Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations.

The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ~2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ~5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ~650 years ago, and into the Iraqi-Jewish community ~450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.

Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel.

The spectrum of germline mutations among Jewish non Ashkenazi high risk breast/ovarian cancer families includes a few predominant mutations in BRCA1 (185delAG and Tyr978X) and BRCA2 (8765delAG). A few additional recurring mutations [A1708E, 981delAT, C61G (BRCA1) R2336P, and IVS2 + 1G > A (BRCA2)] have been reported in Jewish non Ashkenazi families. The 4153delA*BRCA1 C61G*BRCA1 and the 4075delGT*BRCA2 has been reported to recur in Russian/Polish non Jews and Ashkenazim, respectively. The rate of these recurring mutations has not been reported in Israeli high risk families. Genotyping for these recurring mutations by restriction enzyme digest and sequencing method was applied to high risk, predominantly cancer affected, unrelated Israeli individuals of Ashkenazi (n = 827), non Ashkenazi (n = 2,777), non Jewish Caucasians (n = 193), and 395 of mixed ethnicity. Jewish participants included 827 Ashkenazi, 804 Balkans, 847 North Africans, 234 Yemenites, and 892 Asians (Iraq and Iran). Age at diagnosis of breast cancer (median ± SD) (n = 2,484) was 47.2 ± 9.6 for all women participants. Males (n = 236) were also included, of whom 24 had breast cancer and 35 had pancreatic cancer. Overall, 8/282 (2.8%) of the Balkan cases carried the BRCA1*A1708E mutation, 4/180 (2.2%) the R2336P mutation, and 0/270 the IVS2 + 1G > A BRCA2 mutations, respectively. Of North Africans, 7/264 (2.65%) carried the BRCA1*981delAT mutation. The BRCA1*C61G mutation was detected in 3/269 Ashkenazi, non Ashkenazi, and non Jewish Russians; the BRCA1*Tyr978X mutation was detected in 23/3220 individuals of non Ashkenazi origin, exclusively of Asian ethnicity (23/892, 2.6% of the Asians tested). The BRCA1*4153delA mutation was noted in 2/285 non Jewish Caucasians, and none of the Ashkenazim (n = 500) carried the BRCA2*4075delGT mutation. Jewish high risk families of North African, Asian, and Balkan descent should be screened for the 981delAT, Tyr978X, A1708E BRCA1, and the R2336P BRCA2 mutations, respectively.

Pre-operative cardiac workup after anthracycline-based neoadjuvant chemotherapy. Is it really necessary?

INTRODUCTION: In patients receiving pre-operative anthracyclines for locally advanced breast cancer, early cardiotoxicity is a well-recognised complication that may interfere with surgery. The aim of this study was to assess the safety of breast surgery after neoadjuvant treatment with Doxorubicin. PATIENTS AND METHODS: A retrospective study of breast cancer patients treated with Doxorubicin as part of their neoadjuvant protocol. All patients were subsequently operated in our institution. Intra-operative and postoperative haemodynamic, cardiac or respiratory events were collected. RESULTS: A total of 83 patients were included. All patients had a normal left ventricular ejection fraction before starting on chemotherapy. Doxorubicin was given in conjunction with Cyclophosphamide and Paclitaxel. The cumulative dose of Doxorubicin was 240 mg/m(2). All patients completed their chemotherapy less than a year before surgery and were clinically asymptomatic. Of the patients, 2.3% displayed a significant reduction in cardiac function to meet cardiotoxicity criteria, although not clinically apparent. No complications occurred intra-operatively or postoperatively. CONCLUSIONS: Breast surgery can be safely performed after breast neoadjuvant chemotherapy with Doxorubicin. The risk of early cardiotoxicity does not mandate a cardiac function assessment after completion of treatment. Work-up should be individualised according to the anthracycline regimen, patient's cardiac risk factors and functional status before surgery.

Timing of sentinel lymph node biopsy in patients receiving neoadjuvant chemotherapy for breast cancer.

OBJECTIVE: To address optimal timing of sentinel lymph node biopsy (SLNB) in breast cancer patients undergoing neoadjuvant treatment. METHODS: The study population included 117 patients with locally advanced cancer with clinically negative nodes treated with primary chemotherapy. Group 1 underwent SLNB and completion axillary lymph node dissection (ALND) in conjunction with lumpectomy/mastectomy, after neoadjuvant treatment (n = 31). Group 2 underwent SLNB followed by neoadjuvant therapy and subsequently surgery and completion of ALNDs (n = 58). Group 3 was treated using the same sequence as group 2, however, completion ALND was performed only for patients with positive sentinel lymph nodes (SLNs) (n = 28). RESULTS: SLN identification was lowest in group 1 compared to groups 2 and 3 (87% and 98.8% respectively; P = <0.05). The highest false negative rate was in group 1 (15.8% compared with 0% in group 2). CONCLUSION: Neoadjuvant treatment lowers the SLN identification rate, possibly due to fibrosis within the axilla, and increases the false negative rate due to downstaging. SLN biopsy prior to chemotherapy could give a more accurate evaluation of axillary status, unaffected by any previous therapeutic intervention.