Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma.

BACKGROUND: Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma. Alternatively, somatic mutations in BAP1 in UM have been associated with high risk for metastasis. In this study, we compare the risk of metastasis in UM that carry germline versus somatic BAP1 mutations and mutation-negative tumors. METHODS: DNA extracted from 142 UM and matched blood samples was sequenced using Sanger or next generation sequencing to identify BAP1 gene mutations. RESULTS: Eleven of 142 UM (8%) carried germline BAP1 mutations, 43 (30%) had somatic mutations, and 88 (62%) were mutation-negative. All BAP1 mutations identified in blood samples were also present in the matched UM. There were 52 unique mutations in 54 tumors. All were pathogenic or likely pathogenic. A comparison of tumors carrying somatic vs. germline mutations, or no mutations, showed a higher frequency of metastasis in tumors carrying somatic mutations: 74% vs. 36%, P=0.03 and 74% vs. 26% P<0.001, respectively. Tumors with a somatic mutation compared to mutation-negative had an older age of diagnosis of (61.8 vs. 52.2 years, P=0.002), and shorter time to metastasis (16 vs. 26 months, P=0.04). Kaplan-Meier analysis further showed that tumors with somatic (vs. germline) mutations demonstrated a greater metastatic risk (P=0.03). Cox multivariate analysis showed in addition to chromosome-3 monosomy and larger tumor diameter, the presence of BAP1 somatic, but not germline mutations, was significantly associated with risk of metastasis(P=0.02). Personal or family history of BAP1-TPDS was available for 79 of the cases. All eight cases with germline mutations reported a history of BAP1-TPDS, which was significantly greater than what was observed in cases with somatic mutations (10 of 23, P=0.009) or mutation-negative cases (11 of 48, P<0.001). CONCLUSIONS: Defining germline vs. somatic nature of BAP1 mutations in UM can inform the individual about both the risk of metastasis, and the time to metastasis, which are critically important outcomes for the individual. This information can also change the cascade screening and surveillance of family members.

Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: FTO gene single nucleotide polymorphisms (SNPs) have been shown to be associated with obesity-related traits and type 2 diabetes. Several small studies have suggested a greater than expected effect of the FTO rs9939609 SNP on weight in polycystic ovary syndrome (PCOS). We therefore aimed to examine the impact of FTO genotype on BMI and weight in PCOS. METHODS: A systematic search of medical databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted up to the end of April 2011. Seven studies describing eight distinct PCOS cohorts were retrieved; seven were genotyped for SNP rs9939609 and one for SNP rs1421085. The per allele effect on BMI and body weight increase was calculated and subjected to meta-analysis. RESULTS: A total of 2,548 women with PCOS were included in the study; 762 were TT homozygotes, 1,253 had an AT/CT genotype, and 533 were AA/CC homozygotes. Each additional copy of the effect allele (A/C) increased the BMI by a mean of 0.19 z score units (95% CI 0.13, 0.24; p = 2.26 × 10(-11)) and body weight by a mean of 0.20 z score units (95% CI 0.14, 0.26; p = 1.02 × 10(-10)). This translated into an approximately 3.3 kg/m(2) increase in BMI and an approximately 9.6 kg gain in body weight between TT and AA/CC homozygotes. The association between FTO genotypes and BMI was stronger in the cohorts with PCOS than in the general female populations from large genome-wide association studies. Deviation from an additive genetic model was observed in heavier populations. CONCLUSIONS/INTERPRETATION: The effect of FTO SNPs on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between FTO and the metabolic context or polygenic background of PCOS.

Fine mapping of genetic susceptibility to polycystic ovary syndrome on chromosome 19p13.2 and tests for regulatory activity.

CONTEXT: Little is known about genes that contribute to polycystic ovary syndrome (PCOS). We previously found linkage and association of PCOS with the dinucleotide marker D19S884 in two independent sets of families; allele 8 of D19S884 confers increased risk. OBJECTIVE/DESIGN: The objectives of the study were: 1) use the transmission/disequilibrium test (TDT) to assess linkage and association between PCOS and D19S884 (and nearby markers) in a third set of families; and 2) test D19S884 and surrounding DNA sequence for in vitro regulatory activity in lymphoblastoid cell lines (LCLs) and granulosa cells. SETTING/SUBJECTS: We studied 98 new families with a PCOS proband, father, mother, and other available offspring. We analyzed data from these families separately and in combination with data obtained previously. INTERVENTIONS: Interventions were venipuncture. MAIN OUTCOME MEASURES: Measures were transmission frequencies and in vitro functional studies. RESULTS: The first result we found was that in the 98 new families, the TDT was significant for allele 8 of D19S884 (P = 0.043). In the total collection of 465 families, the TDT evidence is very strong (nominal P < 7 x 10(-5)). Results for all other genetic markers near D19S884 were nonsignificant after correction for multiple testing. The second result was that an approximately 800-bp fragment containing various alleles of D19S884 showed modest but reproducible promoter activity in LCLs. However, no allelic differences were detected. No activity of this fragment was detected in granulosa cells. CONCLUSIONS: This is the second independent confirmation of linkage and association of D19S884 with PCOS. We found in addition that some sequence in the region of D19S884 confers in vitro promoter activity in LCLs.

Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2.

CONTEXT: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is believed to have a genetic basis. However, no specific susceptibility gene or region has been conclusively identified. OBJECTIVE: The objective of this study was to duplicate a previous study that localized a PCOS susceptibility region to chromosome 19p13.2 and to narrow the susceptibility region. DESIGN: This study was designed to test for genetic linkage and association between PCOS and short tandem repeat polymorphisms in 367 families, by analysis of linkage and family-based association. SETTING: The study was conducted at academic medical centers. PATIENTS OR OTHER PARTICIPANTS: We studied 367 families of predominantly European origin with at least one PCOS patient. Families included 107 affected sibling (sister) pairs (ASPs) in 83 families, and 390 trios with both parents and an affected daughter. The data set comprises two independent groups. Set 1 consists of 44 ASPs and 163 trios. Set 2 consists of 63 ASPs and 227 trios. INTERVENTION(S): The intervention was the drawing of blood for DNA extraction. MAIN OUTCOME MEASURE: We employed measures of evidence for linkage and association between PCOS and 19 STRs. RESULTS: Linkage with PCOS was observed over a broad region of chromosome 19p13.2. The strongest evidence for association was observed with D19S884 (chi2 = 11.85; nominal P < 0.0006; permutation P = 0.034) and duplicated our earlier findings. CONCLUSIONS: The present analysis suggests that a PCOS susceptibility locus maps very close to D19S884. Additional studies that systematically characterize DNA sequence variation in the immediate area of D19S884 are required to identify the PCOS susceptibility variant.

A functional polymorphism (1858C/T) in the PTPN22 gene is linked and associated with type I diabetes in multiplex families.

Type I diabetes (T1D) is a complex disorder, which arises from the autoimmune destruction of the insulin-secreting beta cells of the pancreas leading to a life-long dependence on exogenous insulin. A recent study of T1D cases and controls provided evidence for association between an allele of a functional single-nucleotide polymorphism (SNP) in the PTPN22 gene and T1D. In the current study, this SNP was genotyped in a collection of 406 multiplex T1D families. Significant evidence of the combined presence of association and linkage to T1D was obtained (P = 2.5 x 10(-5)). Linkage studies in subsets of families defined by PTPN22 SNP genotypes suggest possible interaction with loci on chromosomes 3 and 21. Previous genome scans in this collection of T1D families, and others, have not yielded significant evidence of linkage in the region of the PTPN22 locus. However, the highly significant evidence of allelic association suggests that variation at, or near, this functional SNP contributes to the risk of T1D.