Effect of inactivating heterozygous mutations in DNA repair genes on experimental lung carcinogenesis in mice

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Abstract

Background. Inactivating mutations in Chek2 and Gprc5a genes are known to be associated with cancer development. Experimental carcinogenesis studies in genetically modified mice generate new data on their influence on pathology development.

Aim. In the present study in a model of lung carcinogenesis, survival parameters as well as tumor multiplicity and size in mice with Chek2 and Gprc5a heterozygous inactivating mutations were evaluated.

Material and methods. F2 hybrid mice from crosses between CBAB6F1 males heterozygous for the studied mutations and wild-type BALB / c females were used: Chek2dAA-carriers (76 males and 64 females) and Gprc5ainsA-carriers (60 males and 42 females). Starting at four months of age, mice received urethane (ethyl carbamate) intraperitoneally at a dose of 600 mg / kg weekly for 6 weeks. After genotyping by allele-specific PCR, animals were allocated to groups. Carcinogenesis parameters were evaluated 40 weeks after the beginning of the experiment.

Results. The proportion of mice with mutations surviving to the age of three months roughly followed the Mendelian distribution (35 / 41 males and 33 / 31 females) for the offspring of males heterozygous for Chek2dAA and was significantly lower in the case of Gprc5ainsA (20 / 40 males and 17 / 25 females, p = 0.043). The death of Gprc5ainsA carriers during the experiment was also higher than in the control group (p = 0.0506 in females). Synchronous lung and thymus neoplasms were found in 2 out of 4 Gprc5ainsA females that died before the end of the experiment, which were not found in other groups. At the end of the experiment, no significant differences in tumor multiplicity, mean linear size, and volume were found between the groups of mice with and without mutations.

Conclusion. It was found that heterozygous inactivating mutation Chek2dAA does not affect early age development and does not modify the parameters of induced lung carcinogenesis in mice. Heterozygous carriage of Gprc5ainsA mutation in mice increases the risk of early death and sensitivity to the toxic and carcinogenic effects of urethane.

About the authors

M. A. Maydin

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

Author for correspondence.
Email: mikhail.maydin@gmail.com
ORCID iD: 0000-0002-2264-4857

Mikhail A. Maydin, 

68, Leningradskaia Str., Pesochnyi, Saint Petersburg, 197758.

Russian Federation

M. N. Yurova

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

ORCID iD: 0000-0003-3589-5871

Maria N. Yurova,

68, Leningradskaia Str., Pesochnyi, Saint Petersburg, 197758.

Russian Federation

E. I. Fedoros

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

ORCID iD: 0000-0002-2426-9843

Elena I. Fedoros,

68, Leningradskaia Str., Pesochnyi, Saint Petersburg, 197758.

Russian Federation

P. V. Sergiev

M.V.Lomonosov Moscow State University

ORCID iD: 0000-0001-8866-1863

Petr V. Sergiev,

1, Kolmogorova Str., Moscow 119991.

Russian Federation

S. N. Aleksakhina

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

ORCID iD: 0000-0002-2149-7728

Svetlana N. Aleksakhina,

68, Leningradskaia Str., Pesochnyi, Saint Petersburg, 197758.

Russian Federation

E. A. Otradnova

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

ORCID iD: 0009-0003-0158-1820

Ekaterina A. Otradnova,

68, Leningradskaia Str., Pesochnyi, Saint Petersburg, 197758.

Russian Federation

S. S. Kruglov

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

ORCID iD: 0000-0003-1214-4637

Stepan S. Kruglov,

68, Leningradskaia Str., Pesochnyi, Saint Petersburg, 197758.

Russian Federation

E. N. Imyanitov

N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

ORCID iD: 0000-0003-4529-7891

Evgeny N. Imyanitov,

68, Leningradskaia Str., Pesochnyi, Saint Petersburg, 197758.

Russian Federation

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