PubMed Health⌕ Search

Biomedical subjects

P Peltomäki

Publications and source records attributed to P Peltomäki.

At least 19 recordsLinked to original sources
PubMed2006

Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32-31.1.

BACKGROUND: The best known hereditary colorectal cancer syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), constitute about 2% of all colorectal cancers, and there are at least as many non-FAP, non-HNPCC cases where the family history suggests a dominantly inherited colorectal cancer risk. Recently, a locus on chromosome 9q22.2-31.2 was identified by linkage analysis in sib pairs with colorectal cancer or adenoma. METHODS: Linkage analysis for the suggested locus on chromosome 9 was carried out in an extended Swedish family. This family had previously been investigated but following the identification of adenomas in several previously unaffected family members, these subjects were now considered to be gene carriers. RESULTS: In the present study, we found linkage of adenoma and colorectal cancer to chromosome 9q22.32-31.1 with a multipoint LOD score of 2.4. We were also able to define the region for this locus to 7.9 cM between the markers D9S280 and D9S277. CONCLUSIONS: Our result supports the presence of a susceptibility locus predisposing to adenoma and colorectal cancer in this chromosomal region.

Adenoma↗
PubMed2004

Ethnic variation in the prevalence of AZF deletions in testicular cancer.

Seventy-six percent of testicular cancers of origin in Finns have been reported to exhibit AZF deletions. We analyze here 40 testicular tumor cases from Norway and Argentina and we found that AZF deletions occur also in non-Finnish cases but at significantly lower frequency (25%) than in Finland testicular tumor cases. This frequency difference can be attributed to the condition of genetic isolate of the Finnish population and the subsequent prevalence in this ethnic group of genetic factors involved in the origin of AZF deletions associated with malignancies. The finding of a correlation between AZF deletions and a given Y haplogroup would indicate the existence of Y lineages carrying AZF deletion-enhancing gene or genes. This possibility was explored using a set of Y-DNA-markers allowing the identification of Y lineages occurring at high frequency in Finns. We characterized the Y haplogroups in 32 normal Finn males (control group) and 17 cases of testicular cancer in Finns with and without AZF deletions. We found no association between Y lineages and AZF microdeletions, nor between AZF microdeletions and a Y microdeletion (DYS7C) exhibiting high prevalence (>50%) in Finns. The lack of correlation between AZF deletions and Y haplogroups indicates that the origin of these deletions is independent from the Y chromosome genetic background. No AZF deletions were found in familial cases of testicular tumors; hence, hereditary factors inducing the appearance of testicular malignancies in certain genealogies apparently do not increase the susceptibility to AZF deficiencies. AZF deletions are de novo events occurring in prezygotic or in post-zygotic stages. We propose that most AZF deletions associated with testicular tumors are due to post-zygotic Y microdeletions, while most cases of deletions associated with infertility are due to deletions occurring in the germ cell line of proband fathers.

Chromosomes, Human, Y↗
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↗
PubMed2002

Genetic and clinical characterisation of familial adenomatous polyposis: a population based study.

BACKGROUND: Familial adenomatous polyposis (FAP) is a rare autosomal dominantly inherited disease predisposing to colon cancer and caused by germline mutations in the APC (adenomatous polyposis coli) gene. AIMS: We conducted a population based study to evaluate the prevalence and clinical implications of APC mutations among Finnish FAP kindreds. A possible founder effect in parallel with previous observations in hereditary non-polyposis colon cancer (HNPCC) was addressed. PATIENTS: Affected individuals from 65 kindreds were included. METHODS: The APC gene was screened for mutations using the protein truncation test and heteroduplex analysis. Haplotype analysis was performed with four flanking microsatellite markers. Families that failed to show any mutations were scrutinised with Southern blot hybridisation and allelic expression analysis. RESULTS: Thirty eight different germline mutations in APC were identified in 47 kindreds (72%). The majority of these mutations were novel and unique to each family. Although sharing the classical polyposis phenotype, families without detectable APC mutations differed from mutation positive families in the following respects: firstly, mean age at polyposis diagnosis was higher (38.6 years (48 individuals) v 30.0 years (140 individuals); p=0.001); and secondly, the proportion of kindreds lacking extracolonic disease was higher (6/18 v. 5/47; p=0.04). CONCLUSIONS: Our results may pave the way for predictive testing in mutation positive families and should stimulate further molecular studies in mutation negative families. No founder effect was observed, which is in contrast with HNPCC in the same population.

Adenomatous Polyposis Coli↗
PubMed2001

The role of hPMS1 and hPMS2 in predisposing to colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is attributable to a deficiency of mismatch repair. Inactivation of DNA mismatch repair underlies the genesis of microsatellite instability in colorectal cancer. Germline mutations in three DNA mismatch repair genes, hMSH2, hMLH1, and hMSH6, have been found to segregate in HNPCC and HNPCC-like families. The two DNA mismatch repair genes hPMS1 and hPMS2 have also been suggested to predispose to HNPCC. In this study, 84 HNPCC and HNPCC-like kindreds without known mutations in the other three known DNA mismatch repair genes were screened for germline mutations in the hPMS1 or hPMS2 gene. No clear-cut pathogenic mutations were identified. Conversion technology was used to detect a large hMSH2 deletion in two affected members of the kindred in which the hPMS1 mutation was originally reported, whereas the hPMS1 mutation was only present in one of these two individuals. Since the hPMS1 and hPMS2 genes were first reported, germline mutations in hPMS2 have been demonstrated primarily in patients with Turcot's syndrome. However, no mutation in any of the two genes has been found to segregate in HNPCC families. Until there is better evidence for an increased colorectal cancer risk associated with germline mutations in these genes, a conservative interpretation of the role of mutations in these genes is advised.

Adenosine Triphosphatases↗
PubMed2001

Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study.

PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer. PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1. RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P <.01), high mucinous component (P <.01), and poor differentiation (P =.002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations. CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.

Adaptor Proteins, Signal Transducing↗
PubMed2001

CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer is associated with inherited defects in DNA mismatch repair. Clinical variation even in cases with identical predisposing mutations suggests the existence of other factors contributing to the phenotype. We addressed the modifying role of the common A/G polymorphism in exon 4 and the alternatively spliced transcripts a and b of the CCND1 gene encoding cyclin D1 in a series of 146 affected carriers of 10 MLH1 and 3 MSH2 mutations. No correlation was observed between a particular allele (A versus G) and age at onset. However, the presence of the variant transcript b in blood/normal mucosa, by multiplex reverse transcription-PCR, was associated with a significantly lower age at onset of colon cancer as compared with individuals with transcript a only (35 versus 46 years; P = 0.02). Whereas our data do not support a modifying role of A versus G allele of CCND1, the results do suggest that the relative abundance of a and b transcripts may modify the age at onset of colon cancer in hereditary nonpolyposis colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer syndrome is associated with an inherited predisposition to primarily colorectal cancer (CRC) and endometrial cancer (EC); however, the biological basis of the organ involvement remains unknown. As an attempt to explore whether the expression levels of MLH1, MSH2, and MSH6 may play a role, we used immunohistochemistry to study 42 ECs and 35 CRCs from patients carrying the same predisposing mutations. Among MSH2 mutation carriers, MLH1 was expressed in both tumor types, whereas MSH2 and, in many cases, also MSH6, were absent. Remarkably, among MLH1 mutation carriers, 54% of ECs (21 of 39), but none of the CRCs (0 of 32), lacked the MSH2 and/or MSH6 protein in addition to lacking MLH1 protein expression. These results demonstrate a marked difference between hereditary nonpolyposis colorectal cancer-related CRCs and ECs and suggest that the development of the latter tumors is selectively associated with the MSH2/MSH6 protein complex deficiency.

Adaptor Proteins, Signal Transducing↗
PubMed2001

MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer.

A set of 90 nonpolypotic colon cancer families in which germ-line mutations of MSH2 and MLH1 had been excluded were screened for mutations in two additional DNA mismatch repair genes, MSH6 and MSH3. Kindreds fulfilling and not fulfilling the Amsterdam I criteria, showing early and late onset colorectal (and other) cancers, and having microsatellite stable and unstable tumors were included. Two partly parallel approaches were used: genetic linkage analysis (19 large families) and the protein truncation test (85, mostly smaller, families). Whereas MSH3 was not involved in any family, a large Amsterdam-positive, late-onset family showed a novel germ-line mutation in MSH6 (deletion of CT at nucleotide 3052 in exon 4). The mutation was identified through genetic linkage (multipoint lod score 2.4) and subsequent sequencing of MSH6. Furthermore, the entire MSH6 gene was sequenced exon by exon in families with frameshift mutations in the (C)8 tract in tumors, previously suggested as a predictor of MSH6 germ-line mutations; no mutations were found. We conclude that germ-line involvement of MSH6 and MSH3 is rare and that other genes are likely to account for a majority of MSH2-, MLH1-mutation negative families with nonpolypotic colon cancer.

Adult↗
PubMed2001

DNA mismatch repair and cancer.

Five human DNA mismatch repair genes have been identified that, when mutated, cause susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC). Mutational inactivation of both copies of a DNA mismatch repair gene results in a profound repair defect and progressive accumulation of mutations throughout the genome. Some of the mutations confer selective advantage on the cells, giving rise to cancer. Recent discoveries suggest that apart from postreplication repair, DNA mismatch repair proteins have several other functions that are highly relevant to carcinogenesis. These include DNA damage surveillance, prevention of recombination between nonidentical sequences and participation in meiotic processes (chromosome pairing). A brief overview of these different features of the human DNA mismatch repair system will be provided, with the emphasis in their implications in cancer development.

Animals↗
PubMed2001

Genotype and phenotype in hereditary nonpolyposis colon cancer: a study of families with different vs. shared predisposing mutations.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a multi-organ cancer syndrome associated with heritable mutations in DNA mismatch repair genes, particularly MLH1 (MutL Homologue 1) and MSH2 (MutS Homologue 2). We took advantage of the unique characteristics of the Finnish HNPCC families to assess genotype- phenotype correlations in this disorder. We studied 295 mutation carriers (10 mutations in MLH1 and 3 in MSH2) segregating in 55 families. In addition to the comparison of families with different mutations, the enrichment of two MLH1 mutations, one affecting exon 16 (29 families, 186 individuals) and another one affecting exon 6 (10 families, 45 individuals) allowed the comparison of kindreds with identical predisposing mutations. Extracolonic cancers were more common in MSH2 than MLH1 mutation carriers, with the ratios of 0.48 and 0.64, respectively, of colorectal cancer to all cancers (P = 0.076). Within MLH1, two mutations affecting only the amino terminal portion showed a significant association with late onset of cancer as compared to the remaining mutations. Importantly, families with the MLH1 exon 16 mutation displayed significant variation (P = 0.012) in the age at onset of colon cancer, despite shared predisposition. We conclude that even though characteristics of the inherited mutations may explain part of the observed clinical variation, other factors have a significant impact on HNPCC phenotype determination.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Deficient DNA mismatch repair: a common etiologic factor for colon cancer.

Hereditary non-polyposis colon cancer (HNPCC), the most common form of hereditary colon cancer, is a syndrome of deficient DNA mismatch repair (MMR). Five, possibly six, human MMR genes have been identified that, when mutated in the germline, cause susceptibility to this syndrome. To date, more than 300 different predisposing mutations are known, mainly affecting the MMR genes MLH1 ( approximately 50%), MSH2 ( approximately 40%) and MSH6 ( approximately 10%). Genetically predisposed individuals carry a defective copy of an MMR gene in every cell. Somatic inactivation of the remaining wild-type copy in a target tissue, typically colon, gives rise to a profound repair defect, progressive accumulation of mutations and cancer. Instability at short tandem repeat sequences, microsatellites, is a typical manifestation of MMR deficiency and apart from HNPCC tumors, occurs in approximately 15% of sporadic colon and other tumors. The majority of the latter cases are attributable to one particular MMR gene, MLH1, and unlike HNPCC, an epigenetic rather than a genetic mechanism plays an important role in the inactivation of this gene. The present review provides an update of the genetics of HNPCC and more generally, of cancer development driven by deficient MMR. Recent discoveries suggest that apart from post-replication repair, MMR proteins have several other functions that are highly relevant to carcinogenesis. Knowledge of the complex interplay between the MMR system and other cellular pathways allows us to better understand the phenotypic manifestations of HNPCC and other cancers with deficient MMR.

Base Pair Mismatch↗
PubMed2000

Nuclear and mitochondrial genome instability in human breast cancer.

We analyzed 40 pairs of breast normal/cancer tissues for the presence of mitochondrial (mt) genome instability and nuclear MSI in tumor cells. As mt, markers we used a (CA)n mt microsatellite (MS) starting at the 514-bp position of the D loop region and 4 informative MnlI sites located between the 16,108- and 16,420-bp positions of the D loop region. Nuclear microsatallite instability (MSI) was tested with 8 (CA)n MS, syntenic for the 13q chromosome arm. Moreover, we tested the spontaneous frequency of mtMSI and mt-MnlI mutations in 459 mother/descendant events. Mutations of mt-MnlI sites were found in 19 of 40 (47.5%) breast tumors, representing a 216-fold increase over the spontaneous rate in the female germline. Instability of the mtMS occurred in 17 of 40 (42.5%) breast cancers, which implies a 16-fold increase over the rate of spontaneous mutations. Nuclear MSI was found in 20 of 40 (50%) cases. In 15 of these cases the MSI was restricted to one locus, whereas in 5 instances the change of alleles was detected in 2 or 3 loci. Analysis of the correlation between mt and nuclear mutations showed no significant associations, suggesting that different systems are responsible for mt and nuclear genome instability in tumor cells. We propose that the two main mechanisms producing mtRFLP and mtMSI are damage by free radicals and error repair by the polymerase gamma, the first mechanism being a major cause of MnlI mutations and a secondary cause of mtMSI.

Alleles↗
PubMed2000

DNA copy number changes in malignant ovarian germ cell tumors.

Malignant ovarian germ cell tumors (OGCTs) include immature teratomas (ITs), dysgerminomas (DGs), endodermal sinus tumors (ESTs), choriocarcinomas, and embryonal carcinomas. Knowledge about the genetic changes associated with malignant OGCT development is sparse. We therefore analyzed 25 OGCTs (12 DGs, 4 ESTs, and 9 ITs) for gains and losses by comparative genomic hybridization. In total, more gains than losses were observed, and the number of alterations ranged from 0-20 per tumor. The average number of changes among DGs, ESTs, and ITs was 10, 6, and 1.4, respectively. The most common changes in DGs were gains from chromosome arms 1p (33%), 6p (33%), 12p (67%), 12q (75%), 15q (42%), 20q (50%), 21q (67%), and 22q (58%); gains of the whole of chromosomes 7 (42%), 8 (42%), 17 (42%), and 19 (50%); and losses from 13q (58%). Two of three DGs with a gonadoblastoma component showed gains of 3p21 and loss of 5p, whereas none of the nine pure DGs had these changes, suggesting that they might be characteristic either of gonadoblastoma or of DG developing from a gonadoblastoma. Gain of 12p and gain from 1q were seen in three of four ESTs, whereas gains from 3p, 11q, and Xp and loss from 18q were each found in two tumors. Five of the ITs revealed changes (range, 1-4 changes/tumor), with gains from 1p, 16p, 19, and 22q each being found in two tumors. We conclude that ovarian DGs and ESTs seem to develop via the same genetic pathways that are already known for testicular germ cell tumors. On the other hand, ITs do not exhibit gain of 12p and also typically show fewer changes than other malignant OGCTs, indicating that they arise via different pathogenetic mechanisms.

Adolescent↗
PubMed2000

Predictive genetic testing for hereditary non-polyposis colorectal cancer: uptake and long-term satisfaction.

The aim of this prospective study was to assess the uptake of predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC) and its associations with sociodemographic and other factors, and long-term satisfaction with taking the test. The test was offered to all high-risk members (n = 446) of 36 Finnish HNPCC families in which the mutation was known. The procedure comprised an educational counselling session, a period for reflection, and a test disclosure session. Data were collected by questionnaires sent before the educational counselling and 1 month and 1 year after the test disclosure. Of those eligible, 85% (n = 381) completed the first questionnaire study. Non-participation was more common among men living alone who had not participated in the clinical cancer surveillance programme. Of the 347 subjects who attended counselling, 334 (75% of all subjects) were actually tested. After logistic-regression analysis, the only significant factor predicting test acceptance proved to be employment status: those employed were more likely than others to accept the test (odds ratio = 2.25; 95% confidence intervals, 1.09 to 4.6 1). At follow-up, over 90% of the subjects were fully satisfied with the decision to take the test. In conclusion, acceptance of the test was considerably higher than in previously reported studies. We attribute this to our careful face-to-face individualized counselling, our health care system, and to attitudes of the Finnish population, which are generally favourable towards health care and disease prevention.

Adult↗
PubMed2000

Hereditary nonpolyposis colorectal cancer (Lynch syndrome II) in Uruguay.

PURPOSE: We updated an Uruguayan family with hereditary nonpolyposis colorectal cancer first described in 1977, incorporating knowledge of how the hMLH1 germline mutation has been established and shown to segregate in accord with the expected autosomal dominant mode of genetic transmission. METHODS: DNA-based molecular genetic testing was performed in conjunction with genetic counseling. Individuals were provided with their genetic test results, so that at-risk family members would be able to benefit from targeted management programs. RESULTS: We counseled 19 members of this kindred, 13 of whom were positive for the hMLH1 germline mutation. Specific recommendations for surveillance and management were provided. We were able to describe follow-up, including anecdotal cancer survival and pathology findings extending from the initial 1977 report of this family to the present. A remarkable sibship within this kindred was comprised of eight siblings, six of whom underwent resections for colorectal carcinoma between 1963 and 1971. Colon carcinomas before 1977 in this sibship were treated with classic hemicolectomies. Of those who had hemicolectomies for their first primary colorectal cancers, two had a second colon cancer primary, and two had a third colon cancer primary. CONCLUSIONS: Attention given to this extended family with hereditary nonpolyposis colorectal cancer has had a positive impact on the physician community in Uruguay, leading to the identification of additional families with hereditary nonpolyposis colorectal cancer.

Adaptor Proteins, Signal Transducing↗