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Among Asian countries, Pakistan has the highest rates of breast and ovarian cancer. To assess the contribution of the BRCA1 and BRCA2 germ line mutations to these high rates, we conducted the first study of 176 Pakistani breast and ovarian cancer patients, selected on family history and on age of diagnosis. Comprehensive BRCA mutation screening was performed using a range of techniques, including denaturing high-pressure liquid chromatography, single strand conformational polymorphism analysis and protein truncation test, followed by DNA sequencing. Thirty deleterious germ-line mutations were identified in the 176 families (17.0%), including 23 in BRCA1 and 7 in BRCA2. Four mutations, 185delAG, 185insA, S1503X and R1835X, were recurrent; these accounted for 52% of all identified BRCA1 mutations. Haplotype analyses suggested founder effects for 3 of these. The prevalence of BRCA1 or BRCA2 mutations was 42.8% for families with multiple cases of breast cancer, and was 50.0% for the breast/ovarian cancer families. The prevalence of mutations was 11.9% for single cases of early-onset breast cancer (30 years) and was 9.0% for single cases of early-onset ovarian cancer (45 years). Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer and early-onset breast and ovarian cancer cases in Pakistan. ' 2006 Wiley-Liss, Inc.Key words: BRCA1; BRCA2; germ line mutations; hereditary breast/ ovarian cancer; Pakistan Breast cancer is the most common malignancy among Pakistani women, accounting for 34.6% of all female cancers. Ovarian cancer is the third most common malignancy.1 Among Asian countries, Pakistan not only has the highest rate of breast cancer (excluding Jewish women in Israel) 2 but also of ovarian cancer. 3The Karachi Cancer Registry reported an age-standardized (world) annual rate of breast cancer of 69.1 per 100,000. These rates resemble those reported in parts of Europe and North America. 1,4Affected women typically present below 40 years of age. 5,6Approximately 5% of breast cancers and 10% of ovarian cancers are due to germ-line mutations in the BRCA1 (MIM 113705) and BRCA2 (MIM 600185) genes. 7,8 Mutations in these genes are responsible for familial clustering for the majority of breast and ovarian cancer families and for about one-half of site-specific breast cancer families.9-11 It has been estimated that women carrying deleterious mutations in either of these genes face a lifetime risk of breast cancer ranging from 36 to 92%11-14 and of ovarian cancer between 16 and 63%.11,14 Women and men who carry BRCA2 mutations also have increased risks of pancreatic cancer, prostate cancer and melanoma. 15 The frequency and spectrum of mutations within these genes show considerable variation by ethnic group and by geographic region. To date, the majority of studies on the prevalence of the BRCA1 and BRCA2 mutations have been performed in white populations, but recently studies have also been conducted on Asian populations. 16 Little is known about the contribution...

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Mycobacterium chelonae (formerly known as M. chelonae subspecies chelonae) is a rapidly growing mycobacterium that can cause disseminated infections, especially in immunocompromised hosts. The bacterium is typically resistant to antimicrobial agents; less than 20% of M. chelonae isolates are susceptible to trimethoprim-sulfamethoxazole, doxycycline, erythromycin, or ciprofloxacin. Findings in a recent study suggested that clarithromycin may be the drug of choice for the treatment of cutaneous (disseminated) disease due to M. chelonae. We describe a 60-year-old heart transplant patient with disseminated M. chelonae infection for whom monotherapy with clarithromycin failed because of the rapid development of resistance to the drug.