Reference SummaryFenske TS, Cancer Res 2006 May 15;66(10):5029-38

Title

Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice.

Authors

Fenske TS; McMahon C; Edwin D; Jarvis JC; Cheverud JM; Minn M; Mathews V; Bogue MA; Province MA; McLeod HL; Graubert TA

Journal

Cancer Res

Volume

66

Issue

10

Year

2006

Pages

5029-38

Abstract

Secondary malignancies are a serious adverse consequence of alkylator chemotherapy. The risk of developing an alkylator-associated malignancy is influenced by genetic background, although the relevant genetic factors are poorly understood. To screen for novel susceptibility factors, we established a mouse model of alkylator-induced malignancy. We exposed mice from 20 inbred strains to the prototypical alkylating agent, N-nitroso-N-ethylurea (ENU). ENU was a potent carcinogen in many of the strains tested, inducing 140 tumors in 240 ENU-treated mice (66% incidence of at least one tumor in evaluable mice), compared with a background incidence of 8% spontaneous tumors in 240 strain-, age-, and sex-matched control mice (relative risk, 8.4; P < 0.0001). A wide variety of tumor histologies were noted, including epithelial carcinomas, soft tissue sarcomas, and hematopoietic tumors. Cancer susceptibility was a heritable trait for the most common tumor types, lung adenocarcinoma (H(2) = 0.25), T cell lymphoma (H(2) = 0.19), and myeloid malignancies (H(2) = 0.10). Quantitative trait locus mapping identified regions on chromosomes 3, 6, 9, and 15 containing candidate genes associated with lung adenoma, lung carcinoma, and lymphoma susceptibility. This novel mouse model recapitulates many features of human alkylator-associated cancer and supports the hypothesis that susceptibility to this syndrome is influenced by inherited polymorphisms that could be used to make informed clinical treatment decisions.

Links

J:109061 – Mouse Genome Informatics
16707424 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified] Adrenal gland - Medulla pheochromocytoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Adrenal gland - Medulla

0.58

[not specified] Blood vessel hemangioma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Liver

observed

[not specified] Blood vessel hemangioma Liver

0

[not specified] Blood vessel hemangiosarcoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Blood vessel

0.58

[not specified] Connective tissue - Fibroblast fibroma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Skin

0.58

[not specified] Connective tissue - Fibroblast fibroma Skin

0

[not specified] Connective tissue - Fibroblast fibrosarcoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Connective tissue - Fibroblast

observed

[not specified] Gastrointestinal tract adenoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Gastrointestinal tract

observed

[not specified] Gastrointestinal tract adenoma Gastrointestinal tract

0

[not specified] Gastrointestinal tract carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Gastrointestinal tract

observed

[not specified] Gastrointestinal tract carcinoma Gastrointestinal tract

0

CAST/EiJ Gastrointestinal tract carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Gastrointestinal tract

observed

A/J Gastrointestinal tract carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Gastrointestinal tract

observed

C57L/J Gastrointestinal tract carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Gastrointestinal tract

observed

SM/J Gastrointestinal tract carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Gastrointestinal tract

observed

[not specified] Gastrointestinal tract tumor - epithelial
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Gastrointestinal tract

observed

[not specified] Genital tract adenoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Genital tract

observed

[not specified] Genital tract adenoma Genital tract

0

[not specified] Genital tract carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Genital tract

observed

[not specified] Genital tract carcinoma Genital tract

0

[not specified] Genital tract tumor - epithelial
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Genital tract

observed

[not specified] Intestine - Large Intestine - Colon tumor - epithelial
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Intestine - Large Intestine - Colon

observed

[not specified] Intestine - Large Intestine tumor - epithelial
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Intestine - Large Intestine

observed

[not specified] Kidney tumor - epithelial
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Kidney

observed

[not specified] Leukocyte - Lymphocyte - B-lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte - B-lymphocyte

observed

[not specified] Leukocyte - Lymphocyte - T-lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte - T-lymphocyte

observed

[not specified] Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

observed

[not specified] Leukocyte - Lymphocyte lymphoma Leukocyte - Lymphocyte

observed

AKR/J Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

15 - 100

C58/J Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

66.67 - 70

C57BL/6J Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

50

NOD/ShiLtJ Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

50

FVB/NJ Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

33.33 - 54

PL/J Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

33.33

BALB/cByJ Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

20 - 56

NZB/BlNJ Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

20

DBA/2J Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

16.67

SJL/J Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

16.67

129S1/SvImJ Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

12.5

C57L/J Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

11.11

PERA/EiJ Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

11.11

SM/J Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

10

C3H/HeJ Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

9.09

A/J Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

0

CAST/EiJ Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

0

MOLF/EiJ Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

0

SPRET/EiJ Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

0

SWR/J Leukocyte - Lymphocyte lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

0

FVB/NJ Leukocyte - Lymphocyte lymphoma Leukocyte - Lymphocyte

0

AKR/J Leukocyte - Lymphocyte lymphoma Leukocyte - Lymphocyte

34 - 50

C58/J Leukocyte - Lymphocyte lymphoma Leukocyte - Lymphocyte

0

BALB/cByJ Leukocyte - Lymphocyte lymphoma Leukocyte - Lymphocyte

0

[not specified] Leukocyte - Lymphocyte neoplasm
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Lymphocyte

observed

[not specified] Leukocyte - Monocyte - Macrophage - Histiocyte histiocytic sarcoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Monocyte - Macrophage - Histiocyte

0.58

[not specified] Leukocyte - Monocyte - Macrophage - Histiocyte histiocytic sarcoma Leukocyte - Monocyte - Macrophage - Histiocyte

observed

[not specified] Leukocyte - Myelocyte (Granulocyte) dysplasia
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

observed

[not specified] Leukocyte - Myelocyte (Granulocyte) dysplasia Leukocyte - Myelocyte (Granulocyte)

0.52

[not specified] Leukocyte - Myelocyte (Granulocyte) leukemia Leukocyte - Myelocyte (Granulocyte)

0.52

[not specified] Leukocyte - Myelocyte (Granulocyte) leukemia - acute myeloid (AML)
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

observed

[not specified] Leukocyte - Myelocyte (Granulocyte) lymphoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

observed

[not specified] Leukocyte - Myelocyte (Granulocyte) sarcoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

observed

[not specified] Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

observed

SWR/J Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

80

DBA/2J Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

50

BALB/cByJ Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

33.33

NOD/ShiLtJ Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

25

AKR/J Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

20

PL/J Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

16.67

129S1/SvImJ Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

A/J Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

C3H/HeJ Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

C57BL/6J Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

C57L/J Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

C58/J Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

CAST/EiJ Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

FVB/NJ Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

MOLF/EiJ Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

NZB/BlNJ Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

PERA/EiJ Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

SJL/J Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

SM/J Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

SPRET/EiJ Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Leukocyte - Myelocyte (Granulocyte)

0

[not specified] Liver adenoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Liver

observed

[not specified] Liver adenoma Liver

0

[not specified] Liver carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Liver

observed

[not specified] Liver carcinoma Liver

0

[not specified] Lung adenocarcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

observed

[not specified] Lung adenocarcinoma Lung

0.52

[not specified] Lung adenoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

observed

[not specified] Lung adenoma Lung

observed

SM/J Lung adenoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

observed

129S1/SvImJ Lung adenoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

observed

C3H/HeJ Lung adenoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

observed

[not specified] Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

observed

A/J Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

75 - 86

PERA/EiJ Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

66.67 - 85.5

SWR/J Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

60

FVB/NJ Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

33 - 100

BALB/cByJ Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

20

DBA/2J Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

16.67

MOLF/EiJ Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

14.29

NOD/ShiLtJ Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

12.5

129S1/SvImJ Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

12.5

SPRET/EiJ Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

9.09

SJL/J Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

0

PL/J Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

0

NZB/BlNJ Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

0

CAST/EiJ Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

0

C58/J Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

0

C57L/J Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

0

C57BL/6J Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

0

C3H/HeJ Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

0

AKR/J Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

0

SM/J Lung carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

0

FVB/NJ Lung carcinoma Lung

0

A/J Lung carcinoma Lung

0

PERA/EiJ Lung carcinoma Lung

0

[not specified] Lung carcinoma - acinar
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

observed

[not specified] Lung tumor - benign
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

observed

[not specified] Lung tumor - benign Lung

observed

[not specified] Lung tumor - malignant
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lung

observed

[not specified] Lung tumor - malignant Lung

observed

[not specified] Mammary gland carcinoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Mammary gland

0.58

[not specified] Mammary gland carcinoma Mammary gland

0

[not specified] Mesodermal cell/mesoblast sarcoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Lymph node

observed

[not specified] Mesodermal cell/mesoblast sarcoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Mediastinum

observed

[not specified] Mesodermal cell/mesoblast sarcoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Mesodermal cell/mesoblast

observed

[not specified] Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed

[not specified] Muscle - Striated - Skeletal rhabdomyosarcoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Muscle - Striated - Skeletal

0.58

[not specified] Ovary tumor - epithelial
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Ovary

observed

[not specified] PNS - Schwann cell schwannoma
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
PNS - Schwann cell

0.58

[not specified] Stomach tumor - epithelial
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Stomach

observed

[not specified] Uterus tumor - epithelial
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
Uterus

observed

[not specified] (Unspecified organ) tumor
  • N-ethyl-N-nitrosourea (N-nitrosoethylurea) (ENU)
(Unspecified organ)

observed

[not specified] (Unspecified organ) tumor (Unspecified organ)

observed