Eldon J. Gardner

Genetic Analysis of an Inherited Predisposition to Colon Cancer in a Family with a Variable Number of Adenomatous Polyps

We studied a large kindred with a history of colorectal cancer of early onset. Proctosigmoidoscopic examination of 51 family members identified only 2 with familial polyposis coli, which strongly predisposes those who have it to colorectal cancer and which is defined as the presence of more than 100 polyps in the colon. However, eight family members had 2 to 40 colonic polyps. We suspected that in this family, colorectal cancer was the result of a mutation in the gene on chromosome 5 that is responsible for familial polyposis coli. To test our hypothesis, we obtained genotypic information on 81 family members with respect to seven polymorphic DNA markers previously shown to be linked to the locus for familial polyposis coli. Multilocus analysis of the data demonstrated genetic linkage (lod score, 5.58) between these markers and the locus responsible for the defined syndrome of colonic polyps or colorectal cancer in this kindred. These findings constitute evidence that the genetic defect in this family is a mutation in the gene that causes familial polyposis coli. We conclude that mutations at the genetic locus for familial polyposis coli may be the cause of other, more subtle syndromes involving an inherited susceptibility to colonic adenomatous polyps and colorectal cancer.

Numerical and structural chromosome aberrations in cultured lymphocytes and cutaneous fibroblasts of patients with multiple adenomas of the colorectum

Excessive random loss and gain of single chromosomes at the diploid and tetraploid levels, and numerous chromosomal aberrations, have been observed in lymphocytes and fibroblasts, cultured from Gardner syndrome and familial polyposis coli patients and children at risk for multiple adenomas. This increase in numerical and structural aberrations seems to represent a general instability of chromosomes in the lymphocyte and fibroblast nuclei of patients with multiple adenomas in the colorectum. A consistent heteromorphism of chromosome No. 2 homologues tentatively identified as a deletion was observed in all 17 patients with multiple adenomas in the colorectum, and two younger people of 13 and six years of age who are at risk for Gardner syndrome but do not have colorectal polyps. The chromosome No. 2 aberration was not observed in two symptomatic patients with occasional discrete colorectal adenomas. Eighteen controls who did not have Gardner syndrome nor familial polyposis coli did not show the structural aberration in chromosome No. 2 nor chromosome instability.

Spontaneous mesenteric fibromatosis in Gardner's syndrome

Mesenteric fibromatosis has been reported in frequent association with familial polyposis and with Gardners syndrome. This vague “benign” process has been characterized as a postsurgical phenomenon with low morbidity. Two cases of spontaneous mesenteric fibromatosis, noted at the time of original laparotomy for colectomy in Gardners syndrome patients, are reported. No history of abdominal trauma was present, and both have well‐documented Gardners findings. A 32% incidence of desmoid reaction is reported among affected members of the original Gardners syndrome Kindred 109; five or 55% of these patients had the mesenteric form of the process. The potential fatal course of the mesenteric disease is emphasized.

Villous Adenoma of the Duodenal Papilla Presenting as Necrotizing Pancreatitis in a Patient With Gardner's Syndrome

The majority of patients with Gardners syndrome and familial polyposis coli develop duodenal adenomatous polyps. Duodenal cancer sometimes arises in this setting, but nonmalignant problems from duodenal polyps have not been described. This report presents a patient with Gardners syndrome who developed hemorrhagic pancreatitis and was found to have a villous adenoma encasing the pancreatic duct at the duodenal papilla. The case is important because it suggests that patients with polyposis coli may be at risk for significant nonmalignant problems from duodenal polyps, particularly if polyps exhibit villous histology and occur at the duodenal papilla.

Evaluation of chromosomal diagnosis for hereditary adenomatosis of the colorectum

Hereditary adenomatosis, particularly familial polyposis coli (FPC) and Gardners syndrome (GS), has been investigated from family pedigrees and chromosomal markers for precancer and cancer. FPC and GS are much alike in phenotypes. Studies are in progress to determine if the two adenomatous diseases are controlled by the same DNA sequence. Chromosome numerical and structural instability is a good diagnostic criterion for hereditary adenomatous diseases where risk factors are already determined to the level of 0.5 probability from pedigree analysis. This has been applied successfully at the pediatric age level to identify family members who carry the gene but have no adenomas in the colorectum. Sister chromatid exchange (SCE) did not distinguish plasma samples from FPC, GS, or solitary adenoma patients form each other or from controls with no adenomas. SCE did distinguish invasive from recurrent and noninvasive cancer. The chromosome #2 polymorphism observed at 2q-21.3 has not been confirmed as a deletion, but is under investigation with more refined methods.

Failure to demonstrate a chromosome 2 deletion in adenomatous colorectal polyposis patients

A group of researchers recently reported a specific chromosome abnormality consisting of a deletion in the long arm (q) of chromosome 2 in patients with adenomatous colorectal polyposis. Using a high resolution chromosome banding technique and a blind study design, the authors karyotyped two patients with Gardner syndrome, two patients with familial polyposis, and four normal controls. No deletion was found in chromosome 2.

The use of a tumor promoter for the detection of individuals with the gardner syndrome

The effects of the tumor promoter 12‐O‐tetradecnoyl phorbol‐13‐acetate (TPA) on the proliferation out of cultured skin fibroblasts (SF) obtained from 21 individuals representing a single pedigree of the Gardner variant of hereditary adenomatosis of the colon and rectum (ACR) were analyzed. SF from both gene‐carriers and normal individuals displayed an unusual biphasic dose‐response (concaved upward), but the latter were considerably more sensitive to the toxic effects of this probe at all concentrations tested. Based on the differential sensitivity to TPA (range, 0–100 ng/ml),1,2 a good correlation has been found in this study between the results, the pedigree analysis, and the clinical findings. Of 21 individuals examined, two were apparently false‐negatives. Two other individuals who are currently listed as clinically asymptomatic and, who through pedigree analysis might presumably be disease‐free, appeared strongly positive by the criteria. The results extend the previous observations that the measurement of cloning efficiency in the presence of a TPA probe provides a reliable assay to distinguish SF of colorectal cancer‐prone persons from those of normal subjects within a single pedigree of the Gardner syndrome.

Tumorous Head in Drosophila

Publisher Summary Four different maternal effects have been discussed in this chapter, which are associated with the tumorous-head genetic system in drosophila melanogaster. A third chromosome semidominant gene (tu-3) is basic to the entire system. In the presence of the tu-3, the maternal effect associated with the manifestation of abnormal growths in the head region is controlled by a sex-linked, recessive gene tu-1. It discusses that fertility is influenced by a maternal effect and the viability of one chromosome type also responds to a maternal effect. In addition to tu-3 and tu-1 alleles, modifiers, particularly those in the second chromosome influence the maternal effects. Reduced productivity of homokaryotype females is a function of reduced fecundity, fertility, and longevity. The chapter also explores that, in developmental studies, larvae is examined at different stages, which indicates that the head abnormality was present in structures arising from the eye-antenna1 disc during late third instar. Morphological changes, observable microscopically at this time, were presumed to reflect physiological changes that had occurred during the temperature-sensitive period in the early stages of larval development. Autonomy of the genetic determination through the developmental period was demonstrated by ovary transplantation.

The compound eye in the opaque-eye phenotype ofDrosophila melanogaster

The compound eye of the opaque-eye mutant of Drosophila melanogaster was investigated by means of electron microscopy to determine the morphological and physical properties of ommatidial elements. These elements in the mutant were found to differ from those of the wild-type flies in the following ways: (1) The cuticular lens was thinner than that of the control and lacked the typical lamellar construction. (2) The Semper cells were irregular in shape and contained many membranous inclusions similar to those found in degenerating cells; also their nuclei contained virus-like particles. (3) The primary pigment cells contained an abundance of drosopterin-containing granules which were lacking in those of wild-type flies. (4) The superior and inferior central photoreceptor cells were misplaced and their rhabdomeres evidenced some degeneration. (5) The secondary pigment cells had only one type of pigment granules instead of the three types found in the control. These morphological changes in ommatidial elements induced physical abnormalities such as the apparent opaqueness of the eye, the lack of a pseudopupil, the probable disability of the photoreceptor cells to respond to light and the inability of the dioptric system to produce utilizable geometric images.

Structure of cephalic abnormalities in Drosophila melanogaster (Diptera: Drosophilidae)☆

Abstract Scanning and transmission electron microscopy were utilized in studying the cephalic abnormalities of the tu-h strain of Drosophila melanogaster . Abnormalities, appearing as protuberances (growths) of different shapes and sizes, were observed only on or in close proximity to receptor cites. Compound eyes of some flies, besides having such protuberances, either had modified corneal lenses or were absent altogether. Cuticles of the growths were thinner than that of the normal surrounding layer. The epidermal cells associated with setae on the growths or underlying modified corneal lenses remained undifferntiated. Both setae and growths lacked innervation. The receptor portions (retinular sensory cells and secondary pigment cells) of the abnormal compound eye, where the dioptric portions were replaced by protuberances or remained undifferentiated, were unaffected by the mutation. Nuclei of several cells, including oenocytes and fat bodies, close to or underlying epidermal cells of abnormalities, were large and contained compact nucleoli without nucleonemas. Viruslike particles were observed in several nuclei of growth cells. It was concluded from the present study that the alterations induced by the mutation can be only a localized phenomenon restricted to at least several cephalic epidermal cells and/or their derivatives.