Reference SummaryDeng Q, Nat Commun 2019 Nov 7;10(1):5061

Title

 Tissue-specific microRNA expression alters cancer susceptibility conferred by a TP53 noncoding variant.

Authors

 Deng Q; Hu H; Yu X; Liu S; Wang L; Chen W; Zhang C; Zeng Z; Cao Y; Xu-Monette ZY; Li L; Zhang M; Rosenfeld S; Bao S; Hsi E; Young KH; Lu Z; Li Y

Journal

 Nat Commun

Volume

 10

Issue

 1

Year

 2019

Pages

 5061

Abstract

 A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms. We find a positive association between this variant and soft tissue sarcoma. In sharp contrast, it is protective against breast cancer. We generated a mouse line carrying this variant and found that it accelerates spontaneous tumorigenesis and glioma development, but strikingly, delays mammary tumorigenesis. The variant creates a miR-382-5p targeting site and compromises a miR-325-3p site. Their differential expression results in p53 downregulation in the brain, but p53 upregulation in the mammary gland of polymorphic mice compared to that of wild-type littermates. Thus, this variant is at odds with Li-Fraumeni Syndrome mutants in breast cancer predisposition yet consistent in glioma predisposition. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.

Links

 J:281362 – MGI References
31699989 – National Library of Medicine/PubMed

Strain Notes

Strain Note
B6FVBF1-Tg(MMTVneu)202Mul This cohort was generated by breeding C57BL/6-Trp53em1Yoli/+ mice with FVB/N-Tg(MMTVneu)202Mul mice.
B6FVBF1-Tg(MMTVneu)202Mul Trp53em1Yoli/+ This cohort was generated by breeding C57BL/6-Trp53em1Yoli/+ mice with FVB/N-Tg(MMTVneu)202Mul mice.
B6FVBF1-Tg(MMTVneu)202Mul Trp53tm1Tyj/+ This cohort was generated by breeding B6.129S2-Trp53tm1Tyj/J homozygous mice with FVB/N-Tg(MMTVneu)202Mul mice.
B6;FVB-Tg(MMTV-PyVT)634Mul Conflicting information was given in this paper regarding the genetic background of this cohort. It was referred to as an "F2" generation which would be approximately 50% C57BL/6 and 50% FVB/N, but the specific breeding information stated that it was generated by crossing B6FVBF1-Tg(MMTV-PyVT)634Mul Trp53em1Yoli/+ mice with C57BL/6-Trp53em1Yoli/+ mice (in which case the offspring would have been 75% C57BL/6 and 25% FVB/N, which is the genetic mixture of these mice as stated in the paper).
B6;FVB-Tg(MMTV-PyVT)634Mul Trp53em1Yoli Conflicting information was given in this paper regarding the genetic background of this cohort. It was referred to as an "F2" generation which would be approximately 50% C57BL/6 and 50% FVB/N, but the specific breeding information stated that it was generated by crossing B6FVBF1-Tg(MMTV-PyVT)634Mul Trp53em1Yoli/+ mice with C57BL/6-Trp53em1Yoli/+ mice (in which case the offspring would have been 75% C57BL/6 and 25% FVB/N, which is the genetic mixture of these mice as stated in the paper).
B6;FVB-Tg(MMTV-PyVT)634Mul Trp53em1Yoli/+ Conflicting information was given in this paper regarding the genetic background of this cohort. It was referred to as an "F2" generation which would be approximately 50% C57BL/6 and 50% FVB/N, but the specific breeding information stated that it was generated by crossing B6FVBF1-Tg(MMTV-PyVT)634Mul Trp53em1Yoli/+ mice with C57BL/6-Trp53em1Yoli/+ mice (in which case the offspring would have been 75% C57BL/6 and 25% FVB/N, which is the genetic mixture of these mice as stated in the paper).

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6 CNS - Brain glioma
  • retrovirus expressing human PDGFB
 CNS - Brain

0
C57BL/6-Trp53em1Yoli/+ CNS - Brain glioma
  • retrovirus expressing human PDGFB
 CNS - Brain

0
C57BL/6-Trp53em1Yoli CNS - Brain glioma
  • retrovirus expressing human PDGFB
 CNS - Brain

100
B6.129S2-Trp53tm1Tyj/J CNS - Brain glioma
  • retrovirus expressing human PDGFB
 CNS - Brain

100
B6.129S2-Trp53tm1Tyj/J CNS - Brain glioma
  • retrovirus expressing human PDGFB
 CNS - Brain

100
C57BL/6 Intestine - Small Intestine carcinoma Intestine - Small Intestine

0
C57BL/6-Trp53em1Yoli/+ Intestine - Small Intestine carcinoma Intestine - Small Intestine

observed
C57BL/6-Trp53em1Yoli Intestine - Small Intestine carcinoma Intestine - Small Intestine

observed
C57BL/6-Trp53em1Yoli/+ Leukocyte - Lymphocyte - B-lymphocyte - Follicular center cell lymphoma - follicular Leukocyte - Lymphocyte - B-lymphocyte - Follicular center cell

37
C57BL/6-Trp53em1Yoli Leukocyte - Lymphocyte - B-lymphocyte - Follicular center cell lymphoma - follicular Leukocyte - Lymphocyte - B-lymphocyte - Follicular center cell

31
C57BL/6-Trp53em1Yoli/+ Leukocyte - Lymphocyte - B-lymphocyte - Plasma cell plasmacytoma Leukocyte - Lymphocyte - B-lymphocyte - Plasma cell

5.7
C57BL/6-Trp53em1Yoli Leukocyte - Lymphocyte - B-lymphocyte - Plasma cell plasmacytoma Leukocyte - Lymphocyte - B-lymphocyte - Plasma cell

2.8
C57BL/6-Trp53em1Yoli/+ Leukocyte - Lymphocyte - B-lymphocyte - Plasma cell plasmacytoma - malignant Leukocyte - Lymphocyte - B-lymphocyte - Plasma cell

0
C57BL/6-Trp53em1Yoli Leukocyte - Lymphocyte - B-lymphocyte - Plasma cell plasmacytoma - malignant Leukocyte - Lymphocyte - B-lymphocyte - Plasma cell

2.8
C57BL/6 Leukocyte - Lymphocyte - B-lymphocyte lymphoma
  • gamma-radiation
 Leukocyte - Lymphocyte - B-lymphocyte

observed
C57BL/6-Trp53em1Yoli/+ Leukocyte - Lymphocyte - B-lymphocyte lymphoma
  • gamma-radiation
 Leukocyte - Lymphocyte - B-lymphocyte

observed
C57BL/6-Trp53em1Yoli Leukocyte - Lymphocyte - B-lymphocyte lymphoma
  • gamma-radiation
 Leukocyte - Lymphocyte - B-lymphocyte

observed
C57BL/6-Trp53em1Yoli/+ Leukocyte - Lymphocyte - B-lymphocyte lymphoma - diffuse large cell (DLCL) Leukocyte - Lymphocyte - B-lymphocyte

20
C57BL/6-Trp53em1Yoli Leukocyte - Lymphocyte - B-lymphocyte lymphoma - diffuse large cell (DLCL) Leukocyte - Lymphocyte - B-lymphocyte

17
C57BL/6-Trp53em1Yoli/+ Leukocyte - Lymphocyte - B-lymphocyte lymphoma - splenic marginal zone Leukocyte - Lymphocyte - B-lymphocyte

5.7
C57BL/6-Trp53em1Yoli Leukocyte - Lymphocyte - B-lymphocyte lymphoma - splenic marginal zone Leukocyte - Lymphocyte - B-lymphocyte

14
C57BL/6-Trp53em1Yoli/+ Leukocyte - Lymphocyte - B-lymphocyte tumor - malignant Leukocyte - Lymphocyte - B-lymphocyte

69
C57BL/6-Trp53em1Yoli Leukocyte - Lymphocyte - B-lymphocyte tumor - malignant Leukocyte - Lymphocyte - B-lymphocyte

67
C57BL/6 Leukocyte - Lymphocyte - T-lymphocyte lymphoma
  • gamma-radiation
 Leukocyte - Lymphocyte - T-lymphocyte

observed
C57BL/6-Trp53em1Yoli/+ Leukocyte - Lymphocyte - T-lymphocyte lymphoma
  • gamma-radiation
 Leukocyte - Lymphocyte - T-lymphocyte

observed
C57BL/6-Trp53em1Yoli/+ Leukocyte - Lymphocyte - T-lymphocyte lymphoma Thymus

0
C57BL/6-Trp53em1Yoli Leukocyte - Lymphocyte - T-lymphocyte lymphoma
  • gamma-radiation
 Leukocyte - Lymphocyte - T-lymphocyte

observed
C57BL/6-Trp53em1Yoli Leukocyte - Lymphocyte - T-lymphocyte lymphoma Thymus

0
C57BL/6 Leukocyte lymphoma Leukocyte

6
C57BL/6 Leukocyte lymphoma
  • gamma-radiation
 Leukocyte

60
C57BL/6-Trp53em1Yoli/+ Leukocyte lymphoma Leukocyte

observed
C57BL/6-Trp53em1Yoli/+ Leukocyte lymphoma
  • gamma-radiation
 Leukocyte

observed
C57BL/6-Trp53em1Yoli Leukocyte lymphoma Leukocyte

observed
C57BL/6-Trp53em1Yoli Leukocyte lymphoma
  • gamma-radiation
 Leukocyte

observed
B6FVBF1-Tg(MMTVneu)202Mul Trp53em1Yoli/+ Leukocyte lymphoma Leukocyte

9.5
B6FVBF1-Tg(MMTVneu)202Mul Trp53tm1Tyj/+ Leukocyte lymphoma Leukocyte

33
C57BL/6 Lung adenocarcinoma Lung

0
C57BL/6-Trp53em1Yoli/+ Lung adenocarcinoma Lung

0
C57BL/6-Trp53em1Yoli Lung adenocarcinoma Lung

observed
B6FVBF1-Tg(MMTV-PyVT)634Mul Mammary gland neoplasia Mammary gland

observed
B6FVBF1-Tg(MMTV-PyVT)634Mul Trp53em1Yoli/+ Mammary gland neoplasia Mammary gland

observed
B6FVBF1-Tg(MMTVneu)202Mul Trp53em1Yoli/+ Mammary gland neoplasia
  • lentivirus expressing miR-382
 Mammary gland

observed
B6FVBF1-Tg(MMTV-PyVT)634Mul Mammary gland tumor Mammary gland

100
B6FVBF1-Tg(MMTV-PyVT)634Mul Trp53em1Yoli/+ Mammary gland tumor Mammary gland

100
B6;FVB-Tg(MMTV-PyVT)634Mul Mammary gland tumor Mammary gland

100
B6;FVB-Tg(MMTV-PyVT)634Mul Trp53em1Yoli/+ Mammary gland tumor Mammary gland

100
B6;FVB-Tg(MMTV-PyVT)634Mul Trp53em1Yoli Mammary gland tumor Mammary gland

100
B6FVBF1-Tg(MMTVneu)202Mul Mammary gland tumor Mammary gland

33
B6FVBF1-Tg(MMTVneu)202Mul Mammary gland tumor
  • lentivirus control vector
 Mammary gland

0
B6FVBF1-Tg(MMTVneu)202Mul Mammary gland tumor
  • lentivirus expressing miR-382
 Mammary gland

29
B6FVBF1-Tg(MMTVneu)202Mul Trp53em1Yoli/+ Mammary gland tumor Mammary gland

24
B6FVBF1-Tg(MMTVneu)202Mul Trp53em1Yoli/+ Mammary gland tumor
  • lentivirus control vector
 Mammary gland

0
B6FVBF1-Tg(MMTVneu)202Mul Trp53em1Yoli/+ Mammary gland tumor
  • lentivirus expressing miR-382
 Mammary gland

88
B6FVBF1-Tg(MMTVneu)202Mul Trp53tm1Tyj/+ Mammary gland tumor Mammary gland

40
C57BL/6 Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

0
C57BL/6 Mesodermal cell/mesoblast sarcoma
  • gamma-radiation
 Mesodermal cell/mesoblast

0
C57BL/6-Trp53em1Yoli/+ Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed
C57BL/6-Trp53em1Yoli/+ Mesodermal cell/mesoblast sarcoma
  • gamma-radiation
 Mesodermal cell/mesoblast

observed
C57BL/6-Trp53em1Yoli Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed
C57BL/6-Trp53em1Yoli Mesodermal cell/mesoblast sarcoma
  • gamma-radiation
 Mesodermal cell/mesoblast

0
C57BL/6 Ovary tumor - malignant
  • gamma-radiation
 Ovary

0
C57BL/6-Trp53em1Yoli/+ Ovary tumor - malignant
  • gamma-radiation
 Ovary

0
C57BL/6-Trp53em1Yoli Ovary tumor - malignant
  • gamma-radiation
 Ovary

observed
C57BL/6 (Unspecified organ) tumor (Unspecified organ)

6
C57BL/6 (Unspecified organ) tumor
  • gamma-radiation
 (Unspecified organ)

60
C57BL/6-Trp53em1Yoli/+ (Unspecified organ) tumor (Unspecified organ)

47
C57BL/6-Trp53em1Yoli/+ (Unspecified organ) tumor
  • gamma-radiation
 (Unspecified organ)

88
C57BL/6-Trp53em1Yoli (Unspecified organ) tumor (Unspecified organ)

67
C57BL/6-Trp53em1Yoli (Unspecified organ) tumor
  • gamma-radiation
 (Unspecified organ)

92
B6FVBF1-Tg(MMTVneu)202Mul Trp53em1Yoli/+ (Unspecified organ) tumor (Unspecified organ)

33
B6FVBF1-Tg(MMTVneu)202Mul Trp53tm1Tyj/+ (Unspecified organ) tumor (Unspecified organ)

60