Pattern multiplicity and fumarate hydratase (FH)/S-(2-succino)-cysteine (2SC) staining but not eosinophilic nucleoli with perinucleolar halos differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas from kidney tumors without FH gene alteration.

Hereditary leiomyomatosis and renal cell carcinoma syndrome is characterized by an increased risk of agressive renal cell carcinoma, often of type 2 papillary histology, and is caused by FH germline mutations. A prominent eosinophilic macronucleolus with a perinucleolar clear halo is distinctive of hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma according to the 2012 ISUP and 2016 WHO kidney tumor classification. From an immunohistochemistry perspective, tumors are often FH-negative and S-(2-succino)-cysteine (2SC) positive. We performed a pathology review of 24 renal tumors in 23 FH mutation carriers, and compared them to 12 type 2 papillary renal cell carcinomas from FH wild-type patients. Prominent eosinophilic nucleoli with perinucleolar halos were present in almost all FH-deficient renal cell carcinomas (23/24). Unexpectedly, they were also present in 58% of type 2 papillary renal cell carcinomas from wild-type patients. Renal cell carcinoma in mutation carriers displayed a complex architecture with multiple patterns, typically papillary, tubulopapillary, and tubulocystic, but also sarcomatoid and rhabdoid. Such pattern diversity was not seen in non-carriers. FH/2SC immunohistochemistry was informative as all hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas were either FH- or 2SC+. For FH and 2SC immunohistochemistries taken separately, sensitivity of negative anti-FH immunohistochemistry was 87.5% and specificity was 100%. For positive anti-2SC immunohistochemistry, sensitivity, and specificity were 91.7% and 91.7%, respectively. All FH wild-type renal cell carcinoma were FH-positive, and all but one were 2SC-negative. In conclusion, multiplicity of architectural patterns, rhabdoid/sarcomatoid components and combined FH/2SC staining, but not prominent eosinophilic nucleoli with perinucleolar halos, differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma from type 2 papillary renal cell carcinoma with efficient FH gene. Our findings are crucial in identifying who should be referred to Cancer Genetics clinics for genetic counseling and testing.

Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma.

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.

Factors associated with altered long-term well-being after prophylactic salpingo-oophorectomy among women at increased hereditary risk for breast and ovarian cancer.

BACKGROUND: Prophylactic bilateral salpingo-oophorectomy (PBSO) might alter several components of well-being, such as sexual functioning and endocrine symptoms, in women at high risk for hereditary breast and/or ovarian cancer, compared with the general population. We searched for factors associated with altered long-term well-being in this population (lower quality of life [QOL], altered sexual functioning, greater anxiety, more endocrine symptoms). METHODS: All high-risk women who had undergone PBSO during the past 15 years in a single cancer center were contacted by mail. Upon acceptance, they were sent five questionnaires: (a) general social questions, (b) the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, (c) Sexual Activity Questionnaire, (d) Functional Assessment of Cancer Therapy - Endocrine Symptom, and (5) State-Trait Anxiety Inventory. Logistic analyses were used to identify factors associated with altered results. Because of multiple testing, only p-values ≤ .01 were considered significant. RESULTS: One hundred twelve of 175 women (64%) returned the completed questionnaires at a mean duration (standard deviation) of 6.0 (5.1) years after PBSO. QOL was positively influenced by two baseline factors: a high educational level and occupying an executive position. However, younger age at PBSO was associated with lower social functioning and greater anxiety. At the time of the study, practicing a sport and the avoidance of weight gain (≥10%) were highly related to QOL, sexual pleasure, endocrine symptoms, and anxiety in the univariate analysis and predictive of better QOL and lower anxiety in the multivariate analysis. CONCLUSIONS: Younger women and women with a low educational level and no occupation appear to be at higher risk for altered long-term well-being. After surgery, practicing a sport and stable weight may help maintain overall well-being.

Characteristics, treatment, and outcome of breast cancers diagnosed in BRCA1 and BRCA2 gene mutation carriers in intensive screening programs including magnetic resonance imaging.

BACKGROUND: Breast magnetic resonance imaging (MRI) with conventional screening methods improves sensitivity in high-risk patients without benefits on specific survival. We evaluated the characteristics, treatments, and prognostic features of breast cancers diagnosed among BRCA1/2 mutation carriers either inside or outside screening programs that included MRI. PATIENTS AND METHODS: Two groups of patients diagnosed with a new breast cancer between 2001 and 2007 were compared: group 1, patients included in an intensive screening program; and group 2, patients outside of this program. RESULTS: Twenty-one patients met inclusion criteria for group 1, and 102 for group 2. Seventy-four percent and 65%, respectively, were BRCA1 mutation carriers. Tumors in both groups had the same characteristics (pN, grade, estrogen receptor, progesterone receptor, HER2 expression), except for smaller tumor size in group 1 (median, 6 mm vs. 22 mm; P < .0001). Group 1 patients had more frequent sentinel node procedures (57% vs. 28%; P = .021) and less commonly received chemotherapy (43% vs. 86%; P < .0001). The 3-year disease-free survival (93% vs. 74%; P = .1) and the 3-year overall survival (100% vs. 92%; P = .2) did not differ between groups. CONCLUSION: MRI might provide improvement in BRCA1/2 carriers in terms of smaller tumor size and treatment morbidity. However, because of aggressive intrinsic characteristics, this does not turn into significant survival benefits.

Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries.

The G101W founder mutation is the most common CDKN2A mutation in Italy, Spain, and France. As the background of modifying genes, environmental exposures, and sun behavior vary across countries, studying G101W carriers from distinct countries offers a unique opportunity to evaluate possible modifying factors in melanoma development. We evaluated 76 G101W cases and 59 carrier controls from France, Italy, Spain, and the United States. Hair color and dysplastic nevi distributions differed significantly in cases and controls across the 4 study groups. Cases also varied significantly for eye color, freckling, and nevi. The distribution of MC1R variants in cases differed significantly across study groups because 12% of Italian melanoma patients had > or =2 MC1R variants vs. >50% for the other case groups. Several MC1R covariates showed significant associations with melanoma risk in all groups combined and in the American, French, and Spanish samples; no significant findings were observed in the Italian sample. In multiple-case families, the number and type of MC1R variants varied significantly between multiple-primary-melanoma and single-primary-melanoma patients from the 4 groups; there was also a significant decrease in median age at melanoma diagnosis as the number or type of MC1R variants increased. The variation in the effects of the cutaneous phenotypic and MC1R factors across the study sample suggests that these factors differentially contribute to development of melanoma even on a common genetic background of a germline CDKN2A mutation. Differences in melanoma risk across geographic regions justify the need for individual studies in each country before counseling should be considered.