Identification and characterization of proximal 6q deletions in prostate cancer.

Allelic loss of 8p, 10q, 13q, 16q, and 18q has been frequently demonstrated in prostate cancer, implying the existence of putative tumor suppressor genes in these regions. However, there are likely a number of additional genetic events that define the progression from normal prostatic epithelium to prostate cancer that have yet to be identified. To characterize a novel region of deletion in sporadic prostate cancers, 52 tumors obtained from radical prostatectomy cases were analyzed for loss of heterozygosity (LOH) using 10 polymorphic markers spanning chromosome 6 including one marker on 6p and nine markers on 6q. Markers were selected from available databases, and a comprehensive linkage map was constructed. By this analysis, LOH for one or more polymorphic markers was detected in 17 of 52 sporadic prostate cancer cases (33%). Thirteen of 17 tumors were shown to have a common region of allelic loss extending from D6S286 to D6S283 or 6q14-21, with a minimum region of loss containing markers D6S1082 and D6S501. A second separate region of deletion centered around marker D6S404. LOH of one or more 6q markers did not correlate with Gleason grade or pathological stage of the cancer. In summary, this is the first comprehensive analysis of 6q deletions in prostate cancer, and we conclude that 6q14-21 may harbor a tumor suppressor gene important in prostate carcinogenesis.

Distinct regions of allelic loss on 13q in prostate cancer.

Loss of heterozygosity (LOH) involving the long arm of chromosome 13 has been reported to occur in as many as one third of primary prostate cancers. Candidate tumor suppressor genes on 13q that may be important in the development of prostate cancer include the retinoblastoma susceptibility gene (RBI) and a gene associated with inherited breast cancer (BRCA2). To define the pattern of allelic loss of 13q in prostate cancer, LOH analysis was performed using nine mapped polymorphic markers spanning the entire chromosomal arm. Nineteen (48%) of 40 prostate cancer cases obtained following radical prostatectomy demonstrated atllelic loss with at least one marker. Furthermore, 13 (33%) of 40 cases had evidence of allelic loss involving a region of 13q14 containing RB1. To test the hypothesis that RB1 is the targeted tumor suppressor gene in this region, 37 of 40 cases were assessed for expression of pRB, the protein product of RB1 using immunohistochemical techniques. By this analysis, 8 (22%) of 37 prostate tumors demonstrated no pRB expression. However, allelic loss at RB1, assessed with an intragenic marker, did not correlate with absent pRB expression (Fisher's exact test, P=0.375). Taken together, these data confirm that allelic loss of a common region of 13q14 occurs in approximately one third of prostate cancers. Lack of correlation of LOH at RB1 with absent pRB expression suggests the existence of another tumor suppressor gene in this region important in prostate cancer.

A region of interstitial 17q25 allelic loss in ovarian tumors coincides with a defined region of loss in breast tumors.

Chromosomal regions of allelic imbalance in tumors are predicted to define the general location of tumor suppressor genes. We previously localized a putative breast tumor suppressor gene to a 3 cM region on 17q25 by deletion mapping of microsatellite markers in breast tumors. To determine if the same 17q25 region of loss is important in the genesis of other tumor types, 32 ovarian tumors and 24 prostate tumors, as well as 33 additional breast tumors, were analysed with 17q25 polymorphic microsatellite markers. While no significant loss was observed in prostate tumors, greater than half of ovarian tumors exhibited loss coincident with the candidate region previously defined in breast tumors. These results suggest that one or more novel tumor suppressor genes exist on 17q25 within a concordant region of interstitial loss defined in both breast and ovarian neoplasms.

Evaluation of diagnostic tests for HIV infection in infants born to HIV-infected mothers in Switzerland.

Children born to HIV-infected women in Switzerland were tested every 3 months for HIV-reactive serum immunoglobulin (Ig) G, IgM and IgA antibodies by Western blot, viral antigen, virus replicating in T-lymphocyte cultures, and immunologic and clinical parameters. At birth, 27% were isolation-positive, 68% had IgM, 48% IgA and 10% circulating antigen. The proportion of IgM and IgA declined to about 18 and 27%, respectively, during the first 2 years. Detection of circulating antigen was less frequently positive than virus isolation in all age and disease groups. Clinical symptoms were only seen in infants or children who were or had been positive for IgM and/or IgA, but only 39% of children positive for these markers have developed disease so far. Clinical symptoms combined with signs of immunodeficiency were seen only in children who were isolation-positive or had evidence of HIV-reactive IgA or child-produced IgG. Absorption studies showed that Western blot-detected IgM and IgA antibodies were of two types: 42% were directed against various HIV proteins, while the rest represented rheumatoid-factor-like IgM or IgA binding to HIV-specific IgG. HIV-specific IgG antibodies were detected in all samples up to the age of 12 months and were still found in 83% of infants 13-18 months old. We observed weak HIV-specific IgG above the age of 15 months with no other signs of HIV infection, suggesting that the demonstration of antibodies in children beyond this age does not necessarily indicate HIV infection.

Stable human immunodeficiency virus encephalopathy in two infants receiving early intravenous gammaglobulin plus antimicrobial prophylaxis.

Two infants with human immunodeficiency virus (HIV) infection, encephalopathy, intrathecal anti-HIV IgG antibody production and (in one case) the presence of HIV antigen received monthly doses of intravenous gammaglobulin (IVGG) and daily antimicrobial prophylaxis starting at the ages of 6 and 9 months respectively. The follow-up over 15 and 12 months revealed a favourable course with remarkable improvement in visuo-spatial functions, receptive language, play behaviour and fine motor skills, as well as in muscle tone, pyramidal tract signs and vigilance in case 1, and near normalization in case 2. Viability of HIV in peripheral blood mononuclear cells, antigen in serum and cellular immunodeficiency, however, all remained unchanged. We suggest that neurological complications of encephalopathy in paediatric acquired immunodeficiency syndrome may have a slower progression when IVGG treatment plus antimicrobial prophylaxis is started early.

Immunological evaluation in the early diagnosis of prenatal or perinatal HIV infection.

A longitudinal evaluation was carried out of the clinical, infective, and immunological progress of 34 children (who were aged 6 to 68 months--mean 25 months at the time of writing) born to 31 mothers infected with human immunodeficiency virus (HIV), over a mean observation period of 13.4 months. Clinical symptoms, not always clearly related to HIV became apparent in 11 children, and preceding immune abnormalities were documented in two of them. In eight children culture for HIV was positive, and six of these were symptomatic. No cancers were diagnosed and none of the children died. Immune abnormalities including hypergammaglobulinaemia, IgG subclass deficiency, low serum IgA concentration, antibody deficiency, a decrease in the number of CD4+(T helper) cells, and defective cellular responses to antigens, were found in seven of the children in whom culture for HIV was positive; in two of four who had symptoms and in all four who were symptom free and in whom culture was negative for HIV but in whom HIV antibodies persisted and who were older than 15 months; and in three of nine who were symptom free and in whom culture was negative with loss of HIV antibodies. We conclude that serological diagnosis alone may be misleading and that additional immunological assessment may help to identify affected children. Analysis of humoral and cellular responses to antigens used for vaccination such as tetanus toxoid by measurement of specific antibodies and skin testing are simple and helpful in clinical practice.