PMS2 mutation spectra in Norway and risk of cancer for carriers of pathogenic variants.

Background: In Norway, we have offered testing of PMS2 since 2006, and have a large national cohort of carriers. The aim of this study was to describe all PMS2 variants identified, and to describe frequency, spectrum and penetrance of cancers in carriers of class 4/5 variants.

Methods: All detected PMS2 variants were collected from the diagnostic laboratories and reclassified according to ACMG criteria and gene specific guidelines.

Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers.

Background: Reported prevalence, penetrance and expression of deleterious mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, may reflect differences in the clinical criteria used to select families for DNA testing. The authors have previously reported that clinical criteria are not sensitive enough to identify MMR mutation carriers among incident colorectal cancer cases.

Objective: To describe the sensitivity of the criteria when applied to families with a demonstrated MMR mutation.

Identification of Friend murine retrovirus-infected immune cells and studies of the effects of sex and steroid hormones in the early phase of infection.

Male mice are more susceptible than female mice to the murine retrovirus FIS-2. We previously reported that sex-related factors influence early virus replication via mechanisms involving a glucocorticoid response element (GRE) in the long terminal repeat (LTR) enhancer region. In the present study, we investigated further the influence of sex and steroid hormones on early murine retrovirus dissemination and immune functions.

A glucocorticoid response element in the LTR U3 region of Friend murine leukaemia virus variant FIS-2 enhances virus production in vitro and is a major determinant for sex differences in susceptibility to FIS-2 infection in vivo.

The nucleotide sequence of the Friend murine leukaemia virus variant FIS-2 LTR has high identity with the closely related Friend murine leukaemia virus (F-MuLV) LTR, except for the deletion of one direct repeat, a few point mutations and the generation of a glucocorticoid response element (GRE) in the U3 region. The GRE can mediate gene induction by glucocorticoids, mineral corticoids, progesterone and androgens, and it has been shown that incorporation of a GRE(s) within the LTR can increase the transcriptional activity of retroviral enhancers. We have previously reported an increased early virus replication in male mice compared with female mice when infected with a virus containing the FIS-2 LTR and have proposed that the GRE might contribute to this sex difference.

Early dissemination rates of Friend murine leukaemia virus variants correlate with late pathogenesis.

FIS-2, a less oncogenic, immunosuppressive variant of the Friend murine leukaemia virus (F-MuLV), was used to explore whether the differences in biological features were related to early virus dissemination rates or sites of replication. We found that erythroblasts were the primary target cells for both F-MuLV and FIS-2, while B- and T-cells were infected later in the infection. Although FIS-2 replicated to similar titres as F-MuLV, we observed a delay in peak viraemia titre and in the number of virus-positive cells in bone marrow and spleen.

Gender-related differences in susceptibility, early virus dissemination and immunosuppression in mice infected with Friend murine leukaemia virus variant FIS-2.

An emerging amount of data indicates a correlation between gender-related factors and regulation of virus infection and supports what is known in clinical circles, that these topics are of great importance in many infectious diseases. In the present study we found that young adult NMRI male mice are more susceptible to infection by a variant of Friend murine leukaemia virus, FIS-2, than are female mice. We observed that the level of virus in serum, bone marrow and spleen was initially higher in male mice.