Key Words. Breast cancer x Young age x Family history x BRCA mutations x Haplotype x Lebanon x Arab countries ABSTRACT Purpose. Breast cancer is the most common malignancy among women in Lebanon and in Arab countries, with 50% of cases presenting before the age of 50 years. Methods. Between 2009 and 2012, 250 Lebanese women with breastcancer who were considered to be at high riskof carrying BRCA1 or BRCA2 mutations because of presentation at young age and/or positive family history (FH) of breast or ovarian cancer were recruited. Clinical data were analyzed statistically. Coding exons and intron-exon boundaries of BRCA1 and BRCA2 were sequenced from peripheral blood DNA. All patients were tested for BRCA1 rearrangements using multiplex ligationdependent probe amplification (MLPA). BRCA2 MLPA was done in selected cases. Results. Overall, 14 of 250 patients (5.6%) carried a deleterious BRCA mutation (7 BRCA1, 7 BRCA2) and 31 (12.4%) carried a variant of uncertain significance. Eight of 74 patients (10.8%) aged #40 years with positive FH and only 1 of 74 patients (1.4%) aged #40 years without FH had a mutated BRCA. Four of 75 patients (5.3%) aged 41-50 years with FH had a deleterious mutation. Only 1 of 27 patients aged .50 years at diagnosis had a BRCA mutation. All seven patients with BRCA1 mutations had grade 3 infiltrating ductal carcinoma and triple-negative breast cancer. Nine BRCA1 and 17 BRCA2 common haplotypes were observed. Conclusion. Prevalence ofdeleterious BRCA mutations is lower than expected and does not support the hypothesis that BRCA mutations alone cause the observed high percentage of breast cancer in young women of Lebanese and Arab descent. Studies to search for other genetic mutations are recommended. The Oncologist 2015;20:357-364Implications for Practice: This study provides new data to support discussion and referral of patients of Lebanese and Arab ancestry with high-genetic-risk breast cancer for BRCA counseling and testing.The probability of carrying a deleterious BRCA mutation in this population seems low at 5.6%.The absence of family history in patients aged #40 years reduces the possibility of BRCA mutations to only 1.4%. Young age combined with a positive family history raises the prevalence to 10.8% and increases the yield of testing. Further clarification of the 12.4% of cases with variants of uncertain significance and searches for alternative gene mutations are needed. This study adds missing information to the international BRCA population maps.

Background: The evaluation of respiratory muscle performance can be described in terms of strength and endurance, the latter usually being measured by means of resistive or threshold inspiratory loads, using devices that are also used for respiratory muscle training. Few authors, however, have published endurance reference values for healthy subjects. To that end, we studied two indices of respiratory muscle endurance in a population of 99 healthy volunteers (50 men, 49 women) divided into five age groups (20–70 years old) applying a modification of the methods of Martyn et al. and Nickerson and Keens. Inspiratory muscle endurance (T_lim) was defined as the time the subject was able to sustain breathing against an inspiratory pressure load equivalent to 80% of the maximum tolerated load (C_max). C_max was calculated using a 2-min incremental threshold load. Results: We found that the heaviest inspiratory threshold load tolerated for 2 min and the time a load equivalent to 80% of C_max (T_lim) could be sustained were not significantly different for male and female subjects. T_lim correlated with C_max, age, height, and maximum respiratory pressures.

Genetic mutations affecting chromatin modifiers are widespread in cancers. In malignant peripheral nerve sheath tumors (MPNSTs), Polycomb repressive complex 2 (PRC2), which plays a crucial role in gene silencing, is inactivated through recurrent mutations in core subunits embryonic ectoderm development (EED) and suppressor of zeste 12 homolog (SUZ12), but mutations in PRC2’s main catalytic subunit enhancer of zeste homolog 2 (EZH2) have never been found. This is in contrast to myeloid and lymphoid malignancies, which harbor frequent loss-of-function mutations in EZH2. Here, we investigated whether the absence of EZH2 mutations in MPNST is due to a PRC2-independent (i.e., noncanonical) function of the enzyme or to redundancy with EZH1. We show that, in the absence of SUZ12, EZH2 remains bound to EED but loses its interaction with all other core and accessory PRC2 subunits. Through genetic and pharmacological analyses, we unambiguously establish that EZH2 is functionally inert in this context, thereby excluding a PRC2-independent function. Instead, we show that EZH1 and EZH2 are functionally redundant in the slowly proliferating MPNST precursors. We provide evidence that the compensatory function of EZH1 is alleviated upon higher proliferation. This work reveals how context-dependent redundancies can shape tumor-type specific mutation patterns in chromatin regulators.