RGD Reference Report - Multiple susceptibility loci for radiation-induced mammary tumorigenesis in F2-intercross rats. - Rat Genome Database

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Multiple susceptibility loci for radiation-induced mammary tumorigenesis in F2-intercross rats.

Authors: Herrera, VL  Ponce, LR  Ruiz-Opazo, N 
Citation: Herrera VL, etal., PLoS One. 2013;8(8):e72143. doi: 10.1371/journal.pone.0072143. eCollection 2013.
RGD ID: 7794780
Pubmed: PMID:23967281   (View Abstract at PubMed)
PMCID: PMC3743793   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0072143   (Journal Full-text)

Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity of human populations. As with other complex diseases, dissection of genetic determinants in animal models provides key insight since genetic heterogeneity and environmental factors can be experimentally controlled, thus facilitating the detection of quantitative trait loci (QTL). We therefore, performed the first genome-wide scan for loci contributing to radiation-induced mammary tumorigenesis in female F2-(Dahl S x R)-intercross rats. Tumorigenesis was measured as tumor burden index (TBI) after induction of rat mammary tumors at forty days of age via (1)(2)(7)Cs-radiation. We observed a spectrum of tumor latency, size-progression, and pathology from poorly differentiated ductal adenocarcinoma to fibroadenoma, indicating major effects of gene-environment interactions. We identified two mammary tumorigenesis susceptibility quantitative trait loci (Mts-QTLs) with significant linkage: Mts-1 on chromosome-9 (LOD-2.98) and Mts-2 on chromosome-1 (LOD-2.61), as well as two Mts-QTLs with suggestive linkage: Mts-3 on chromosome-5 (LOD-1.93) and Mts-4 on chromosome-18 (LOD-1.54). Interestingly, Chr9-Mts-1, Chr5-Mts-3 and Chr18-Mts-4 QTLs are unique to irradiation-induced mammary tumorigenesis, while Chr1-Mts-2 QTL overlaps with a mammary cancer susceptibility QTL (Mcs 3) reported for 7,12-dimethylbenz-[alpha]antracene (DMBA)-induced mammary tumorigenesis in F2[COP x Wistar-Furth]-intercross rats. Altogether, our results suggest at least three distinct susceptibility QTLs for irradiation-induced mammary tumorigenesis not detected in genetic studies of chemically-induced and hormone-induced mammary tumorigenesis. While more study is needed to identify the specific Mts-gene variants, elucidation of specific variant(s) could establish causal gene pathways involved in mammary tumorigenesis in humans, and hence novel pathways for therapy.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Mcs31RatExperimental Mammary Neoplasms  IAGP  RGD 
Mcs32RatExperimental Mammary Neoplasms  IAGP  RGD 
Mcs33RatExperimental Mammary Neoplasms  IAGP  RGD 
Mcs34RatExperimental Mammary Neoplasms  IAGP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Mcs31Ratincreased mammary gland tumor incidence  IDA  RGD 
Mcs32Ratincreased mammary gland tumor incidence  IDA  RGD 
Mcs33Ratincreased mammary gland tumor incidence  IDA  RGD 
Mcs34Ratincreased mammary gland tumor incidence  IDA  RGD 
Objects Annotated

Mcs31  (Mammary carcinoma susceptibility QTL 31)
Mcs32  (Mammary carcinoma susceptibility QTL 32)
Mcs33  (Mammary carcinoma susceptibility QTL 33)
Mcs34  (Mammary carcinoma susceptibility QTL 34)

SR/JrHsd  (Dahl Salt-Resistant)
SS/JrHsd  (Dahl Salt-Sensitive)

Additional Information