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PURPOSE: Activating FGFR2 mutations have been identified in ~10% of endometrioid endometrial cancers (ECs). We have previously reported that mutations in FGFR2 are associated with shorter disease free survival (DFS) in stage I/II EC patients. Here we sought to validate the prognostic importance of FGFR2 mutations in a large, multi-institutional patient cohort. METHODS: Tumors were collected as part of the GOG 210 clinical trial "Molecular Staging of Endometrial Cancer" where samples underwent rigorous pathological review and had more than three years of detailed clinical follow-up. DNA was extracted and four exons encompassing the FGFR2 mutation hotspots were amplified and sequenced. RESULTS: Mutations were identified in 144 of the 973 endometrioid ECs, of which 125 were classified as known activating mutations and were included in the statistical analyses. Consistent with FGFR2 having an association with more aggressive disease, FGFR2 mutations were more common in patients initially diagnosed with stage III/IV EC (29/170;17%) versus stage I/II EC (96/803; 12%; p=0.07, Chi-square test). Additionally, incidence of progression (progressed, recurred or died from disease) was significantly more prevalent (32/125, 26%) among patients with FGFR2 mutation versus wild type (120/848, 14%; p<0.001, Chi-square test). Using Cox regression analysis adjusting for known prognostic factors, patients with FGFR2 mutation had significantly (p<0.025) shorter progression-free survival (PFS; HR 1.903; 95% CI 1.177-3.076) and endometrial cancer specific survival (ECS; HR 2.013; 95% CI 1.096-3.696). CONCLUSION: In summary, our findings suggest that clinical trials testing the efficacy of FGFR inhibitors in the adjuvant setting to prevent recurrence and death are warranted.

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PURPOSE: Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC). PATIENTS AND METHODS: Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of ≤2. Treatment consisted of brivanib 800 mg orally every day until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at six months and objective tumor response. Expression of multiple angiogenic proteins and FGFR2 mutation status was assessed. RESULTS: Forty-five patients were enrolled. Forty-three patients were eligible and evaluable. Median age was 64 years. Twenty-four patients (55.8%) received prior radiation. Median number of cycles was two (range 1-24). No GI perforations but one rectal fistula were seen. Nine patients had grade 3 hypertension, with one experiencing grade 4 confusion. Eight patients (18.6%; 90% CI 9.6%-31.7%) had responses (one CR and seven PRs), and 13 patients (30.2%; 90% CI 18.9%-43.9%) were PFS at six months. Median PFS and overall survival (OS) were 3.3 and 10.7 months, respectively. When modeled jointly, VEGF and angiopoietin-2 expression may diametrically predict PFS. Estrogen receptor-α (ER) expression was positively correlated with OS. CONCLUSION: Brivanib is reasonably well tolerated and worthy of further investigation based on PFS at six months in recurrent or persistent EMC.

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BACKGROUND: Familial hyperaldosteronism type II is a hereditary form of primary aldosteronism not attributable to the hybrid CYP11B1/CYP11B2 mutation that causes glucocorticoid remediable aldosteronism (or familial hyperaldosteronism type I). Although genetic defect(s) underlying familial hyperaldosteronism type II have not yet been elucidated, linkage to chromosome 7p22 was previously reported in two Australian families and a South American family with familial hyperaldosteronism type II. OBJECTIVE: To seek evidence of linkage to chromosome 7p22 in two Italian families with familial hyperaldosteronism type II based on markers that have already yielded evidence of linkage in one South American and two Australian familial hyperaldosteronism type II families and to assess the combined multipoint logarithm of odds score in these five families (two Australian, two Italian, and one South American). METHODS: Primary aldosteronism was diagnosed or excluded using widely accepted clinical and biochemical criteria. Genotypes of affected and unaffected Italian patients from two families were analysed using seven closely spaced microsatellite markers at 7p22, and multipoint logarithm of odds scores were calculated to assess linkage with familial hyperaldosteronism type II. RESULTS: All known affected individuals (four and two, respectively) from each of two Italian families shared identical haplotypes for the seven markers, consistent with linkage of the disease locus with the 7p22 region. The combined multipoint logarithm of odds score for five families showing linkage at 7p22 was highly significant at 5.22 (theta = 0) for markers D7S462 and D7S517. CONCLUSION: Linkage in two Italian families makes this the third geographical area to show linkage of familial hyperaldosteronism type II at 7p22, emphasizing the likely importance of this locus in identifying the causative mutation.

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In hyperinsulinism of infancy (HI), unregulated insulin secretion causes hypoglycemia. Pancreatectomy may be required in severe cases, most of which result from a defect in the beta-cell KATP channel, encoded by ABCC8 and KCNJ11. Pancreatic histology may be classified as diffuse or focal disease (the latter associated with single paternal ABCC8 mutations), indicated by the presence of islet cell nuclear enlargement in areas of diffuse abnormality. We investigated genotype-phenotype associations in a heterogeneous Australian cohort. ABCC8 and KCNJ11 genes were sequenced and case histology was reviewed in 21 infants who had pancreatectomy. Ninety-eight control DNA samples were tested by single nucleotide polymorphism analysis. Eighteen ABCC8 mutations were identified, 10 novel. Eleven patients (4 compound heterozygote, 4 single mutation, 3 no mutation detected) had diffuse hyperinsulinism. Nine patients had focal hyperinsulinism (6 single paternal mutation, 2 single mutation of undetermined parental origin, 1 none found) with absence of islet cell nuclear enlargement outside the focal area, although centroacinar cell proliferation and/or nesidiodysplasia was present in 7 cases. Regeneration after near-total pancreatectomy was documented in 4 patients, with aggregates of endocrine tissue observed at subsequent operations in 3. Although the absence of enlarged islet cell nuclei is a useful discriminant of focal hyperinsulinism associated with a paternal ABCC8 mutation, further research is needed to understand the pathophysiology of other histological abnormalities in patients with HI, which may have implications for mechanisms of ductal and islet cell proliferation. Previous surgery should be taken into account when interpreting pancreatic histology.

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BACKGROUND: Familial hyperaldosteronism type II (FH-II) is characterized by the familial occurrence of primary aldosteronism; unlike FH-I, it is not glucocorticoid-remediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. Linkage to a 5-Mbp region of chromosome 7p22 was previously reported in an Australian family with eight affected members. Mutations in the exons or intron-exon boundaries of PRKAR1B (7p22, closely related to PRKAR1A, which is mutated in Carney complex) have been excluded in this family. OBJECTIVE: To refine the region of linkage, and to seek evidence of linkage in a South American family and in three other Australian families with FH-II, using seven closely spaced markers at 7p22. METHODS: To establish phenotypes (affected, uncertain or unaffected), blood pressure, plasma aldosterone and plasma renin (activity or concentration) were measured and the aldosterone: renin ratio (ARR) calculated. Individuals with consistently increased ARR underwent fludrocortisone suppression testing. The genotypes of the five pedigrees were analysed using seven closely spaced microsatellite markers at 7p22, and two-point and multipoint logarithm of odds (LOD) scores were calculated to assess linkage with FH-II. RESULTS: The combined multipoint LOD score for three families (the original Australian, the South American and a new Australian family) showing linkage at 7p22 was highly significant at 4.61 (theta = 0) for markers D7S462 and D7S517. A newly found recombination event in the first Australian family narrowed the area of linkage by 1.8 Mbp, permitting exclusion of approximately half the candidate genes in the originally reported locus. It was not possible to demonstrate linkage at the 7p22 region in the remaining two Australian families. CONCLUSION: This study provides further evidence for linkage of FH-II to 7p22, refines the locus, and supports the notion that FH-II may be genetically heterogeneous.

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OBJECTIVE: Familial hyperaldosteronism type II (FH-II) is characterized by inheritance of primary aldosteronism (PAL) but, unlike FH-I, is not glucocorticoid remediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. Analysis of two pedigrees previously demonstrated linkage of FH-II with a locus at chromosome 7p22. We sought to determine whether mutations in the exons or intron/exon boundaries in PRKAR1B (encoding protein kinase A regulatory subunit R1-beta), which resides within the linked locus, are associated with FH-II. METHODS: Primers enabling sequencing of all exons and intron/exon boundaries were designed by BLAT search using known mRNA sequence, and comparison with an orthologous mouse gene. Sequences from four affected and two unaffected subjects from an Australian family with FH-II demonstrating linkage at 7p22 were compared with published sequences. RESULTS: A probable two-nucleotide GenBank sequence error, resulting in an amino acid change, was detected. Two of seven single nucleotide polymorphisms (SNPs) identified were in exons and five in introns. Neither exon-localized SNP resulted in an amino acid change. All intron-localized SNPs were at least 16 nucleotides from the closest intron/exon boundary and therefore unlikely to interfere with gene splicing. Importantly, none of the identified SNPs was exclusively associated with affectation status. CONCLUSIONS: Mutations in the exons or intron/exon boundaries of PRKAR1B do not appear to be responsible for FH-II in this family, but a mutation in the promoter or remaining intronic or 5' or 3' untranslated regions could be. Alternatively, a mutation within another gene residing at the 7p22 locus may be responsible.

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OBJECTIVE: Mutations in the gene for the POU domain transcription factor POU1F1 (human Pit-1) have been reported in patients with GH, TSH and PRL deficiencies. PROP1 (Prophet of Pit-1) gene mutations also cause gonadotrophin deficiencies and in some cases partial ACTH deficiency. This study analyses the POU1F1 and PROP1 genes in a cohort of Australian children with combined pituitary hormone deficiency (CPHD) and correlates results with patient phenotype. PATIENTS AND DESIGN: Genomic analysis was carried out on 33 patients with CPHD referred from centres around Australia. Clinical data were collected from medical records and referring physicans. RESULTS: POU1F1 mutations were identified in two of four patients with a suggestive phenotype. In a female patient, novel compound heterozygous POU1F1 mutations were identified: Arg143Leu in exon 3 and Leu194Gln in exon 4. This patient presented with failure to thrive at 6 weeks of age and has deficiencies of TSH and GH. A previously described heterozygous Arg271Trp mutation in exon 6 of the POU1F1 gene was identified in a female infant who presented with growth failure and was diagnosed with TSH then GH deficiencies. No PROP1 mutations were identified; however, we describe a number of previously unreported PROP1 polymorphisms. No patients presenting with deficiencies of all anterior pituitary hormones early in life had POU1F1 or PROP1 gene mutations. CONCLUSIONS: In 33 Australian children with CPHD we have identified POU1F1 mutations in two patients and no PROP1 mutations. We speculate that in the majority of children other genes must be responsible for the CPHD phenotype.

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We report a 12-month-old infant who presented with a 4-month history of isosexual precocious puberty secondary to an estrogenizing Sertoli-Leydig cell tumor of the ovary. Total serum immunoreactive inhibin and subunits A and B were markedly elevated before surgical resection and subsequently decreased 7 wk later into the normal prepubertal range. Twenty weeks following surgical removal, the patient presented again with central precocious puberty; inhibin B levels were raised on this occasion, a luteinizing releasing hormone stimulation test confirmed central precocious puberty. This is the youngest reported occurrence of this rare sex cord stromal neoplasm. The prognosis of this extremely rare tumor presenting at this early juvenile stage is uncertain. This report illustrates the usefulness of serum inhibin as a tumor marker during therapeutic suppression with leuprorelin acetate for central precocious puberty. Analysis of genomic and tumor DNA revealed a normal nucleotide sequence for the LH receptor and the Galpha(s) gene. To understand the molecular pathogenesis of this tumor we analyzed mRNA levels for the inhibin A and B subunits, FSH receptor, LH receptor aromatase, steroidogenic factor-1 and the ER beta genes. Molecular characterization reveals the presence of genes specific for granulosa and Leydig cells; the relative expression of these genes, in addition to its histologic characteristics, suggests that this tumor may result from a dysdifferentiation of a primordial follicle.

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