Ethical issues in genetic screening for cancer

Genetically-based diseases with a late onset, such as BRCA1-dependent breast cancer or Huntington's disease, can be predicted by the screening of relevant mutations in members of high-risk families. Genetic screening is characterized by a conflict between respect for autonomy – e.g., the right not to know – and responsibility toward future generations (the duty to know for the sake of one's descendants). Other ethical conflicts are related to uncertainty as to benefits deriving from screening for mutations, since for most conditions no clearly effective therapeutical strategy has as yet been defined. In addition to monogenic high-penetrance conditions, polygenic low-penetrance susceptibility is attracting increasing attention, in particular with respect to environmental-genetic interactions (metabolic polymorphisms). A simple approach to genetic screening would be to weigh the benefits and costs of genetic screening against those of primary prevention, and a superficial conclusion might be that genetic screening is less expensive and, overall, more practicable than restriction of toxic exposures or other known risk factors for the disease. Economic advantage notwithstanding, however, giving precedence to screening over primary prevention would be unacceptable. A serious hazard of genetic screening is the implicit limitation of research efforts aimed at primary prevention, and a serious drawback is its potential application for selection of non-susceptible employees. The principle of equity is easily violated by genetic screening of workers in view of the fact that genetically-based metabolic polymorphisms are distributed unevenly among different ethnic groups.     

Oligogenic determination of morphine analgesic magnitude: A genetic analysis of selectively bred mouse lines

Two ongoing selective breeding projects have produced mice that display divergent analgesic responses to morphine. These two projects have selected for similar phenotypes: high and low levorphanol analgesia (HAR/LAR lines; Portland, OR) and high and low swim stress-induced analgesia (HA/LA lines; Jastrzebiec, Poland). Evidence suggests genetic commonalities between mice of the two projects. Using a Mendelian breeding protocol, we have recently found that one or two genetic loci predominantly determine the high morphine analgesia exhibited by HA mice. In the present study we demonstrate that the differential morphine analgesia (5 mg/kg. i.p.) displayed by HAR and LAR mice is similarly oligogenic, predominantly determined by two unlinked loci. A complementation analysis, in which the analgesic responses to morphine of the recessive homozygotes of each project (HAR and HA) were compared to those of their hybrid offspring (HAR x HA), revealed that different genetic loci have been fixed in each project. An intriguing bimodal distribution was observed in the HAR x HA population: Some HAR x HA hybrids displayed greater morphine analgesia than either HAR or HA mice, whereas others displayed minimal analgesia. LAR x LA hybrids displayed less analgesia than either LAR or LA mice. The analgesic responses of HAR x LA and LAR x HA mice were comparable to those of their low-line parents. These findings indicate not only that different loci were responsible for producing high morphine responders in each selection project but that these distinct loci can interact synergistically to produce superhigh and superlow responders.     

Effect of adeno-tonsilectomy on hearing threshold and middle ear pressure

Out of 50 children (100 ears) undergoing adeno-tonsillectomy, 34 ears had hearing threshold 20–50 dB (20dB is normal) and 32 ears showed negative middle ear pressure of 100 to 400 mmH₂O (100 mmH₂O is normal). Post-operatively only 7 ears had hearing threshold of 20–30 dB and negative middle ear pressure of 100 to 200 mmH₂O. Thus adenoidectomy improves eustachian tube functions.     

Genetic evolution of breast cancers III: Age-dependent variations in the correlations between biological indicators of prognosis

The influence of age on the occurrence of phenotypic features of prognostic significance was studied in relation to the DNA index values, measured on DNA histograms from a series of 1019 breast cancer patients. Globally, the distributions of all parameters showed variations with age, the most prominent being the decreases in the percentage of estrogen receptor-negative and high proliferative activity cases with increasing age. When analyzed according to the DNA index classes, all parameters were found to some extent linked with the stage of genetic evolution. However, the associations varied with age, defining two extreme groups. The younger patients (less than 40 years) presented a more complete acquisition of the aggressive phenotype and near-triploid tumors from this group were very frequently steroid hormone receptor-negative, high proliferation, and grade III. By contrast, near-triploid tumors in patients above 65 presented relatively frequently as receptor-positive, low proliferative activity, and even grade I. The correlation of the proliferative status with steroid hormone receptor content led to similar conclusions, high proliferation being more strongly correlated with the absence of estrogen and progesterone receptors in younger patients. Interestingly, the association between high proliferation and negative progesterone receptors was much weaker in patients above 55. Our results suggest that the currently established biological prognostic factors, including DNA profile, steroid hormone receptors, and histopathological grade, show patterns of association which vary with age. Of these, only progesterone receptor could be influenced by menopausal status. These findings have to be taken into consideration for future prognostic factor-related treatment decisions, but also for future methodological improvements of multivariate survival analyses.     

Homosexuality,type 1: An Xq28 phenomenon

Despite the absence of phenotypic manifestations in alternating generations characteristic of X-linked disorders, a thesis is presented that a major type of Kinsey grades 5 and 6 male homosexuality is determined by a gene in the Xq28 region. A total of 133 families in 78 kinships of male and female homosexual probands, in addition to 116 families (including those of 40 famous homosexuals) from the literature, revealed an unbalanced secondary sex ratio in the maternal generation of male, but not of female, homosexuals. On the maternal side, in this study, the ratio of all uncles to all aunts of 90 males homosexuals was 132/209, ² = 8.52, p = 0.004. On the maternal side for the total of all sources, the ratio of uncles to aunts of male homosexuals was 241/367, ² = 13.20; p < 0.0001. The male/female ratio of the total number of maternal sibships bearing homosexuals (310/628: 0.491) was a measure of fetal wastage of the mothers' male sibs: 49%. This ratio was very close to that of the total number of children born to fathers affected with any one of nine Xq28-linked male semilethal conditions (255/508: ratio 0.556); for the difference between the two populations ² = 0.859, p = 0.354. The male/female ratio of the total number of children born to female carriers of any one of these same conditions (1,232/1,062: ratio 1.16), ² = 13.8 p 0.0001, is close to that of the total number of children in homosexual sibships: 511/413, ² = 10.4, p = 0.005. Between the number of children born to Xq28 mothers and to those born of mothers of homosexuals ² = 0.581, p = 0.446. One may readily surmise that the maternal influence so often related to homosexuality may lie in the mother being a genetic carrier, with traits thereto associated. In this study, 65% of the mothers of homosexuals had no or only one live-born brother. Additional support for a genetic hypothesis is found in the occurrence of multiple instances—almost exclusively among maternal relatives—of infertility, spontaneous abortions, miscarriages, stillbirths, remaining single past age 30, and suicide. Of 109 male and 43 female homosexual index cases in the present series there were 6 instances of brother/sister homosexual sibships. Instances of homosexual parent-to-homosexual child transmission occurred as follows: one father-to-son; one father-to-daughter; one bisexual father-son; one father/mother-to-2 sons; one of mother-to-son, and one of father-to-son and father-to-bisexual daughter. There were 16 instances of presumptive transmissions from heterosexual father-to-homosexual son and 5 of heterosexual father-to-homosexual daughter. A hypothesis is proposed: Homosexuality is due to a gene at Xq28 characterized by (i) elongated cytosine-containing trinucleotide repeats upstream to translation of a gene, (ii) elongated CpG islands upstream of the trinucleotides, and (iii) cytosine methylation of CpG islands and of the cytosine-containing trinucleotides.A limited number of long tables of data, and pedigree charts, which provide the details from which this paper was developed, may be obtained on paper or on disc from the author or, for a modest fee, from the Librarian, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York 11794.     

Holmium: YAG laser surgery in obliterated cochleas: an experimental study in human cadaver temporal bones

A pulsed holmium: YAG laser ( = 2120 nm) was used to reopen the basal turn of artificially obliterated human cochleas in freshly dissected cadavers. This allowed intracochlear insertion of the stimulation electrode of a cochlear implant under simulated surgical conditions. Laser energy was transmitted through a 400-m nylon fiber via the opened facial recess directly to the round window niche. At an energy level of 500 mJ per 2.5 s pulse, a repetition rate of 2 Hz, and an exposure time of 20–30 s, the photo-ablative mechanism of laser-bone interaction led to a 8–10 mm recanalization of the basal turn of the cochlea without damaging surrounding structures. The artificial bony occlusion and the recanalized basal turn of the cochlea were visualized by means of computed tomography and studied under light microscopy, using a histologic thin-section technique.Presented at the XVth World Congress of Otorhinolaryngology, Istanbul, Turkey, 23 June 1993     

The amyloid precursor protein of Alzheimer's disease and the Abeta peptide

Alzheimer's disease is characterized by the accumulation of beta amyloid peptides in plaques and vessel walls and by the intraneuronal accumulation of paired helical filaments composed of hyperphosphorylated tau. In this review, we concentrate on the biology of amyloid precursor protein, and on the central role of amyloid in the pathogenesis of Alzheimer's disease. Amyloid precursor protein (APP) is part of a super-family of transmembrane and secreted proteins. It appears to have a number of roles, including regulation of haemostasis and mediation of neuroprotection. APP also has potentially important metal and heparin-binding properties, and the current challenge is to synthesize all these varied activities into a coherent view of its function. Cleavage of amyloid precursor protein by beta-and gamma-secretases results in the generation of the Abeta (betaA4) peptide, whereas alpha-secretase cleaves within the Abeta sequence and prevents formation from APP. Recent findings indicate that the site of gamma-secretase cleavage is critical to the development of amyloid deposits; Abeta1-42 is much more amyloidogenic than Abeta1-40. Abeta1-42 formation is favoured by mutations in the two presenilin genes (PS1 and PS2), and by the commonest amyloid precursor protein mutations. Transgenic mouse models of Alzheimer's disease incorporating various mutations in the presenilin gene now exist, and have shown amyloid accumulation and cognitive impairment. Neurofibrillary tangles have not been reproduced in these models, however. While aggregated Abeta is neurotoxic, perhaps via an oxidative mechanism, the relationship between such toxicity and neurofibrillary tangle formation remains a subject of ongoing research.     

The use of genetic instability as a clinical tool for cancer diagnosis

Human tumors exhibit two fundamentally important characteristics, extensive genetic alteration and clonality. Although it is still unclear to what extent tumors have an elevated mutational burden as compared with normal tissue, their clonality results in their ready detection. Thus, assaying tissues for clonal alterations at frequently mutated microsatellite loci represents a viable approach to cancer diagnosis. The most remarkable extension of this concept is that not only can cancer cells be detected in biological samples, but tumor DNA can also be directly detected in the serum or plasma of patients with some forms of cancer. This recent finding is currently being explored but may represent an important contribution to future diagnostic strategies.     

Diffusion of information about genetic risk within families

Recent developments in genetics are likely to exacerbate the ethical issues in clinical practice, especially with regard to privacy and disclosure of genetic information. To evaluate the behaviour of patients with respect to transmitting carrier information, we undertook a survey of 283 families with a balanced chromosomal rearrangement as a model. In these families, 1816 relatives were considered at risk and 806 of them were karyotyped (44.4%). The percentage of karyotypes performed is significantly related to the number of living children of the index couple, the reason for referral, the nature of the anomaly, the training of the counsellor and the age of the index case. This study shows the limits of the screening of at risk individuals within families, based on the willingness of the patients, and addresses practical and ethical issues around family disclosure in medical genetics.     

Reduced platelet MAO activity in healthy male students with blood group O

The association between the two genetic markers of affective disorders, ABO blood group system and platelet MAO (monoamine oxidase) activity was studied in 70 healthy young males. The platelet MAO activity of subjects with blood type O was significantly lower than that of subjects with blood type A and with blood types A + B AB + B together. This finding could constitute a "bridge" between the two genetic approaches to affective disorders.