Ma Caligo

Down-regulation of the nm23.h1 gene inhibits cell proliferation

nm23 gene expression is strictly related to the state of cell growth. The level of its expression parallels the fraction of thymidine‐incorporating cells (S‐phase cells) in neoplastic mammary tissues and in the synchronously cycling fraction of MCF10A cells. nm23.h1 reaches a peak of expression in the S‐phase, and is present at very low level during the G0/G1 phase. Two strategies are used to demonstrate the direct involvement of the nm23.h1 gene in the process of cell proliferation. The first consists of transient inhibition of nm23.h1 expression by using anti‐sense oligonucleotide treatment; weak inhibitory effect on cell proliferation is observed. The second strategy involves the stable inhibition of nm23.h1 expression by transfection of MCF10A cells with a plasmid vector expressing the human nm23.h1 anti‐sense mRNA. The anti‐sense‐transfected cells show consistently slower proliferative activity than the control. Int. J. Cancer 73:297–302, 1997.

A low NM23.H1 gene expression identifying high malignancy human melanomas.

The NM23 gene has been proposed as a metastasis-suppressor gene, and its use has been suggested as prognostic factor. NM23 was identified in a system of murine melanoma cell lines, in which an inverse relationship was found between NM23 expression and metastatic ability. In a human malignant melanoma study NM23 expression was found to be significantly lower in metastases that developed less than 24 months after diagnosis of the primary tumours. The present paper studies the expression of the NM23.H1 gene in cell lines which derive from primary or metastatic human malignant melanomas in relation to staging, infiltration degree, lymphocytic infiltration, cell morphology, cell pigmentation, karyotype, and disease-free survival. The level of mRNA expression of the NM23 gene is significantly lower in cell lines that derive from more infiltrating primary melanomas than in cell lines obtained from less infiltrating tumours. Moreover, cell lines derived from tumours of patients with a disease-free survival of more than 24 months (24-58 months) express the NM23 gene at higher levels than cell lines obtained from melanomas of patients with a disease-free survival of less than 24 months (6-15 months)

Reconstructing the Genealogy of a BRCA1 Founder Mutation by Phylogenetic Analysis

Estimating the age of founder mutations may contribute to improve our knowledge of population genetics and evolutionary history of diseases. Previous haplotype analysis suggested that the BRCA1*1499insA mutation was a founder allele, probably originated in Tuscany (Italy). Here, we collected additional pedigrees carrying this mutation, and applied a phylogenetic method for estimating mutation age. A chromosome segment of about 25 cM, including 37 short tandem repeats (STRs) on both sides of the BRCA1 gene (DeCode map), was typed in 50 subjects (28 mutation carriers) from 14 unrelated families. The time to the most recent common ancestor (MRCA) of the mutation carriers was estimated by the length of the shared haplotype between all possible pairs of individuals. A function relating the length of the shared haplotype to the time to the MRCA was obtained by a computer simulation. This approach gives results comparable with those of other existing mutation‐dating methods, but does not depend explicitly on population‐specific parameters such as allele frequencies, provides narrower confidence intervals (CI), and allows one to build an extended genealogical tree of all mutation carriers. The 1499insA mutation shared by the investigated subjects was estimated to be present in an individual living about 30 generations ago (95% CL 22‐56), or 750 years (95% CL 550‐1,400).