Body mass, age, and the APC I1307K allele in Ashkenazi Jewish prostate cancer patients.

The I1307K mutation of the adenopolyposis coli gene (APC), located on chromosome 5q21-q22, is associated with an increased risk of cancer in Ashkenazi Jews. In the present study, we analyzed age and body mass of Ashkenazi Jewish prostate cancer patients, with and without the APC I1307K mutation. Participants in our study were found through urology and radiation oncology clinics, and all eligible patients were asked to take part. A familial history was obtained by interview or self-report questionnaire. Histological confirmation of diagnosis was obtained for all subjects. The I1307K allele of the APC gene was detected by amplification of lymphocyte DNA from peripheral blood according to standard polymerase chain reaction (PCR) and dot blot procedures. We studied 135 Ashkenazi Jewish men with prostate cancer. The youngest was 49, the oldest 80, average age 68 +/- 6.88 (mean +/- SD). The older patients carrying the wild type APC allele tended to have a lower body mass than the younger ones (r = -.27, P =.002). Of 71 patients under 70 years old, 65 carried the wild type APC allele, and had a body mass index of 28. 7 +/- 4.23 kg/m(2). The six men under age 70 carrying the I1307K APC allele had a body mass index of 26.87 +/- 1.44 kg/m(2). The difference in body mass index of the two groups is significant (P =. 032, t test for unequal variance). Increased body mass is a prostate cancer risk factor, and hereditary prostate cancer is associated with younger patients. Therefore, our finding, that patients under age 70 carrying the I1307K allele are significantly thinner than those carrying the wild type allele, suggests that the APC I1307K allele is also a prostate cancer risk factor. Our results are in accord with other studies indicating that APC mutations increase the risk of prostate cancer.

Founder BRCA 1 and 2 mutations among a consecutive series of Ashkenazi Jewish ovarian cancer patients.

OBJECTIVE: The purpose of this study was to describe the incidence of the three Ashkenazi Jewish founder genetic BRCA 1 and 2 mutations among an unselected, consecutive group of Ashkenazi Jewish ovarian cancer patients. MATERIALS AND METHODS: From 7/30/96 to 4/12/99, 92 Ashkenazi Jewish patients with histologically confirmed epithelial ovarian cancer had surgery. All of these patients had DNA extracted from 5-microm sections of their paraffin-embedded surgical specimen tissue blocks using the Qiagen QIAamp tissue extraction kit. A multiplex (triplex) polymerase chain reaction was performed to amplify fragments for the 185delAG, 5382insC, and 6174delT mutations. The products were hybridized with normal and mutant probes for each of the three mutations. All clinical data were collected retrospectively and statistical significance was evaluated using the chi(2) test or a two-tailed Fisher's exact test, depending on the sample size. RESULTS: There were 23 patients positive for one of the three founder BRCA mutations. Fourteen patients were positive for the 185delAG mutation, 2 patients were positive for the 5382insC mutation, and 7 patients were positive for the 6174 delT mutation (61, 9, and 30%, respectively). This represented a 25% incidence (95% CI: 16-34%) of one of the three founder BRCA mutations among our 92 Ashkenazi Jewish ovarian cancer patients. None of the patients was positive for more than one mutation. There was no statistically significant difference in parity, histology, grade, or stage between the BRCA founder mutation positive and negative patients. The difference between the percentage of mutation carriers among patients with one affected first-degree relative (13/22 or 59%) compared to those without at least one affected first-degree relative (10/70 or 14%) was highly significant (P = 0.001). CONCLUSIONS: Ashkenazi Jewish ovarian cancer patients represent a group with a high likelihood of being carriers of BRCA 1 and 2 genetic mutations, regardless of family history. As a result, all ovarian cancer patients who are of Ashkenazi Jewish descent should be counseled regarding BRCA 1 and 2 genetic screening, as well as the potential implications of these results for the patient as well as her relatives in terms of prognosis, screening, chemoprevention, and consideration of prophylactic surgical procedures.

Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients.

Based on breast cancer families with multiple and/or early-onset cases, estimates of the lifetime risk of breast cancer in carriers of BRCA1 or BRCA2 mutations may be as high as 85%. The risk for individuals not selected for family history or other risk factors is uncertain. We determined the frequency of the common BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutations in a series of 268 anonymous Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset. DNA was analyzed for the three mutations by allele-specific oligonucleotide hybridization. Eight patients (3.0%, 95% confidence interval [CI] 1.5%-5.8%) were heterozygous for the 185delAG mutation, two (0.75%, 95% CI 0.20-2.7) for the 5382insC mutation, and eight (3.0%, 95% CI 1.5-5.8) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was calculated to be 36%, approximately three times the overall risk for the general population (relative risk 2.9, 95% CI 1.5-5.8). For the 5382insC mutation, because of the low number of carriers found, further studies are necessary. The results differ markedly from previous estimates based on high-risk breast cancer families and are consistent with lower estimates derived from a recent population-based study in the Baltimore area. Thus, presymptomatic screening and counseling for these common mutations in Ashkenazi Jewish women not selected for family history of breast cancer should be reconsidered until the risk associated with these mutations is firmly established, especially since early diagnostic and preventive-treatment modalities are limited.

Prenatal detection and molecular characterization of a de novo duplication of the distal long arm of chromosome 19.

A tandem duplication of the distal long arm of chromosome 19 was identified in a 10 week fetus by analysis of chorionic villi. The fetal karyotype from two primary cultures was 46,XY,dir dup(19)(q13.2q13.4). The origin of the extra material was confirmed by fluorescence in situ hybridization using a chromosome 19 whole chromosome probe. Parental chromosomes were normal, indicating a de novo origin of the extra chromosome material. This is the first case of dup(19q) detected by prenatal diagnosis. Molecular studies demonstrated that the duplication involved a maternal chromosome 19.

Paternal uniparental disomy for chromosome 14: a case report and review.

Uniparental disomy (UPD) for several chromosomes has been associated with disease phenotypes. Maternal UPD for chromosome 14 has been described and has a characteristic abnormal phenotype. Paternal UPD14 is rare and only three previous cases have been reported. We describe a new case of paternal UPD for chromosome 14 in an infant with a 45,XX,der(13q;14q) karyotype, which was confirmed by molecular analysis. The proposita had findings similar to those of the previous cases of patUPD14 and we conclude that there is a characteristic patUPD14 syndrome most likely due to imprinting effects. Couples with Robertsonian translocations involving chromosome 14 should be counseled as to the possibility of UPD14 and the option of prenatal diagnosis when indicated.

Mosaic trisomy 14 with hepatic involvement.

Mosaic trisomy 14 in liveborns is rare and may be accompanied by uniparental disomy in the euploid cell line. We report the case of a 6 month old male with growth failure, microcephaly, macroglossia, developmental delay, hypotonia, congenital heart disease, neonatal hepatitis, cryptorchidism, talipes equinovarus, limb length asymmetry, bilateral overriding of 1st by 2nd toe, and extended abnormal pigmentation in a linear-whorl distribution. The proband's karyotype in peripheral lymphocytes and skin fibroblasts was mos47,XY,+14/46,XY. Parental blood chromosomes were normal. Molecular analysis excluded uniparental disomy in the euploid cell line of the proband.

Homozygosity for pericentric inversions of chromosome 9. Prenatal diagnosis of two cases.

The finding of homozygosity for a pericentric inversion of chromosome 9 [inv(9)] is rare, and previously has not been reported at prenatal diagnosis. We describe two unrelated cases of homozygosity for inv(9) identified in amniocytes. In each case, both parents were heterozygotes for the inv(9); 46,XX,inv(9)(p11q13) and 46,XY,inv(9) (p11q13). Case 1 resulted in a normal term infant who at age 5 years was phenotypically and developmentally normal. Case 2 was referred for severe intrauterine growth retardation (IUGR) and oligohydramnios, and subsequently expired in utero. Even though inv(9) is a normal chromosome variant with a frequency of 1 to 3% in the general population, the finding of homozygosity for inv(9) and IUGR in this fetus suggested the possibility of uniparental disomy (UPD). Molecular studies confirmed the presence of both parental inv(9) chromosomes, excluding the possibility of chromosome 9 UPD as the cause of IUGR in this fetus. Presumably, inv(9) homozygosity results from the high frequency of inv(9) heterozygosity, and is a normal variant. However, until the effects of UPD for chromosome 9 are established, parental karyo types and, where appropriate, molecular studies should be performed to exclude UPD. In addition, more reports of inv(9) homozygosity detected prenatally are needed to assess its frequency and outcome.