Aryl hydrocarbon receptor interacting protein mutations seem not to associate with familial non-medullary thyroid cancer.

BACKGROUND: Over 95% of all thyroid malignancies are non-medullary thyroid carcinomas (NMTC). Familial NMTC are more aggressive and mortality is higher as compared with sporadic carcinomas. Known genetic factors do not explain all familial NMTC. Recently, thyroid disorders have been observed in families with germline mutations in aryl hydrocarbon receptor interacting protein (AIP) but, due to frequent occurrence of these conditions in the population, the significance of this co-occurrence is not clear. AIM, SUBJECTS AND METHODS: To examine whether AIP is involved in familial NMTC, we performed AIP mutation screening in 93 familial NMTC cases. In addition, the AIP status was studied in one follicular thyroid adenoma patient with a known AIP mutation from an additional cohort. RESULTS: No potentially pathogenic changes were identified, but two likely rare polymorphisms were detected. AIP mutation-positive patient's follicular thyroid adenoma showed no loss of heterozygosity or lack of immunohistochemical AIP staining. CONCLUSION: Our study indicates that germline AIP mutations are rare or do not exist in familial NMTC.

Mutation analysis of MEN1, HRPT2, CASR, CDKN1B, and AIP genes in primary hyperparathyroidism patients with features of genetic predisposition.

OBJECTIVE: Primary hyperparathyroidism (PHPT), a common endocrine condition, is usually caused by sporadically occurring parathyroid adenoma. A subset of patients carry germline mutations in genes such as MEN1 (multiple endocrine neoplasia type 1), HRPT2 (hyperparathyroidism 2), and CASR (calcium-sensing receptor) predisposing to syndromic forms of PHPT or familial isolated hyperparathyroidism (FIHP). Recently, germline mutations in two novel genes AIP (aryl hydrocarbon receptor-interacting protein) and CDKN1B (cyclin-dependent kinase inhibitor 1B) have been found to be associated with endocrine tumors. The purpose of this study was to evaluate the role of MEN1, HRPT2, CASR, AIP, and CDKN1B genes in PHPT patients with clinical features suggestive of genetic predisposition. PATIENTS AND DESIGN: Medical records of patients treated for PHPT from 1974 to 2001 at Oulu University Hospital were reviewed. Patients with multiglandular or recurrent/persistent disease, other MEN1- related manifestations, aged 40 yr or younger at onset or with a family history of PHPT/MEN1-related tumor were invited to the study. Twenty patients with previously diagnosed MEN1 were excluded. Participants were interviewed and blood samples obtained for biochemical screening and mutation analysis of MEN1, HRPT2, CASR, AIP, and CDKN1B. RESULTS: Of the 56 invited patients, 29 took part in the study. One patient was found to carry the c. 1356_1367del12 MEN1 founder mutation. Mutations in other genes were not detected. CONCLUSIONS: Apart from MEN1, mutations in other genes predisposing to PHPT seem to be rare or non-existing in Northern Finnish PHPT patients. No evidence was found for a role of AIP or CDKN1B in PHPT predisposition.

Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype phenotype correlation.

OBJECTIVE: The existence of genotype-phenotype correlation in multiple endocrine neoplasia type 1 (MEN1) is controversial. Two founder mutations of the MEN1 gene in Northern Finland gave us an opportunity to compare clinical features among heterozygotes of different mutations. DESIGN AND METHODS: Study cohort included 82 MEN1 heterozygotes who were tested for MEN1 during the years 1982-2001. Medical records were reviewed for manifestations of MEN1, other tumours and cause of death by the end of August 2003. Logistic regression analysis was used in evaluating the impact of age, gender and mutational status of affected heterozygotes on the likelihood of developing manifestations of MEN1. RESULTS: Founder mutations 1466del12 and 1657insC were found in 39 and 29 individuals, and D418N, G156R and R527X mutations in 9, 3 and 2 individuals respectively. Except for pituitary adenoma and nonfunctional pancreatic tumour (NFPT), age was a risk factor for all the disease manifestations. For NFPT, frameshift/nonsense mutations (1657insC, R527X) gave an odds ratio (OR) of 3.26 (95% confidence intervals (CI), 1.27-8.33; P = 0.014) compared with in-frame/missense mutations (1466del12, D418N, G156R); including the founder mutation carriers (n = 68) only, the 1657insC mutation gave an OR of 3.56 (CI, 1.29-9.83; P = 0.015). For gastrinoma, in-frame/missense mutations predicted the risk with an OR of 6.77 (CI, 1.31-35.0; P = 0.022), and in the founder mutations group the 1466del12 mutation gave an OR of 15.09 (CI, 1.73-131.9, P = 0.014). CONCLUSIONS: In this study population, NFPT was more common in the frameshift/nonsense or 1657insC mutation carriers, whereas gastrinoma was more common in the in-frame/missense or 1466del12 mutation carriers.

Increased risk of cancer in patients with fumarate hydratase germline mutation.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n = 98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n = 22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15-29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC.

Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations.

Estimation of mortality and the natural course of a disease is usually based on information of carefully studied individuals with or at risk for a specific disease. Genealogical information has rarely been accurate enough for such studies. With the help of church records and multiple endocrine neoplasia type 1 (MEN1) family information of the two founder MEN1 mutations in Northern Finland (1466del12 and 1657insC), we could trace back common ancestors born in the beginning of the 1700s (1466del12) and approximately 1850 (1657insC) and find 67 probable gene carriers born between 1728 and 1929, which were identified among their offspring. Information was gathered from 34 obligatory MEN1 gene carriers and 31 spouses. The mean age (+/- sd) of death of affected males (n = 16) was 61.1 +/- 12.0 yr vs. 65.8 +/- 15.3 yr for unaffected males (n = 16) and for affected females (n = 16) was 67.2 +/- 10.7 yr vs. 67.7 +/- 14.7 yr for unaffected females (n = 13). The ages of death of the obligatory heterozygotes did not differ from that of the spouses in sex groups or from the sex-matched life expectancy estimates derived from Finnish national statistics. Causes of death differed significantly between female probands and spouses. In conclusion, obligatory MEN1 gene carrier status did not show a harmful effect on survival in this retrospective analysis tracing back to almost 300 yr.

Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology.

Little has been known about the molecular background of familial multiple cutaneous leiomyomatosis (MCL). We report here a clinical, histopathological, and molecular study of a multiple cutaneous leiomyomatosis kindred with seven affected members. This detailed study revealed strong features of a recently described cancer predisposition syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). The family was compatible with linkage to the HLRCC locus in 1q. Also, all seven cutaneous leiomyomas derived from the proband and analyzed for loss of heterozygosity displayed loss of the wild-type allele, confirming the association with a susceptibility gene in chromosome 1q. One individual had had renal cell cancer at the age of 35 years. This tumor displayed a rare papillary histopathology, which appears to be characteristic for HLRCC. The derived linkage, loss of heterozygosity, and clinical data suggest that MCL and HLRCC are a single disease with a variable phenotype. The possibility that members of leiomyomatosis families are predisposed to renal cell cancer should be taken into account.

Extensive somatic microsatellite mutations in normal human tissue.

Microsatellite (MS) instability occurs in tumors with DNA mismatch repair (MMR) deficiencies but is typically absent in adjacent normal tissue. However, MS mutations have been observed in normal tissues from rare individuals with congenital MMR deficiencies. Autopsy tissues from a 4-year-old with congenital MMR deficiency (MLH1-/-) were examined for MS mutations. Insertions and deletions were observed in CA-repeat MS loci. Approximately 0.26 to 1.4 mutations per MS locus per cell were estimated to be present in normal heart, lymph node, kidney, and bladder epithelium. These findings illustrate that phenotypically normal MMR-deficient cells commonly accumulate MS mutations. Loss of MMR and the accumulation of some MS mutations may occur early in MMR-deficient tumor progression, even before a gatekeeper mutation.

Inherited susceptibility to uterine leiomyomas and renal cell cancer.

Herein we report the clinical, histopathological, and molecular features of a cancer syndrome with predisposition to uterine leiomyomas and papillary renal cell carcinoma. The studied kindred included 11 family members with uterine leiomyomas and two with uterine leiomyosarcoma. Seven individuals had a history of cutaneous nodules, two of which were confirmed to be cutaneous leiomyomatosis. The four kidney cancer cases occurred in young (33- to 48-year-old) females and displayed a unique natural history. All these kidney cancers displayed a distinct papillary histology and presented as unilateral solitary lesions that had metastasized at the time of diagnosis. Genetic-marker analysis mapped the predisposition gene to chromosome 1q. Losses of the normal chromosome 1q were observed in tumors that had occurred in the kindred, including a uterine leiomyoma. Moreover, the observed histological features were used as a tool to diagnose a second kindred displaying the phenotype. We have shown that predisposition to uterine leiomyomas and papillary renal cell cancer can be inherited dominantly through the hereditary leiomyomatosis and renal cell cancer (HLRCC) gene. The HLRCC gene maps to chromosome 1q and is likely to be a tumor suppressor. Clinical, histopathological, and molecular tools are now available for accurate detection and diagnosis of this cancer syndrome.

Clinical and genetic findings in Finnish ataxia patients with the spinocerebellar ataxia 8 repeat expansion.

Spinocerebellar ataxia 8 (SCA8) is caused by a CTG repeat expansion in an untranslated region of a recently cloned gene on 13q21. The pathogenic role of this trinucleotide repeat was evaluated by examining 154 Finnish ataxia patients and 448 controls. Expansions ranging from 100 to 675 repeats were present in 9 (6%) unrelated patients and in 13 (3%) controls. There was a threefold excess of shorter expansions (<204 repeats) in the ataxia series, and the expansions tended to cluster in patients with a family history for the disease. Clinical and genetic data were subsequently collected from 15 patients. Common initial symptoms included gait instability, dysarthria, and tremor. A marked cerebellar atrophy in magnetic resonance imaging or computed tomography was found in all patients. Pyramidal affection was often seen, and various kinds of cognitive impairment were evident in 40% of patients. Disease progression was slow, and fluctuation of symptoms was commonly observed. A maternal penetrance bias was not seen, nor was there any clear-cut negative correlation between age of onset and repeat number. Meiotic but not mitotic instability of the repeat expansion was evident. Haplotype analysis suggests multiple origins for the Finnish spinocerebellar ataxia 8 repeat expansions.

Splicing mutations in the COL3 domain of collagen IX cause multiple epiphyseal dysplasia.

We report on a three-generation family with multiple epiphyseal dysplasia (MED). The propositus had typical MED findings of knees, ankles, elbows, and hands in childhood. The 2 other affected relatives were adults. The main clinical findings consisted of osteochondritis dissecans and osteoarthritis of the knees. DNA of the propositus was screened for mutations by conformation sensitive gel electrophoresis in all known candidate genes for MED, cartilage oligomeric matrix protein, and the COL9A1, COL9A2, and COL9A3 genes coding for the alpha1, alpha2, and alpha3 chains of collagen IX. The screening identified a unique change in PCR products of exon 3 of the COL9A3 gene. Sequencing indicated a G to A mutation in the acceptor splice site (G(-1)IVS2-->A) of intron 2 in all affected relatives, but not in unaffected relatives. Analysis of RNA from the propositus indicated a skipping of exon 3, and thus, a deletion of 12 amino acid residues as a consequence of the mutation. All four other collagen IX mutations previously described in MED have consequences identical to that characterized here, thus it seems likely that this type of mutation in collagen IX plays an important role in the pathogenesis of MED.