing radiation according to a well-established protocol, development of lymphomas starts around three months after the exposure to radiation and is terminated around ten months. Radiation-induced lymphomas are mostly of thymic origin. Several laboratory strains of mice such as BALB/c and C57BL reside in
3. Current status of the studies on tumor susceptibility in mice
Numerous tumor susceptibility loci have been mapped by analyzing genetic crosses between strains of mice exhibiting different tumor susceptibility . Several genes responsible for tumor susceptibility have been identified, some of which are validated by supporting evidences:
Despite the availability of strains of mice with obvious difference in susceptibility to radiation lymphomagenesis, it is much difficult to analyze such traits as to be expressed in a binominal fashion (tumor-free survivals of animals after exposure to radiation). However, there is one successful case: a suggestive linkage near D4Mit12 at 57.8 centimorgan (cM) position on chromosome 4 with susceptibility to radiation lymphomagenesis, which was detected in the genetic cross between BALB/c and MSM, is confirmed by exploiting congenic mice with the MSM allele at D4Mit12 on the BALB/c background [32, 33]. Because BALB/c mice had a hypomorphic allele at the
4. Mapping of lymphoma susceptibility loci on mouse chromosome 4 using genetic crosses between BALB/c and STS strains of mice
We so far showed that the protein kinase, DNA activated, catalytic polypeptide (
Previously, M. Okumoto
To narrow down the tumor susceptibility gene regions, we generated congenic strains of mice with different portions of STS-derived chromosome 4 on the BALB/c background by backcrossing (BALB/c x STS)F1 mice to the BALB/c. Establishment of the congenic lines was facilitated by positive and negative selections with typing of microsatellite markers on chromosome 4 and markers distributed in the whole genome . Because the
5. Loss of heterozygosity (LOH) in radiation-induced lymphomas from various F1 hybrids: common loss and cross-dependant loss
Tumor suppressors frequently undergo loss of heterozygosity (LOH) in a variety of tumors in humans and mice. We previously reported that frequent LOH (more than 20%) occurred on chromosomes 4, 12 and 19 in radiation-induced lymphomas from (BALB/c x STS) F1 mice, with incidences 27% (20 of 74 lymphomas), 57% (42 of 74 lymphomas) and 50% (37 of 74 lymphomas) on chromosomes 4 (at D4Mit31), 12 (at D12Mit17) and 19 (at D19Mit11), respectively  (Table 2). Importantly, STS allele-specific loss occurred on chromosome 4. The bias was confirmed using reciprocal F1 hybrids between BALB/c and STS .
|(CXS)F1||74||4||D4Mit31 (106.8)||20 (27%)|||
|19||D19Mit11 (42.5)||37 (50%)|
|(SXM)F1||20||4||D4Mit54 (137.4)||5 (25%)|||
|12||D12Mit233 (109.5)||12 (60%)|
|(CXM)F1 d||81||12||D12Mit181 (110.0)||53 (65%)|||
|16||D16Mit122 ( 74.5 )||38 (45%)|
In these crosses, allele loss involved almost entire chromosomes 4 and 19, without showing any peaks in LOH frequencies. Cytogenetic analysis showed that allele loss in such large areas was not caused by chromosomal deletion, but ascribable to mitotic recombination . In lymphomas from (STS x MSM)F1 mice, LOH occurred on chromosomes 4 and 12 with incidences 25% (5 of 20 lymphomas) and 60% (12 of 20 lymphomas) on chromosome 4 (at D4Mit54) and chromosome 12 (at D12Mit233), respectively . In these lymphomas, LOH on chromosome 19 was infrequent (1/20, 5% at D19Mit63). In radiation-induced lymphomas from (BALB/c x MSM)F1 mice, allele loss frequently occurred on chromosomes 12 (53/81, 65% at D12Mit181) and 16 (38/81, 45% at D16Mit122) .
Interestingly, LOH on chromosome 12 commonly occurred in radiation-induced lymphomas from these three F1 hybrids, while LOH frequencies on chromosomes 4 and 19 markedly varied. Frequent LOH was detected on chromosome 4 in lymphomas from (STS x MSM)F1 mice, but not (0/20 at D4Mit13) in lymphomas from (BALB/c x MSM)F1 mice . LOH on chromosome 19 was infrequent (0/20 and 1/20, at D19Mit63 and D19Mit123) in lymphomas from (STS x MSM)F1 mice. In the context of LOH on chromosome 19, results were similar in lymphomas from the (BALB/c x MSM)F1 hybrid. Thus, LOH on chromosomes 4 and 19 occurred in a cross-dependent manner. This suggests that LOH frequencies on these chromosomes are controlled by genetic interaction, possibly between putative tumor suppressors, the locations of which are indicated by LOH, and by genetic variations in the background. Moreover, the situation of LOH on chromosome 4 is somewhat different from that on chromosome 19. We present allele loss frequencies at several markers on chromosome 4 in these lymphomas in Table 3.
|(CXS)F1||47||D4Mit17 (63.0)||14 (30%)|||
|D4Mit9 (94.7)||14 (30%)|
|D4Mit13 (142.0)||14 (30%)|
|(SXM)F1||20||D4Mit9 (94.7)||1 (5%)|||
|D4Mit54 (137.4)||5 (25%)|
|(CXM)F1 c||20||D4Nds2 (124.4)||0 (0%)|||
|D4Mit13 (142.0)||0 (0%)|
|(CXM)F1||43||D4Mit9 (94.7)||3 (7%)||Unpublished data|
|51||D4Mit13 (142.0)||4 (8%)|||
Notably, LOH frequency at D4Mit9 was reduced compared to that at D4Mit54, a marker in the proximity of D4Mit13 and approximately 43 Mb distal to D4Mit9, in lymphomas from (STS x MSM)F1 hybrid mice. Using lymphomas from (BALB/c x MSM)F1 mice, we reconfirmed that allele loss at markers D4Mit9 and D4Mit13 on chromosome 4 was very infrequent (3/4 and 4/51 , respectively). Because D4Mit9 is located very close to cyclin-dependent kinase inhibitor 2A (
The LOH frequencies at markers on chromosome 12 formed a sharp peak near telomere , and a putative tumor suppressor B cell leukemia/lymphoma 11B (
6. The STS allele-specific loss occurred in the Lyr region on chromosome 4
Allele loss on chromosome 4 was significantly biased towards loss of the STS allele in lymphomas from (BALB/c x STS)F1 mice . It is of interest to examine whether putative tumor susceptibility genes on chromosome 4, which we identified in different regions of chromosome 4, are associated with the strain-specific allele loss on chromosome 4 by using congenic strains of mice with various regions of chromosome 4 from the donor strain STS on the background strain BALB/c, namely the C.S congenic series. LOH was studied in lymphomas generated in (BALB/c x C.S163–31)F1 and (BALB/c x C.S302–9)F1 mice. Both C.S163–31 and C.S302–9 strains of mice showed resistance to lymphomagenesis as shown in Figure 1. The C.S163–31 strain harbors the STS allele at two tumor susceptibility loci, one locus near D4Mit17 and the other,
Frequent allele loss at markers in the chromosome 4 segments was detected in lymphomas from (BALB/c x C.S163–31)F1 (cross A) and (BALB/c x C.S302–9)F1 (cross B) with incidences 11/34 (32%) and 10/34 (29%), respectively. The LOH frequencies in these F1 hybrids were concordant with the original data in (BALB/c x STS)F1 ( in Table 3). The STS-allele loss ratios were 9/11 (D4Mit302) and 10/11 (D4Mit9) in the cross A; 8/10 (D4Mit302) and 9/10 (D4Mit9) in the cross B. Because the STS-allele loss occurred with similar ratio in both crosses, we combined the data from crosses A and B (presented as A + B in Table 4). Analysis of the combined ratios 17/21 (D4Mit302) and 19/21 (D4Mit9) indicate that the distortions are significant at both markers D4Mit304 and D4Mit9 (χ2 values were 8.0 and 13.7, p<0.005, degree of freedom = 1, respectively). The data indicating the STS-allele specific loss (D4Mit31) in lymphomas from reciprocal (BALB/c x STS)F1 and (STS x BALB/c)F1 hybrids are also presented ( in Table 4). Thus, the skewed allele loss that was originally observed in a wide area of chromosome 4 in (BALB/c x STS)F1 and (STS x BALB/c)F1 hybrids is reproducible in the limited segments of the STS-derived chromosome 4. Our results suggest that tumor suppressor(s) associated with susceptibility to lymphomagenesis exist in the limited areas of chromosome 4. Since C.S39–86 mice carry the STS allele in the vicinity of D4Mit17, i. e., the secondary locus controlling susceptibility to lymphomagenesis, we further examined allele loss at markers D4Mit7 (67.7 Mb), a marker in the vicinity of D4Mit17, and D4Mit86 using 25 lymphomas from (BALB/c x C.S39–86)F1 x BALB/c mice . Allele loss at these markers was detected in only one of 25 tumors (less than 5%). In this case the BALB/c allele was lost. Hence, approximately 40 Mb of the D4Mit39–86 segment, to which the secondary locus for tumor susceptibility was localized, was excluded from the skewed loss region. Analysis on congenic strains strongly suggest that the STS-strain specific loss is ascribable to the D4Mit302–D4Mit9 segment of chromosome 4, which harbors a putative tumor susceptibility gene
|A. (C x C.S163–31)F1||34||D4Mit17 (63.0)||11 (32%)||9||2 c|
|D4Mit302 (85.2)||11 (32%)||9||2 c|
|D4Mit9 (94.7)||11 (32%)||10||1 c|
|D4Mit31 (106.8)||11 (32%)||10||1 c|
|B. (C x C.S302–9)F1||34||D4Mit302 (85.2)||10 (29%)||8||2 d|
|D4Mit9 (94.7)||10 (29%)||9||1 d|
|A + B||68||D4Mit302 (85.2)||21 (31%)||17||4|
|D4Mit9 (94.7)||21 (31%)||19||2|
|(C x S)F1||39||D4Mit31 (106.8)||11 (28%)||10||1 e|
|(S x C)F1||35||D4Mit31 (106.8)||9 (26%)||7||2 e|
|(C x S)F1 + (S x C)F1||74||D4Mit31 (106.8)||20 (27%)||17||3 e|
Frequent LOH occurs on chromosomes 4, 12 and 19 in radiation-induced lymphomas from various F1 hybrid mice. These allele losses are classified into two groups: common loss and cross-dependent loss. The putative tumor suppressor harbored in common loss on chromosome 12 might be a key player in radiation-induced lymphomgenesis. Cross-dependent allele loss such as those on chromosomes 4 and 19 reflects genetic interaction between tumor suppressors harbored in the LOH region and the genetic background. BALB/c and STS strains of mice are susceptible and resistant to radiation-induced lymphomagenesis, respectively. Allele loss occurs on chromosome 4 in approximately 30% of lymphomas induced by radiation in (BALB/c x STS)F1 mice and shows preferential loss of the STS allele. Our analysis of congenic lines with various portions of STS-derived chromosome 4 on the BALB/c background shows a link between the skewed LOH and the tumor susceptibility
AcknowledgmentsWe thank Ms. Yuko Mitaki and Ms. Ikuko Kinoshita for their contribution to tumor sampling and genotyping. We thank Emeritus Professor M. Okumoto for his helpful discussion in preparation of this manuscript.
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