Comparative mapping of Xp22 genes in hominoids--evolutionary linear instability of their Y homologues.

Several genes located within or proximal to the human PAR in Xp22 have homologues on the Y chromosome and escape, or partly escape, inactivation. To study the evolution of Xp22 genes and their Y homologues, we applied multicolour fluorescence in situ hybridization (FISH) to comparatively map DNA probes for the genes ANT3, XG, ARSD, ARSE (CDPX), PRK, STS, KAL and AMEL to prometaphase chromosomes of the human species and hominoid apes. We demonstrate that the genes residing proximal to the PAR have a highly conserved order on the higher primate X chromosomes but show considerable rearrangements on the Y chromosomes of hominoids.

Rapid detection of rare variants and common polymorphisms in the APC gene by PCR-SSCP for presymptomatic diagnosis and showing allele loss.

During the course of screening the 5' half of exon 15 of the APC gene for germline and somatic mutations in two groups of patients, those with the inherited cancer prone syndrome adenomatous polyposis coli (APC) or with sporadic colorectal cancer, we have identified a number of intragenic changes that are not associated with the disease phenotype. Four of these changes are rare variants, each confined to one or two families and not detected in 50 additional unrelated people. Two common polymorphisms, at codon 1493 (exon 15I) and codon 1678 (exon 15J), were extensively investigated and found to be in almost complete linkage disequilibrium not only with each other but with a previously described polymorphism at codon 1960 (exon 15N).

Haplotype comparison in fresh mutation cases of adenomatous polyposis coli due to deletion AAAGA at codon 1309.

To determine whether the common 5 base pair deletion (delta AAAGA) at codon 1309 of the APC gene occurs preferentially on a particular haplotype background, three intragenic polymorphisms were typed using the polymerase chain reaction in ten patients with this deletion as the disease-causing mutation. Each case was due to fresh mutation. The data obtained provide no evidence in support of a preferential haplotype predisposing to this mutation.

Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli.

Germline mutation in APC at 5q21-22 results in the dominantly inherited syndrome adenomatous polyposis coli (APC). Somatic mutation in this gene is an early event in colorectal tumourigenesis. Both types of mutation are concentrated in the 5' half of exon 15.

Linkage analysis in adenomatous polyposis coli: the use of four closely linked DNA probes in 20 UK families.

Linkage analysis was carried out on 20 unselected UK families segregating for adenomatous polyposis coli (APC) using four closely linked DNA probes. Significant lod scores were obtained between APC and three markers: pi 227 (D5S37) theta = 0.16; C11p11 (D5S71) theta = 0.

The UK Northern region genetic register for familial adenomatous polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk calculations.

A polyposis register has been established in the Northern Region of England. A total of 48 families with 71 living affected subjects has been identified during the first three years of operation, a prevalence of 2.29 x 10(-5).

Chromosome breakage in lymphocytes from members of cancer families showing autosomal dominant inheritance.

We have conducted investigations on members of three families with increased predisposition to cancer which appears to be inherited as an autosomal dominant trait. The aim of our studies overall is to provide markers for the mutant genes involved, so that gene carriers may be monitored closely for signs of malignant disease. This paper reports on studies of chromosome breakage in lymphocytes from affected and at-risk family members and control subjects.

Spontaneous and induced chromosome damage in lymphocytes of medullary thyroid carcinoma patients and their family members.

Detailed chromosome analysis failed to reveal any evidence for spontaneous chromosome instability in lymphocytes from patients with multiple endocrine neoplasia, type 2 (MEN-2), whereas, with one exception, lymphocytes from MEN-2 patients were significantly more sensitive to chromosome damage by bleomycin and, to a lesser extent, MNNG than those from controls. The exceptional case suggests possible genetic heterogeneity in MEN-2.