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Biomedical subjects

L A Aaltonen

Publications and source records attributed to L A Aaltonen.

At least 19 recordsLinked to original sources
PubMed2006

No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer.

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.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2006

Nordic collaborative study of the BARD1 Cys557Ser allele in 3956 patients with cancer: enrichment in familial BRCA1/BRCA2 mutation-negative breast cancer but not in other malignancies.

BACKGROUND: BARD1 was originally identified as a BRCA1-interacting protein but has also been described in tumour-suppressive functions independent of BRCA1. Several studies have indicated that the BARD1 gene is a potential target for germline changes predisposing to breast and ovarian cancer. The C-terminal Cys557Ser change has previously been uncovered to associate with an increased risk of breast cancer and was recently shown to result in defective apoptotic activities. AIM AND METHODS: Conformation-sensitive gel electrophoresis, minisequencing, TaqMan assays, denaturing high-performance liquid chromatography analysis and DNA sequencing were used to investigate the prevalence of the Cys557Ser allele in a large Nordic case-control study cohort consisting of 2906 patients with breast or ovarian cancer, 734 with prostate cancer, 188 with colorectal cancer, 128 men with breast cancer, and 3591 controls from Finland, Iceland, Denmark, Sweden and Norway. RESULTS: The frequency of the BARD1 Cys557Ser variant seemed to increase among patients from families with breast or ovarian cancer lacking BRCA1 or BRCA2 mutations: a significant difference was obtained compared with controls (6.8% v 2.7%; p<0.001; odds ratio (OR) 2.6; 95% confidence interval (CI) 1.7 to 4.0) and with patients from BRCA1/BRCA2 mutation-positive families (6.8% v 2.2%; p = 0.01; OR 3.2; 95% CI 1.2 to 8.3). In contrast, no major association with male breast, ovarian, colorectal or prostate cancer was observed. Additionally, a novel BARD1 allele resulting in Ser558Pro was identified in familial breast cancer cases. CONCLUSION: These results provide further evidence that BARD1 Cys557Ser confers a slightly increased risk of breast cancer in women.

Adolescent↗
PubMed2006

Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis.

Serrated colorectal carcinomas (CRCs) are morphologically different from conventional CRCs and have been proposed to follow a distinct pathway of CRC formation. Despite studies of single molecular events in this tumor type, the diagnosis of serrated CRC relies on morphology and the putative unique biological character of these tumors has not been established. Here we show that the gene expression profiling of 37 CRCs separated serrated and conventional CRCs into two distinct branches in unsupervised hierarchical clustering (P-value 7.8 x 10(-7)), and revealed 201 differentially expressed genes representing potential biomarkers for serrated CRC. Immunohistochemistry was utilized to verify the key findings in the 37 CRCs examined by expression profiling, and a separate validation set of 37 serrated and 86 conventional CRCs was examined to evaluate the candidate biomarkers in an extended sample material. Ephrin receptor B2, hypoxia-inducible factor 1-alpha and patched appeared as proteins important for genesis of serrated CRC. This study establishes serrated CRCs as a biologically distinct subclass of CRC and represents a step forward in the molecular classification of these cancers. The study also provides a platform to understand the molecular basis of serrated CRC and in long term may contribute to the development of specific treatment options for this tumor type.

Adenocarcinoma, Mucinous↗
PubMed2006

CHEK2 I157T associates with familial and sporadic colorectal cancer.

BACKGROUND: Recently, a functionally defective CHEK2 variant I157T has been proposed to associate with an increased risk of several types of cancer. We investigated the CHEK2 I157T variant for colorectal cancer (CRC) predisposition in a large population based study including a significant number of familial CRC cases. METHODS: We screened the CHEK2 I157T variant in a population based series of 1042 Finnish CRC patients using restriction fragment length polymorphism. Mutation status was studied for correlation with clinical characteristics and family history of CRC and other cancers. RESULTS: The frequency of CHEK2 I157T was significantly higher in CRC patients (7.8%, 76/972) than in healthy population controls (5.3%, 100/1885) (OR = 1.5, 95% CI 1.1 to 2.1, p = 0.008). The significant association of CHEK2 I157T with CRC was observed among patients with (10.4%, 14/135) and without (7.4%, 62/837) a family history of CRC (OR = 2.1, 95% CI 1.1 to 3.7, p = 0.01; OR = 1.4, 95% CI 1.0 to 2.0, p = 0.03; respectively). A trend towards higher variant frequency was also noted among patients with multiple primary tumours and a family history of any cancer. CONCLUSIONS: CHEK2 I157T associates with an increased risk of CRC: the association was observed both among familial and sporadic CRC patients. Furthermore, the higher frequency of I157T among patients with multiple primary tumours as well as those with a family history of any cancer supports a role for CHEK2 I157T as a susceptibility allele for multiple cancer types.

Case-Control Studies↗
PubMed2006

LKB1 exonic and whole gene deletions are a common cause of Peutz-Jeghers syndrome.

BACKGROUND: LKB1/STK11 germline mutations cause Peutz-Jeghers syndrome (PJS). The existence of a second PJS locus is controversial, the evidence in its favour being families unlinked to LKB1 and the low frequency of LKB1 mutations found using conventional methods in several studies. Exonic and whole gene deletion or duplication events cannot be detected by routine mutation screening methods. OBJECTIVE: To seek evidence for LKB1 germline deletions or duplications by screening patients meeting clinical criteria for PJS but without detected mutations on conventional screening. METHODS: From an original cohort of 76 patients, 48 were found to have a germline mutation by direct sequencing; the remaining 28 were examined using multiplex ligation dependent probe amplification (MLPA) analysis to detect LKB1 copy number changes. RESULTS: Deletions were found in 11 of the 28 patients (39%)--that is, 14% of all PJS patients (11/76). Five patients had whole gene deletions, two had the promoter and exon 1 deleted, and in one patient exon 8 was deleted. Other deletions events involved: loss of exons 2-10; deletion of the promoter and exons 1-3; and loss of part of the promoter. No duplications were detected. Nine samples with deletions were sequenced at reported single nucleotide polymorphisms to exclude heterozygosity; homozygosity was found in all cases. No MLPA copy number changes were detected in 22 healthy individuals. CONCLUSIONS: These results lessen the possibility of a second PJS locus, as the detection rate of germline mutations in PJS patients was about 80% (59/76). It is suggested that MLPA, or a suitable alternative, should be used for routine genetic testing of PJS patients in clinical practice.

AMP-Activated Protein Kinase Kinases↗
PubMed2005

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.

Adolescent↗
PubMed2005

Gene expression signatures for colorectal cancer microsatellite status and HNPCC.

The majority of microsatellite instable (MSI) colorectal cancers are sporadic, but a subset belongs to the syndrome hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability is caused by dysfunction of the mismatch repair (MMR) system that leads to a mutator phenotype, and MSI is correlated to prognosis and response to chemotherapy. Gene expression signatures as predictive markers are being developed for many cancers, and the identification of a signature for MMR deficiency would be of interest both clinically and biologically. To address this issue, we profiled the gene expression of 101 stage II and III colorectal cancers (34 MSI, 67 microsatellite stable (MSS)) using high-density oligonucleotide microarrays. From these data, we constructed a nine-gene signature capable of separating the mismatch repair proficient and deficient tumours. Subsequently, we demonstrated the robustness of the signature by transferring it to a real-time RT-PCR platform. Using this platform, the signature was validated on an independent test set consisting of 47 tumours (10 MSI, 37 MSS), of which 45 were correctly classified. In a second step, we constructed a signature capable of separating MMR-deficient tumours into sporadic MSI and HNPCC cases, and validated this by a mathematical cross-validation approach. The demonstration that this two-step classification approach can identify MSI as well as HNPCC cases merits further gene expression studies to identify prognostic signatures.

Adenocarcinoma↗
PubMed2005

Mutation analysis of three genes encoding novel LKB1-interacting proteins, BRG1, STRADalpha, and MO25alpha, in Peutz-Jeghers syndrome.

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, STRADalpha, and MO25alpha, in 28 LKB1-negative PJS patients. No disease-causing mutations were detected in the studied genes in PJS patients from different European populations.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Differential gene expression in colon cancer of the caecum versus the sigmoid and rectosigmoid.

BACKGROUND AND AIMS: There are epidemiological, morphological, and molecular differences between normal mucosa as well as between adenocarcinomas of the right and left side of the large bowel. The aim of this study was to investigate differences in gene expression. METHODS: Oligonucleotide microarrays (GeneChip) were used to compare gene expression in 45 single samples from normal mucosa and sporadic colorectal carcinomas (Dukes' B and C) of the caecum compared with the sigmoid and rectosigmoid. Findings were validated by real time polymerase chain reaction. RESULTS: Fifty eight genes were found to be differentially expressed between the normal mucosa of the caecum and the sigmoid and rectosigmoid (p<0.01), including pS2, S100P, and a sialyltransferase, all being expressed at higher levels in the caecum. A total of 118 and 186 genes were differentially expressed between normal and right or left sided tumours of the colon, showing more pronounced differences in Dukes' C than B tumours. Thirty genes differentially expressed in tumour tissue were common to adenocarcinomas of both sides, including known tumour markers such as the matrix metalloproteinases. Keratins 8, 19, and 20 as well as carbonic anhydrases (II, IV, VII) showed side specific expression and were downregulated in left sided tumours whereas teratocarcinoma growth factor and cyclooxygenase 2 (COX-2) were upregulated in left sided adenocarcinomas. Immunohistochemical analysis confirmed differences in side specific expression for cytokeratin 20 and COX-2. CONCLUSIONS: Differences in gene expression between normal mucosa as well as between adenocarcinomas of the caecum and sigmoid or rectosigmoid exist and should be taken into account when examining new targeted therapeutic regimens.

Adenocarcinoma↗
PubMed2005

The C/C-13910 genotype of adult-type hypolactasia is associated with an increased risk of colorectal cancer in the Finnish population.

BACKGROUND AND AIMS: The role of nutrition in the pathogenesis of colorectal cancer is not fully understood. Milk products are an essential part of human nutrition in Western countries. Absorption of lactose, the main sugar of milk, is regulated by the activity of the lactase enzyme in the gut wall. The activity of lactase is genetically determined and is associated with a C/T single nucleotide polymorphism residing 13910 bp upstream of the lactase coding sequence. Here we have studied the relationship between the C/T(-13910) polymorphism and colorectal cancer in Finnish, British, and Spanish populations. PATIENTS AND METHODS: A total of 2766 subjects, including 963 Finnish, 283 British, and 163 Spanish subjects with colorectal cancer, and 773 Finnish, 363 British, and 221 Spanish control subjects, were genotyped for the C/T(-13910) variant by polymerase chain reaction minisequencing. RESULTS: The C/C(-13910) genotype, which is a robust molecular marker of low lactase activity (lactase non-persistence), was found to significantly associate with the risk of colorectal cancer (p = 0.015) in the Finnish subjects, with an odds ratio of 1.40 (95% confidence interval 1.07-1.85). No association was found with site, histology, or stage of the tumour. No significant risk was detected in the British or Spanish populations. CONCLUSION: Low lactase enzyme activity, defined by genotyping of the C/T(-13910) variant, may increase the risk of colorectal cancer. Further studies are warranted to investigate the role of milk and other dairy products in the pathogenesis of colon cancer in different populations.

Adult↗
PubMed2005

No MSH6 germline mutations in breast cancer families with colorectal and/or endometrial cancer.

BACKGROUND: The genetic background in breast cancer families with colorectal and/or endometrial cancer is mostly unknown. The functional connection between MSH6 and the known breast cancer predisposition gene product BRCA1 suggests that the MSH6 gene may also play a role in breast cancer predisposition. METHODS: We analysed 38 breast cancer families with colorectal and/or endometrial cancer for germline mutations in MSH6. RESULTS: No disease associated mutations were detected among the breast cancer families. However, mutation analysis revealed a Glu995STOP mutation in an atypical HNPCC family. The same mutation was found in a patient with both breast and colorectal carcinoma in our previous study, and haplotype analysis confirmed a common ancestral origin. The Glu995STOP mutation was further examined in an extensive series of 245 colorectal and 142 breast carcinoma patients with a family history of breast, colorectal, and/or endometrial carcinoma, and in 268 healthy population controls, but none was found to carry the mutation. CONCLUSIONS: Our results suggest that MSH6 may not be the underlying gene in breast cancer families with a history of colorectal and/or endometrial cancer. The Glu995STOP founder mutation is not a familial breast cancer predisposition allele and makes only a limited contribution to colorectal cancer burden in Finland.

Breast Neoplasms↗
PubMed2005

The MDM2 promoter polymorphism SNP309T-->G and the risk of uterine leiomyosarcoma, colorectal cancer, and squamous cell carcinoma of the head and neck.

BACKGROUND: MDM2 acts as a principal regulator of the tumour suppressor p53 by targeting its destruction through the ubiquitin pathway. A polymorphism in the MDM2 promoter (SNP309) was recently identified. SNP309 was shown to result, via Sp1, in higher levels of MDM2 RNA and protein, and subsequent attenuation of the p53 pathway. Furthermore, SNP309 was proposed to be associated with accelerated soft tissue sarcoma formation in both hereditary (Li-Fraumeni) and sporadic cases in humans. METHODS: We evaluated the possible contribution of SNP309 to three tumour types known to be linked with the MDM2/p53 pathway, using genomic sequencing or restriction fragment length polymorphism as screening methods. Three separate Finnish tumour materials (population based sets of 68 patients with early onset uterine leiomyosarcomas and 1042 patients with colorectal cancer, and a series of 162 patients with squamous cell carcinoma of the head and neck) and a set of 185 healthy Finnish controls were analysed for SNP309. RESULTS: Frequencies of SNP309 were similar in all four cohorts. In the colorectal cancer series, SNP309 was somewhat more frequent in women and in patients with microsatellite stable tumours. Female SNP309 carriers were diagnosed with colorectal cancer approximately 2.7 years earlier than those carrying the wild type gene. However, no statistically significant association of SNP309 with patients' age at disease onset or to any other clinicopathological parameter was found in these three tumour materials. CONCLUSION: SNP309 had no significant contribution to tumour formation in our materials. Possible associations of SNP309 with microsatellite stable colorectal cancer and with earlier disease onset in female carriers need to be examined in subsequent studies.

Adult↗
PubMed2004

The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.

BACKGROUND: Juvenile polyposis (JP) is an autosomal dominant syndrome predisposing to colorectal and gastric cancer. We have identified mutations in two genes causing JP, MADH4 and bone morphogenetic protein receptor 1A (BMPR1A): both are involved in bone morphogenetic protein (BMP) mediated signalling and are members of the TGF-beta superfamily. This study determined the prevalence of mutations in MADH4 and BMPR1A, as well as three other BMP/activin pathway candidate genes in a large number of JP patients. METHODS: DNA was extracted from the blood of JP patients and used for PCR amplification of each exon of these five genes, using primers flanking each intron-exon boundary. Mutations were determined by comparison to wild type sequences using sequence analysis software. A total of 77 JP cases were sequenced for mutations in the MADH4, BMPR1A, BMPR1B, BMPR2, and/or ACVR1 (activin A receptor) genes. The latter three genes were analysed when MADH4 and BMPR1A sequencing found no mutations. RESULTS: Germline MADH4 mutations were found in 14 cases (18.2%) and BMPR1A mutations in 16 cases (20.8%). No mutations were found in BMPR1B, BMPR2, or ACVR1 in 32 MADH4 and BMPR1A mutation negative cases. DISCUSSION: In the largest series of JP patients reported to date, the prevalence of germline MADH4 and BMPR1A mutations is approximately 20% for each gene. Since mutations were not found in more than half the JP patients, either additional genes predisposing to JP remain to be discovered, or alternate means of inactivation of the two known genes are responsible for these JP cases.

Activin Receptors, Type I↗
PubMed2004

BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing.

BACKGROUND: According to the international criteria for hereditary non-polyposis colorectal cancer (HNPCC) diagnostics, cancer patients with a family history or early onset of colorectal tumours showing high microsatellite instability (MSI-H) should receive genetic counselling and be offered testing for germline mutations in DNA repair genes, mainly MLH1 and MSH2. Recently, an oncogenic V600E hotspot mutation within BRAF, a kinase encoding gene from the RAS/RAF/MAPK pathway, has been found to be associated with sporadic MSI-H colon cancer, but its association with HNPCC remains to be further clarified. METHODS: BRAF-V600E mutations were analysed by automatic sequencing in colorectal cancers from 206 sporadic cases with MSI-H and 111 HNPCC cases with known germline mutations in MLH1 and MSH2. In addition, 45 HNPCC cases showing abnormal immunostaining for MSH2 were also analysed. RESULTS: The BRAF-V600E hotspot mutation was found in 40% (82/206) of the sporadic MSI-H tumours analysed but in none of the 111 tested HNPCC tumours or in the 45 cases showing abnormal MSH2 immunostaining. CONCLUSIONS: Detection of the V600E mutation in a colorectal MSI-H tumour argues against the presence of a germline mutation in either the MLH1 or MSH2 gene. Therefore, screening of these mismatch repair (MMR) genes can be avoided in cases positive for V600E if no other significant evidence, such as fulfilment of the strict Amsterdam criteria, suggests MMR associated HNPCC. In this context, mutation analysis of the BRAF hotspot is a reliable, fast, and low cost strategy which simplifies genetic testing for HNPCC.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2003

Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability.

Exonuclease 1 (EXO1) is a candidate gene for colorectal tumor susceptibility because it is believed to play a role in mismatch repair. There have been several studies investigating the role of EXO1 in mismatch repair but few investigating its role in causing clinical disease. In one recent study, germline variants of EXO1 were reported to be associated with predisposition to colorectal cancer in families with phenotypes similar to hereditary nonpolyposis colon cancer (HNPCC). We recently identified nine individuals from two British families with multiple cutaneous and uterine leiomyomatosis with independently arising heterozygous germline deletions of 1q42.3 approximately q43 encompassing not only FH, the multiple leiomyomatosis-associated gene, but also several flanking genes, including EXO1. We investigated these families for any indication of predisposition to colorectal cancer or other HNPCC spectrum cancers by means of detailed questionnaires, interviews, and examination of EXO1-null skin leiomyomata for microsatellite instability (MSI). No individual in these families had developed colorectal cancer or known colorectal adenomas, and none had any symptoms warranting gastrointestinal or other investigation. EXO1-null tumors showed no evidence of MSI. This study questions the functional significance of previously reported variants of EXO1 reported in HNPCC-like families and suggests that in humans there may be other as yet undiscovered proteins that have exonuclease function overlapping with that of EXO1 in DNA mismatch repair. Also of interest is the absence of phenotypic abnormality apart from multiple leiomyomatosis in any deletion carrier even though the adjacent genes RGS7, KMO, CHML, and OPN3 were also deleted.

Adult↗