A major histocompatibility complex-linked locus in the rat critically influences resistance to diethylnitrosamine carcinogenesis.

Abstract

Major histocompatibility complex (MHC)-linked deletions in the rat are associated with defects in growth and development and increased susceptibility to chemical carcinogens. The present study maps a locus critical for determining susceptibility to diethylnitroamine (DEN) carcinogenesis by using two groups ofMHC-recombinant rats congenic for the MHC and its linked region. Resistance to DEN segregates with a locus (rec+) that maps between RTL.E and ft, and its homozygous loss markedly increases susceptibility to DEN. Non-MHC genes do not significantly influence the susceptibility of these strains to DEN. The existence of the rec locus adds support to our hypothesis that some genes in the MHC-linked region play a major role in both normal and abnormal growth.The role of hereditary factors in the susceptibility to cancer was first proposed in 1866 by Brocca (1), who documented the general susceptibility to cancer in his family. Similar observations have been made periodically since then (2), and recently they have been documented by detailed epidemiological studies (3,4). A variety of human malignancies have been associated with genes of the major histocompatibility complex (MHC) (5), and some of these malignancies have been associated with deletions in chromosome 6, which carries the MHC, either exclusively (6, 7) or in association with other deletions (5). At the molecular level, deletion of tumor-suppressor genes and activation of oncogenes have been demonstrated in humans and in experimental animals (8, 9).We have developed the hypothesis that MHC-linked genes, or genetic defects, influence reproduction, development, and susceptibility to chemical carcinogens (10, 11) on the basis of experimental work in rats (12)(13)(14) and clinical studies in humans (15)(16)(17). Deletions in the MHC-linked region derived from the BIL/1 strain (grc-) ( Fig. 1) exposure to dimethylbenzanthracene, whereas the ACP strain does not. There is no evidence for an immune defect in the grc rats as a basis for their tumor susceptibility because they can make normal antibody responses to synthetic polypeptide antigens and to skin grafts and display normal firstand second-set rejection of allogeneic skin grafts (33-35).The present study was undertaken to map the critical MHC-linked locus affecting susceptibility to DEN carcinogenesis and to rule out a significant effect on susceptibility of non-MHC genes by using two sets ofinbred and recombinant rats congenic for the MHC plus the MHC-linked region or for the MHC-linked region alone. MATERIALS AND METHODSCongenic Strains. The pedigrees of the strains are shown in Fig. 1 1967The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Physical Map and Expression Profile of Genes of the Telomeric Class I Gene Region of the Rat MHC

“…An example is the Ppp1r10 gene (alias designations Fb19 and Pnuts) that has been detected because of its expression in pancreatic cancer (53). In this context it is noteworthy that the Grc controls susceptibility to diethylnitrosamine-induced hepatocellular carcinomas (36). Unexpectedly, the Grc, as far as defined by the grc1.4 probe (37), maps into the second class I subregion without including known framework genes.…”

Phenotypic reversion of rat neoplastic liver nodules is under genetic control

“…13 A putative suppressor gene (rccϩ), mapping to chromosome 12p, critical for determining the sensitivity of rats to diethylnitrosamine-induced liver carcinogenesis, has been identified in MHC-recombinant rat ACP strains, congenic for the MHC-linked growth reproduction complex (grc) region. 14 Clonal expansion of initiated cells in rat liver carcinogenesis is characterized by the progressive development of foci of preneoplastic hepatocytes and neoplastic nodules exhibiting fast growth and a number of morphologic, biochemical and molecular commonalties with preneoplastic and neoplastic human liver lesions. 4,15,16 Most early preneoplastic and neoplastic liver lesions undergo progressive decreases in biochemical marker expression and growth rate and finally regress (remodeling, phenotypic reversion [17][18][19][20][21][22] ).…”

Mapping of the TNFA locus in the rat

“…The TNFA locus is pivotal for mapping the class III region of the rat major histocompatibility complex (MHC), and, depending upon its location, it could also be a useful starting point for chromosome walking of the RT1.E-grc region, which contains loci affecting resistance to chemical carcinogens (rcc), fertility Oct), and growth (dw-3; Melhem et al 1993). The rat TNFA molecule was obtained from a polymerase chain reaction reaction using genomic DNA of the DA.1H strain and mouse TNFA primers (MAPPing Amplimers for mouse TNFA; Clontech, Palo Alto, CA).…”

“…Digestion with Hin cII of DNA from BIL/2 and ACP, from R22 and DA.R22V1, and from R33 and R34 place TNFA on either side of RT1.E ,. Analysis of the Hin cII-digested DNA from the congenic recombinant strains R34 and R16 (Melhem et al 1993) indicates that TNFA maps between RT1.D and RT1.E because they have the same RFLP pattern. Digestion of DNA from DA.…”