Arie Figer

The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic gastrointestinal tract tumours in Israel.

Inherited predisposition occurs in 5–10% of all gastrointestinal (GI) cancer patients, but with the exception of colorectal cancer (CRC), the genes involved in conferring genetic susceptibility remain largely unknown. Indirect evidence indicates that germline mutations in BRCA2 might be associated with an increased risk for various GI malignancies. A single mutation (6174delT) occurs in the BRCA2 gene in high-risk breast ovarian cancer families of Jewish Ashkenazi origin, in about 1% of the general Ashkenazi population, and rarely in non-Ashkenazi Jews. In order to assess the contribution of this germline mutation to non-CRC GI cancer in Jewish Israeli patients, we tested 70 unselected, consecutive Jewish Ashkenazi patients with gastrointestinal malignancies for this mutation by PCR amplification and modified restriction enzyme digests. Patients’ age range was 38–90 years (mean 65.8±11.8 years). The most common malignancies were gastric cancer (n = 35) and exocrine pancreatic cancer (n = 23). Overall, 6 mutation carriers were detected: 3/23 (13%) of the patients with pancreatic cancer, 2/35 (5.7%) of patients with gastric cancer and 1/4 (25%) of patients with bile duct cancer. The 8.6% mutation carrier rate among patients is a rate significantly higher than that of the general Ashkenazi population (1.16%P = 0.0002). We conclude that the rate of the predominant Jewish BRCA2 mutation in patients with gastric and pancreatic cancer significantly differ from that of the general population of the same ethnic origin. Thus, BRCA2 mutations probably contribute to gastrointestinal tumorigenesis other then colon cancer, and the surveillance scheme for mutation carriers should incorporate this information.

Successful co-treatment with LHRH-agonist for ovarian over-stimulation and cystic formation in premenopausal tamoxifen exposure

The present study evaluates the potential beneficial effect of co‐treatment with LHRH‐agonist in resolving premenopausal tamoxifens induced supraphysiological serum 17β estradiol levels and persistent ovarian cysts. Ultrasonographic and serum hormonal evaluations were performed before, during, and following three consecutive injections of long acting LHRH‐agonist administered to 14 premenopausal breast cancer patients treated with tamoxifen, who had supraphysiological serum 17β estradiol levels and simultaneous persistent ovarian cysts. Within 3 weeks of the first LHRH‐agonist injection, all patients had menopausal serum estradiol levels. Ovarian cysts completely disappeared within 2 months following the first injection. Following the discontinuation of LHRH‐agonist co‐treatment, serum estradiol levels remained in physiological levels and the ovaries remained a normal size in 64.3% of the patients for 13.3 ± 11.5 months. 28.6% of the patients had a gradual reappearance of high serum estradiol levels and of ovarian cysts, and were, therefore, treated with a second course of LHRH‐agonist. Following the second course, serum estradiol levels remained in physiological levels and the ovaries remained a normal size for 8–15 months. It is concluded that short duration of co‐treatment with long acting LHRH‐agonist administered to premenopausal breast cancer patients treated with tamoxifen, successfully resolved the tamoxifen‐induced supraphysiological serum 17β estradiol levels and the ovarian cysts.

Dose-dependent effect of tamoxifen therapy on endometrial pathologies in postmenopausal breast cancer patients.

To assess whether a higher cumulative tamoxifen dose is associated with increased incidence of various types of endometrial pathologies, we compared cumulative dose of tamoxifen treatment as well as demographic characteristics, risk factors for endometrial cancer, transvaginal ultrasonographic endometrial thickness, and various treatments for the primary breast cancer between 159 postmenopausal breast cancer tamoxifen-treated patients without endometrial pathologies (group I) and 67 similar patients with endometrial pathologies (group II). A similar comparison was made between group I patients and similar patients with proliferative endometrium (group IIa), with endometrial hyperplasia (group IIb), with endometrial polyps (group IIc), and with endometrial cancer (group IId). Overall cumulative tamoxifen dose was significantly higher in group II as compared to group I (27.4 ± 33.4 and 17.4±20.2, respectively;P < 0.0252). Transvaginal ultrasonographic endometrial thickness was significantly higher in group II than in group I patients (16.3 ± 11.3 mm and 12.1 ± 6.3 mm, respectively; P < 0.0147). The frequency of diabetes mellitus, of previous postmenopausal bleeding, and of previous exposure to hormone replacement therapy was significantly higher in group II than in group I patients (P < 0.001, P < 0.0001 and P < 0.001, respectively). There were no significant differences in all parameters tested between group I, group IIa, group IIb, group IIc, and group IId. However, there was an obvious trend for higher cumulative tamoxifen dose in patients with benign endometrial pathologies as compared to those without endometrial pathologies or to those with endometrial cancer (Group I = 17.4 ± 20.2g, group IIa = 22.5 ± 18.5g, group IIb = 28.1 ± 20.3g, group IIc = 31.4 ± 42.7g and group IId = 10.4 ± 12.6g).Endometrial pathologies, except for endometrial cancer, are associated with a high cumulative dose of tamoxifen in postmenopausal breast cancer patients.

The frequency of the predominant Jewish mutations in BRCA1 and BRCA2 in unselected Ashkenazi colorectal cancer patients

It is presently unclear whether carriers of BRCA1 mutations have an increased risk for colorectal cancer (CRC). To gain insight into this issue, 225 unselected Ashkenazi Jewish CRC patients were tested for the presence of the three common Jewish BRCA1/2 germline mutations: 185delAG and 5382insC (BRCA1) and 6174delT (BRCA2). A total of four carriers was found (4/225, 1.78%). This frequency is similar to the estimated normal Ashkenazi population frequency, thus suggesting that these specific mutations do not contribute to CRC predisposition.

Genetic analysis of the APC gene regions involved in attenuated APC phenotype in Israeli patients with early onset and familial colorectal cancer

The genetic basis for the majority of early onset or non-syndromic ‘familial’ colorectal cancer (CRC) is unknown. Attenuated APC phenotype is characterized by relatively few colonic polyps, early age at onset of colon cancer compared with the general population, and inactivating germline mutations within specific regions of the APC gene. We hypothesized that germline mutations within these APC gene regions, might contribute to early onset or familial CRC susceptibility. To test this notion, we analysed 85 Israeli patients with either early onset (< 50 years at diagnosis) or familial CRC for harbouring mutations within the relevant APC gene regions: exons 1–5, exon 9 and a region within exon 15 (spanning nucleotides c.3900 to c.4034; codons 1294 to 1338) using denaturing gradient gel electrophoresis (DGGE), and all of exon 15 employing protein truncation test (PTT). No inactivating, disease-associated mutations were detected in any patient. A novel polymorphism in intron 5 was detected in 16 individuals, 8 patients were carriers of the 11307K variant, a mutation prevalent among Jewish individuals with colorectal cancer, and 4 displayed the E1317Q variant. We conclude that in Israeli individuals with early onset or familial CRC, truncating mutations in the APC gene regions associated with attenuated APC phenotype probably contribute little to disease pathogenesis.

Phenotypic characteristics of colo-rectal cancer in I1307K APC germline mutation carriers compared with sporadic cases.

The I1307K APC germline mutation is associated with an increased risk to colo-rectal cancer (CRC). Whether and to what extent the phenotype of CRC in mutation carriers differs from sporadic cases, remains unknown. To gain insight into this issue, we analysed 307 unselected Israeli patients with CRC, who were treated in a single medical centre, for harbouring the I1307K mutation. Twenty-eight mutation carriers (9.1%) were detected. Two of 28 mutation carriers (7.1%) and 93/277 (33.6%) of non-carriers, were of non-Ashkenazi origin (P< 0.01). In 74/278 (26.6%) of the sporadic cases, and only 1/28 (3.6%) of mutation carriers (3.6%) the tumour was located in the right colon (P< 0.01). Mutation carriers had a more advanced disease stage (14/28 – 50% Dukes C), as compared with 60 (19.5%) of non-carriers (P= 0.02). The mean age at diagnosis was similar: 65 (+/– 9.7) years and 66.3 (+/– 11.6) years, for mutation carriers and non-carriers, respectively. No statistical differences were noted between the two groups in sex distribution, tumour grade, and family history of cancer. We conclude that early age at diagnosis and family history of cancer cannot be used to predict who is likely to harbour the I1307K APC germline mutation carriers. However, the tumours in patients with this mutation appear different than those without, are less likely to be proximal and more likely to be advanced than tumours in non-carriers.

Common origin of the I1307K APC polymorphism in Ashkenazi and non-Ashkenazi Jews.

A common germline missense mutation within the APC gene, I1307K, has recently been described in Ashkenazi Jews. We detected this polymorphism in two non-Ashkenazi Jewish women using denaturing gradient gel electrophoresis (DGGE), and hypothesized that in Jewish individuals it might not be restricted to Ashkenazim, and actually reflect a common ancestral polymorphism. To test this notion we performed allelic pattern determination using APC-linked markers in these two women and in nine Ashkenazi carrier controls. The pattern of the intragenic markers, as well as a single downstream marker 30–70 Kb from the APC gene was identical in all individuals, regardless of ethnic origin. We conclude that the I1307K polymorphism in Jewish individuals, is not restricted to Ashkenazim and probably reflects a founder mutation.

Genetic Analyses in Consecutive Israeli Jewish Colorectal Cancer Patients

OBJECTIVES:Two APC germline mutations, E1317Q and I1307K, have been linked to colorectal cancer (CRC) risk. Whereas the I1307K variant is almost exclusively encountered in (Ashkenazi) Jews, E1317Q is not restricted to certain ethnic populations. Data on its contribution to CRC risk in Jewish patients are sparse.AIMS:To assess the contribution of E1317Q to CRC development in the Jewish population.METHODS:A total of 538 consecutive Israeli Jewish CRC patients and 440 controls were genotyped for E1317Q. In addition, the rate of the I1307K APC missense mutation and the two predominant Jewish mutations in hMSH2, A636P, and 324delCA, associated with hereditary nonpolyposis colon cancer (HNPCC), were determined.RESULTS:The E13117Q missense mutation was detected in 6/538 (1%) of CRC patients and 5/440 (1%) of controls. The I1307K variant was found in 8% of all patients and in 11% (35/322) of patients of Ashkenazi Jewish descent. Carriers and noncarrier CRC patients did not differ in age of onset or associated colonic adenomatous polyps. The carrier rate among controls was 5% among Ashkenazim and 1.6% among non-Ashkenazi individuals. The 324delCA hMSH2 mutation was not observed in this cohort, and 4 of 322 Ashkenazi patients (1.2%) displayed the A636P mutation.CONCLUSION:In Jewish CRC patients the E1317Q variant plays little if any role in colorectal cancer susceptibility and genetic testing for this variant is not warranted. The I1307K mutation is associated with a moderate excess risk for CRC, but age of onset seems not to be earlier and this variant is not associated with a multiple colonic polyp phenotype. Founder mutations in hMSH2 are rare in consecutive CRC patients.

Case Report: Umbilical Metastases of Gallbladder Carcinoma Unrelated to a Laparoscopic Procedure

Sister Mary Joseph’s nodules (SMJN), or neoplasms metastatic to the umbilicus, were first described by Sister Mary Joseph, a surgical assistant at the Mayo Clinic. To date, SMJN have been reported mainly in association with primary abdominal and pelvic malignancies (1–3). Gallbladder carcinoma (GBC) metastatic to the umbilicus has also been described (4, 5), occurring almost exclusively after laparoscopic cholecystectomy; the literature contains only a single case of spontaneous umbilical metastases of GBC (6). Umbilical metastases of all origins are considered an ominous prognostic sign (7–9). In the present study, we report on a case of umbilical metastases of GBC origin unrelated to a laparoscopic procedure and review the relevant literature.