Auli Karhu

Publications (78) View all

• Article: No evidence of somatic aryl hydrocarbon receptor interacting protein mutations in sporadic endocrine neoplasia.

  A Raitila, M Georgitsi, A Karhu, K Tuppurainen, M J Mäkinen, K Birkenkamp-Demtröder, K Salmenkivi, T F Orntoft, J Arola, V Launonen, P Vahteristo, L A Aaltonen
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  ABSTRACT: Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently observed in patients with pituitary adenoma predisposition (PAP). Though AIP mutation-positive individuals with prolactin-, mixed growth hormone/prolactin-, and ACTH-producing pituitary adenomas as well as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age. Pituitary adenomas are also component tumors of some familial endocrine neoplasia syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Genes underlying MEN1 and CNC are rarely mutated in sporadic pituitary adenomas, but more often in other lesions contributing to these two syndromes. Thus far, the occurrence of somatic AIP mutations has not been studied in endocrine tumors other than pituitary adenomas. Here, we have analyzed 32 pituitary adenomas and 79 other tumors of the endocrine system for somatic AIP mutations by direct sequencing. No somatic mutations were identified. However, two out of nine patients with prolactin-producing adenoma were shown to harbor a Finnish founder mutation (Q14X) with a complete loss of the wild-type allele in the tumors. These results are in agreement with previous studies in that prolactin-producing adenomas are component tumors in PAP. The data also support the previous finding that somatic AIP mutations are not common in pituitary adenomas and suggest that such mutations are rare in other endocrine tumors as well.
  Endocrine Related Cancer 10/2007; 14(3):901-6. · 4.36 Impact Factor
• Article: No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer.

  S Tuupanen, A Karhu, H Järvinen, J P Mecklin, V Launonen, L A Aaltonen
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  ABSTRACT: Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56%) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P=0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.
  Oncogene 05/2007; 26(17):2513-7. · 6.37 Impact Factor
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  Article: Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers.

  M Georgitsi, A Karhu, R Winqvist, T Visakorpi, K Waltering, P Vahteristo, V Launonen, L A Aaltonen
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  ABSTRACT: Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently identified in individuals with pituitary adenoma predisposition (PAP). These patients have prolactin (PRL) or growth hormone (GH) oversecreting pituitary adenomas, the latter exhibiting acromegaly or gigantism. Loss-of-heterozygosity (LOH) analysis revealed that AIP is lost in PAP tumours, suggesting that it acts as a tumour-suppressor gene. Aryl hydrocarbon receptor interacting protein is involved in several pathways, but it is best characterised as a cytoplasmic partner of the aryl hydrocarbon receptor (AHR). To examine the possible role of AIP in the genesis of common cancers, we performed somatic mutation screening in a series of 373 colorectal cancers (CRCs), 82 breast cancers, and 44 prostate tumour samples. A missense R16H (47G>A) change was identified in two CRC samples, as well as in the respective normal tissues, but was absent in 209 healthy controls. The remaining findings were silent, previously unreported, changes of the coding, non-coding, or untranslated regions of AIP. These results suggest that somatic AIP mutations are not common in CRC, breast, and prostate cancers.
  British Journal of Cancer 02/2007; 96(2):352-6. · 5.04 Impact Factor
• Article: Analysis of microsatellite variation in Pinus radiata reveals effects of genetic drift but no recent bottlenecks.

  A Karhu, C Vogl, G F Moran, J C Bell, O Savolainen
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  ABSTRACT: Most conifer species occur in large continuous populations, but radiata pine, Pinus radiata, occurs only in five disjunctive natural populations in California and Mexico. The Mexican island populations were presumably colonized from the mainland millions of years ago. According to Axelrod (1981), the mainland populations are relicts of an earlier much wider distribution, reduced some 8,000 years ago, whereas according to Millar (1997, 2000), the patchy metapopulation-like structure is typical of the long-term population demography of the species. We used 19 highly polymorphic microsatellite loci to describe population structure and to search for signs of the dynamics of population demography over space and time. Frequencies of null alleles at microsatellite loci were estimated using an approach based on the probability of identity by descent. Microsatellite genetic diversities were high in all populations [expected heterozygosity (H(e)) = 0.68-0.77], but the island populations had significantly lower estimates. Variation between loci in genetic differentiation (F(ST)) was high, but no locus deviated statistically significantly from the rest at an experiment wide level of 0.05. Thus, all loci were included in subsequent analysis. The average differentiation was measured as F(ST) = 0.14 (SD 0.012), comparable with earlier allozyme results. The island populations were more diverged from the other populations and from an inferred common ancestral gene pool than the mainland ones. All populations showed a deficiency of expected heterozygosity given the number of alleles, the mainland populations more so than the island ones. The results thus do not support a recent important contraction in the mainland range of radiata pine.
  Journal of Evolutionary Biology 02/2006; 19(1):167-75. · 3.28 Impact Factor
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  Article: Mutation analysis of three genes encoding novel LKB1-interacting proteins, BRG1, STRAD, and MO25, in Peutz–Jeghers syndrome

  P Alhopuro, P Katajisto, R Lehtonen, S K Ylisaukko-oja, L N|[auml]||[auml]|tsaari, A Karhu, A M Westerman, J H P Wilson, F W M de Rooij, T Vogel, G Moeslein, I P Tomlinson, L A Aaltonen, T P M|[auml]|kel|[auml, V Launonen
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  ABSTRACT: Mutations in LKB1 lead to Peutz–Jeghers syndrome (PJS). However, only a subset of PJS patients harbours LKB1 mutations. We performed a mutation analysis of three genes encoding novel LKB1-interacting proteins, BRG1, STRAD, and MO25, in 28 LKB1-negative PJS patients. No disease-causing mutations were detected in the studied genes in PJS patients from different European populations.Keywords: Peutz–Jeghers syndrome, BRG1, STRAD, MO25, LKB1
  British Journal of Cancer 03/2005; 92(6):1126-1129. · 5.04 Impact Factor