Mouse Genome Informatics
ht1
    Krastm3Tyj/Kras+
involves: 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• Background Sensitivity: mean age at death is ~250 days on pure 129/Sv background compared to 200 days on mixed background

tumorigenesis
• Background Sensitivity: about 40% of mice develop skin papillomas, with slightly higher incidence than on mixed 129 and C57BL/6 background
• Background Sensitivity: ~30% of animals develop thymic lymphoma; incidence is higher than on pure 129/Sv background
• 100% of mice examined at 3-4 months of age have developed lung tumors

integument
• Background Sensitivity: about 40% of mice develop skin papillomas, with slightly higher incidence than on mixed 129 and C57BL/6 background

Mouse Models of Human Disease
OMIM IDRef(s)
Lung Cancer 211980 J:68981


Mouse Genome Informatics
ht2
    Krastm3Tyj/Kras+
involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• Background Sensitivity: mean age at death is ~200 days

tumorigenesis
• all animals at time of death/sacrifice have extensive tumor burden
• mice display a more rapid tumor phenotype than Krastm2Tyj heterozygotes
• Background Sensitivity: animals are prone to skin papillomas (seen in ~20% of animals); tumors typically arising on ears and snout are predominantly pedunculated and show limited tendency to progress to squamous cell carcinoma
• Background Sensitivity: animals are prone to thymic lymphomas (seen in ~40% of animals)
• 100% of animals show multifocal tumors at time of death/sacrifice
• tumors are detectable at 1 week of age as small pleural nodules; multiplicity and size of tumors increases with age, and ultimately result in respiratory distress and death
• tumors range from mild hyperplasia/dysplasia to overt carcinoma; small lesions consist of hyperplastic alveolar epithelium
• in older mice, infrequent metastases to thoracic lymph nodes, the kidney and other visceral organs
• as lesions enlarge, they form small alveolar adenomas; some show areas of glandular differentiation
• 5-10% of tumors have features of well-differentiated human papillary adenocarcinoma

digestive/alimentary system
• mutants have multiple aberrant crypt foci (ACF) of the colon

endocrine/exocrine glands
• mutants have multiple aberrant crypt foci (ACF) of the colon

integument
• Background Sensitivity: animals are prone to skin papillomas (seen in ~20% of animals); tumors typically arising on ears and snout are predominantly pedunculated and show limited tendency to progress to squamous cell carcinoma

Mouse Models of Human Disease
OMIM IDRef(s)
Lung Cancer 211980 J:68981


Mouse Genome Informatics
cx3
    Ccne1tm1Jro/?
Krastm3Tyj/?

either: (involves: 129S2/SvPas * 129S4/SvJaeSor) or (involves: 129S2/SvPas * 129S4/SvJaeSor * C57BL/6)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mean survival is reduced to 160 days compared to 260 days for mice homozygous for Kras alone

cellular
• 2 of 6 tumors from double mutants display significant gains or losses of whole chromosomes while no gains or losses of whole chromosomes are seen in Kras homozygotes


Mouse Genome Informatics
cx4
    Krastm3Tyj/Kras+
Mir21tm1.1Eno/Mir21tm1.1Eno

involves: 129S/SvEv * 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
N
• unlike Krastm3Tyj heterozygotes, mice do not develop skin papillomas or lung adenomcarcinomas (J:164198)
• mice exhibit decreased total tumor area relative to lung area compared with Krastm3Tyj heterozygotes
• however, tumor cell proliferation is the same as in Krastm3Tyj heterozygotes
• mice develop fewer thymic lymphoma, lung hyperplasia and lung adenomas than in Krastm3Tyj heterozygotes
• fewer lung adenoma than in Krastm3Tyj heterozygotes
• mice develop fewer lung adenoma than in Krastm3Tyj heterozygotes
• fewer than in Krastm3Tyj heterozygotes

respiratory system
• mice develop fewer lung hyperplasia than in Krastm3Tyj heterozygotes


Mouse Genome Informatics
cx5
    Krastm3Tyj/Kras+
Tg(CAG-Mir21,-EGFP)#Eno/0

involves: 129S2/SvPas * C3H * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice exhibit premature death compared with wild-type mice
• however, mice exhibit the same mortality as Krastm3Tyj heterozygotes

tumorigenesis
• increased proliferation of tumor cells compared with tumor cells from Krastm3Tyj heterozygotes
• of thymic tumors compared with Krastm3Tyj heterozygotes
• at 18 weeks compared with Krastm3Tyj heterozygotes
• mice develop increased incidence of all tumor grades without increasing the rate of conversion to adenocarcinoma compared with Krastm3Tyj heterozygotes


Mouse Genome Informatics
cx6
    Dmtf1tm1Cjs/Dmtf1+
Krastm3Tyj/Kras+

involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mean survival time of double mutants is 21 weeks compared to 35 weeks for Kras+/-, Dmtf1-sufficient mice

tumorigenesis
• 10-20% of animals develop tail papillomas
• <5% of animals show distant metastases (liver/intr-abdominal or leg) of lung tumors, while no metastases are observed in KrasLA+/-, Dmtf1-sufficient mice
• ~35% of mice develop thymic lymphomas
• ~50% of largest tumors are well, moderately, or poorly differentiated adenocarcinomas, with signs of intrabronchial or intravascular invasion
• all mice develop lung adenomas or lung adenocarcinomas
• greater than 50% of mice develop lung carcinomas by 40 weeks of age, and tumors are significantly larger than those found in KrasLA+/- single mutants
• number of tumor nodules increase as animals become sick, with trend to increased nodule size
• tumorigenesis is accelerated relative to heterozygous Kras, wild-type Dmtf1 mice

integument
• 10-20% of animals develop tail papillomas


Mouse Genome Informatics
cx7
    Dmtf1tm1Cjs/Dmtf1tm1Cjs
Krastm3Tyj/Kras+

involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mean survival time of double mutants is 21 weeks compared to 35 weeks for Kras+/-, Dmtf1-sufficient mice

tumorigenesis
• 10-20% of animals develop tail papillomas
• ~20% of mice develop thymic lymphomas
• all mice develop lung adenomas or lung adenocarcinomas
• greater than 50% of mice develop lung carcinomas by 40 weeks of age, and tumors are significantly larger than those found in KrasLA+/- single mutants
• number of tumor nodules increase as animals become sick, with trend to increased nodule size
• tumorigenesis is accelerated relative to heterozygous Kras, wild-type Dmtf1 mice

integument
• 10-20% of animals develop tail papillomas


Mouse Genome Informatics
cx8
    Krastm3Tyj/Kras+
Pik3catm1Jdo/Pik3catm1Jdo

involves: 129S2/SvPas * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• zero to two visible tumors are found compared to forty or so tumors in Krastm3Tyj mice
• apoptotic rates in small lesions are increased compared to in Krastm3Tyj mice
• one mouse did not show any evidence of lung tumor formation up to 6 months of age