What would you do? Specialists' perspectives on cancer genetic testing, prophylactic surgery, and insurance discrimination.

PURPOSE: To examine what cancer genetics specialists predict they would do personally if they were at 50% risk of carrying a mutation that predisposes to hereditary breast/ovarian cancer (BRCA1/BRCA2) and hereditary nonpolyposis colon cancer (HNPCC). METHODS: Questionnaire survey of the membership of the National Society of Genetic Counselors (NSGC) Special Interest Group (SIG) in Cancer. RESULTS: Of the 296 active members of the NSGC Cancer-SIG surveyed, 163 (55%) responded. Eighty-five percent predicted that if they had a 50% risk of carrying a BRCA1/BRCA2 mutation, they would pursue genetic testing. If they tested positive for a mutation at age 35, 25% predicted they would pursue prophylactic bilateral mastectomies and 68%, prophylactic oophorectomy. Ninety-one percent of respondents believe they would pursue genetic testing for HNPCC, and 17% would elect prophylactic colectomy; 54%, prophylactic hysterectomy; and 52%, prophylactic oophorectomy if they tested positive for a mutation. The majority (68%) would not bill their insurance companies for genetic testing because of fear of discrimination, and 26% would use an alias when undergoing testing. Fifty-seven percent of counselors would seek professional psychologic support to help them cope with the results of testing. CONCLUSION: A large percentage of cancer genetic counseling providers predicted they would opt for prophylactic surgery at a young age if they carried a BRCA or HNPCC mutation, and most would seek professional psychologic assistance when undergoing testing. More than half of respondents would not bill their insurance companies for genetic testing, largely because of fear of genetic discrimination. The vast majority of those providers most familiar with cancer genetic testing and its associated medical, psychologic, and legal implications would still pursue genetic testing.

The polymorphic exon 1 androgen receptor CAG repeat in men with a potential inherited predisposition to prostate cancer.

Recent studies have provided epidemiological evidence in support of a possible prostate cancer susceptibility locus on the X chromosome. The androgen receptor (AR) gene, located at Xq11-12, has been implicated as a risk factor for the development of prostate cancer. To examine the potential role of the AR locus in prostate cancer susceptibility, the AR CAG repeat length was measured in 270 Caucasian men with prostate cancer from 133 unrelated families. Each of these families has two or more confirmed cases of prostate cancer occurring in first- and/or second-degree relatives. No evidence for linkage of the AR gene to prostate cancer was observed. We tested for the previously reported association of short CAG alleles with prostate cancer using t tests, Pearson's chi2 tests, and logistic regression; analyses were subsequently repeated to incorporate only men with moderate- to high-grade prostate cancer. No association between AR CAG allele length and prostate cancer was detected when either a subset of unrelated patients or a subset of unrelated patients with moderate- to high-grade cancer was compared with a set of unrelated controls. We failed to detect an association between short AR CAG alleles and early age of prostate cancer diagnosis. Once specific hereditary prostate cancer genes have been identified, future studies can more carefully delineate the potential role of this AR polymorphism as a modifier locus in high-risk families.

Linkage analysis of 153 prostate cancer families over a 30-cM region containing the putative susceptibility locus HPCX.

Several genetic epidemiological studies have provided data to support the hypothesis that there are genes on the X chromosome that may contribute to prostate cancer susceptibility. A recent linkage study of 360 prostate cancer families described evidence for a prostate cancer predisposition gene, termed HPCX, which maps to Xq27-28. To confirm the potential contribution of this locus to prostate cancer susceptibility in an independent dataset, we studied 153 unrelated families who are participants in the University of Michigan Prostate Cancer Genetics Project. Families selected for this analysis have at least two living family members with prostate cancer that are related in a way that they could potentially share a common ancestral copy of an X chromosome. DNA samples were genotyped using a panel of seven polymorphic markers spanning 30 cM and containing the HPCX candidate region. The resulting data were analyzed using both nonparametric and parametric linkage methods. Analysis of all 153 families using multipoint non-parametric linkage (NPL) methods resulted in positive NPL Z-scores across the entire candidate interval (NPL Z-scores of 0.23-1.06, with corresponding one-sided Ps of 0.41 and 0.15, respectively). The 11 African-American families had negative NPL Z-scores across the same 30-cM interval. Analysis of the 140 Caucasian families produced a maximal NPL Z-score of 1.20, with a corresponding one-sided P of 0.12 at marker DXS1113. The subset of families with no evidence of male-to-male disease transmission and with early-onset prostate cancer (average age at diagnosis within a family < or = 65 years) contributed disproportionately to the evidence for linkage for the entire dataset in the HPCX candidate region (near marker DXS1113). In conclusion, this study of 153 families, each with two or more living members with prostate cancer, provides some additional support for the existence of a prostate cancer susceptibility gene at Xq27-28.

Minute chromatin structures in cells of amniotic fluid-an interpretative dilemma.

Single copies of tiny chromosome fragments, appearing either as single or as double minutes, were observed in a high frequency in amniotic fluid cultures of five mothers who underwent prenatal testing because of advanced age. In four cases, the minutes had arisen de novo. The minutes were later confirmed in fetal skin following termination of pregnancy in one case; in another, in cord blood following the birth of a normal boy; and in the third, in peripheral blood of a normal 3-year-old girl. In the fourth case, the minutes were not confirmed in cord blood following the birth of a normal boy. A follow-up chromosome study of the baby boy in the fifth case was not possible but the minutes were maternally transmitted.

A mobile element on a virus particle surface identified by nuclear magnetic resonance spectroscopy.

The presence of a mobile element in the coat protein of pepper ringspot tobravirus (PRV) has been established by 1H n.m.r. spectroscopy; two-dimensional correlation spectroscopy (COSY) measurements show that this element consists of alanine, asparagine, glycine, proline, serine and threonine only. By reference to the amino acid sequence of the coat protein, it is concluded that the mobile element is associated with the C-terminal region and consists of between 11 and 38 residues.

Developments in the understanding of the particle structure of tobraviruses.

Particles of tobraviruses resemble those of tobacco mosaic tobramovirus (TMV) in having helical symmetry and in being rod-shaped. However, isolated tobravirus coat protein and TMV coat protein respond to changes in the ionic strength and pH of the solute in contrasting ways. The types of aggregate formed in solutions of coat protein also differ which may be related to differences in the apparent mechanism of reconstitution of virus particles from isolated protein and RNA. The amino acid sequences of tobravirus and tobramovirus coat proteins have been shown to be similar in some regions known to be important for the structure of TMV particles. These alignments also show that tobravirus proteins are larger than tobramoviral proteins in part because of extra residues at the C-terminus. Tobravirus particles give a signal in proton NMR spectroscopy but TMV particles do not. The signal is caused by segmental mobility of the C-terminal peptide. This difference between TMV and tobraviruses may be related to a property not shared by tobraviruses and TMV and it is therefore speculated that the mobile C-terminal peptide of tobravirus coat proteins may be important in the transmission of tobravirus particles by nematode vectors.

46,XX/46XY chromosome complement in amniotic fluid cell culture followed by the birth of a normal female child.

Experience indicates that the most likely explanation for a mixture of 46,XX/46,XY cells in an amniotic fluid sample is that of maternal cell contamination and that a normal male child is to be expected at birth. We report the bith of a normal female child following prenatal diagnosis of such a mixture. Extensive postnatal studies failed to reveal an XY cell line. The possible sources of the XY cell line are discussed, as are the various techniques that were applied in an effort to discover it's origin. Cross-contamination of samples could be ruled out and there was no evidence of an unsuspected twin pregnancy. It is clear from this case that not all 46,XX/46,XY results obtained in amniotic fluid can be assumed to represent maternal cell contamination and some effort should be made to eliminate other potential sources for such a mixture.