Global blood gene expression profiles following a breast cancer diagnosis-Clinical follow-up in the NOWAC post-genome cohort.

OBJECTIVE: This explorative study aimed to assess if there are any time-dependent blood gene expression changes during the first one to eight years after breast cancer diagnosis, which can be linked to the clinical outcome of the disease. MATERIAL AND METHODS: A random distribution of follow-up time from breast cancer diagnosis till blood sampling was obtained by a nested, matched case-control design in the Norwegian Women and Cancer Post-genome Cohort. From 2002-5, women were invited to donate blood samples, regardless of any cancer diagnosis. At end of the study period in 2015, any cancer diagnoses in the 50 000 participants were obtained via linkage to the Norwegian Cancer Registry. For each breast cancer patient (n = 415), an age- and storage time-matched control was drawn. The design gave a uniform, random length of follow-up time, independent of cancer stage. Differences in blood gene expression between breast cancer cases and controls were identified using the Bioconductor R-package limma, using a moving window in time, to handle the varying time elapsed from diagnosis to blood sample. RESULTS: The number of differentially expressed genes between cases and controls were close to 2,000 in the first year after diagnosis, but fell sharply the second year. During the next years, a transient second increase was observed, but only in women with metastatic disease who later died, both compared to invasive cases that survived (p<0,001) and to metastatic cases that survived (p = 0.024). Among the differentially expressed genes there was an overrepresentation of heme metabolism and T cell-related processes. CONCLUSION: This explorative analysis identified changing trajectories in the years after diagnosis, depending on clinical stage. Hypothetically, this could represent the escape of the metastatic cancer from the immune system.

Rethinking the carcinogenesis of breast cancer: The theory of breast cancer as a child deficiency disease or a pseudo semi-allograft.

The theory of breast cancer as a child deficiency disease is an inversion of the current paradigm, which considers full-term pregnancies to be a protective factor and uses nulliparous women as the reference group. Instead, the theory of breast cancer as a child deficiency disease says that women with the highest parity (about 20, which is the limit of human fertility) are those with the lowest risk and should be used as the reference group in risk estimations. This theory is explained biologically by converting parity from the simple value of number of children into an understanding of the long-lasting biological and immunological effects of pregnancy. These effects can be reflected, as measured by functional genomics, in gene expression of the immune cells in the blood. Each pregnancy represents a unique fetus or semi-allograft, which provokes the creation and deposit of memory cell clones in the mother. Gene expression levels have been found to change linearly with number of full-term pregnancies in healthy women, but not in breast cancer patients. High hormone levels are necessary for a successful pregnancy, as they modulate the immune response from adaptive to innate in order to protect the fetus (considered as a semi-allograft) from rejection. At the end of the pregnancy, hormone levels drop, and the immune system recognizes the semi-allograft, but not in time for rejection to occur before birth. High hormones levels are also classified as carcinogens illustrating that carcinogenesis in the breast could be viewed as a war or balance between later exposures to hormonal carcinogens and the protection of the immune system. We propose that breast tumors are pseudo semi-allografts made up of transformed breast tissue cells. Assuming that the sensitivity to the exposure to increased levels of endogenous or exogenous hormones in women with breast cancer mimic those that occur in pregnancy, these breast tumor cells are protected against the body's immune reaction, just as the fetus is during pregnancy. However, with more pregnancies, the potential to eradicate the pseudo semi-allograft might increase due to enhanced immune surveillance. The theory of breast cancer as a child deficiency disease proposes that the protective effect of pregnancy on breast cancer incidence via the immune system is independent of other risk factors.

Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer.

Lung cancer is the leading cause of cancer deaths. Novel predictive biomarkers are needed to improve treatment selection and more accurate prognostication. PAX6 is a transcription factor with a proposed tumour suppressor function. Immunohistochemical staining was performed on tissue microarrays from 335 non-small cell lung cancer (NSCLC) patients for PAX6. Multivariate analyses of clinico-pathological variables and disease-specific survival (DSS) was carried out, and phenotypic changes of two NSCLC cell lines with knockdown of PAX6 were characterized. While PAX6 expression was only associated with a trend of better disease-specific survival (DSS) (p = 0.10), the pN+ subgroup (N = 103) showed significant correlation between high PAX6 expression and longer DSS (p = 0.022). Median survival for pN + patients with high PAX6 expression was 127.4 months, versus 22.9 months for patients with low PAX6 expression. In NCI-H661 cells, knockdown of PAX6 strongly activated serum-stimulated migration. In NCI-H460 cells, PAX6 knockdown activated anchorage-independent growth. We did not observe any significant effect of PAX6 on proliferation in either of cell lines. Our findings strongly support the proposition of PAX6 as a valid and positive prognostic marker in NSCLC in node-positive patients. There is a need for further studies, which should provide mechanistical explanation for the role of PAX6 in NSCLC.