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Genetic and epidemiological studies of hereditary colorectal cancer
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap.
2005 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC) is the most common hereditary syndrome predisposing to colorectal cancer, accounting for 1-3% of all colorectal cancer. This multi-organ cancer predisposition syndrome is caused by mutations in the mismatch repair (MMR) genes, especially MLH1 and MSH2, and to lesser extents MSH6 and PMS2, which lead to widespread genetic instability and thus microsatellite instability (MSI). Hereditary cancer often manifests in two or more tumours in a single individual; 35-40% of Lynch syndrome patients have synchronous or metachronous tumours of the two major Lynch syndrome-related cancers: colorectal and endometrial.

The main purposes of the work underlying this thesis were to identify persons at risk of Lynch syndrome or other types of hereditary colorectal cancer, to estimate the cancer risks associated with these predispositions and to identify the underlying genetic causes.

A population-based cohort of 78 persons with double primary colorectal or colorectal and endometrial cancer was identified. Cancer risks in their 649 first-degree relatives were estimated in relation to tumour MSI status (positive or negative) and age at diagnosis (before or after 50 years of age) in the probands. The overall standardised incidence ratio was 1.69 (95% CI; 1.39-2.03). The highest risks for Lynch syndrome-associated cancers: (colorectal, endometrial, ovarian and gastric) were found in families with young MSI-positive probands, likely representing Lynch syndrome families. Importantly, no overall risk was found in families with old probands, irrespective of MSI status.

Blood samples were available from 24 MSI-positive patients for mutation screening of MLH1, MSH2 and MSH6. Sequence variants or rearrangements predicted to affect protein function were found in 16 patients. Six novel variants were found: two large rearrangements, two truncating and two missense mutations. The missense mutations were found to segregate in the families. Studies of allele frequencies, MSI and loss of immunostaning in tumours from family members further supports the hypothesis that these missense changes play a role in Lynch syndrome, as do the non-conservative nature and evolutionary conservation of the amino acid exchanges. Five families had mutations in MLH1, five in MSH2, and six in MSH6. The unexpectedly large impact of MSH6 was in genealogical studies shown to be due to a founder effect. Cumulative risk studies showed that the MSH6 families, despite their late age of onset, have a high lifetime risk for all Lynch syndrome-related cancers, significantly higher in women (89% by age 80 years) than in men (69%). The gender differences are in part due to high endometrial (70%) and ovarian cancer risk (33%) in addition to the high colorectal cancer risk (60%). These findings are of great importance for counselling and surveillance of families with MSH6 mutations.

Finally, in a large family with MSI-negative hereditary colorectal cancer for which the MMR genes and APC had been excluded as possible causes, a genome-wide linkage analysis was performed, resulting in a suggested linkage to chromosome 7.

Conclusions: Relatives of probands with MSI-positive, double primary colorectal and endometrial cancer diagnosed before the age of 50 years have significantly increased risks of Lynch syndrome-related cancers. MSH6 mutations, which have unusually high impact in this study population due to a founder effect, confer high cumulative risks of cancer despite the generally late age of onset.

Ort, förlag, år, upplaga, sidor
2005. , s. 86
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 980
Nyckelord [en]
Genetics, Lynch syndrome, HNPCC, colorectal cancer, endometrial cancer, cancer risk, MSI, MLH1, MSH2, MSH6, genome-wide scan
Nyckelord [sv]
Genetik
Nationell ämneskategori
Medicinsk genetik
Forskningsämne
medicinsk genetik
Identifikatorer
URN: urn:nbn:se:umu:diva-615ISBN: 91-7305-937-4 (tryckt)OAI: oai:DiVA.org:umu-615DiVA, id: diva2:143996
Disputation
2005-11-18, Betula, 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2005-10-19 Skapad: 2005-10-19 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Delarbeten
1. A population based cohort study of patients with multiple colon and endometrial cancer: correlation of microsatellite instability (MSI) staus, age at diagnosis and cancer risk
Öppna denna publikation i ny flik eller fönster >>A population based cohort study of patients with multiple colon and endometrial cancer: correlation of microsatellite instability (MSI) staus, age at diagnosis and cancer risk
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2001 (Engelska)Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 91, nr 4, s. 486-491Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Hereditary non-polyposis colorectal cancer, HNPCC, is an autosomal dominant condition predisposing to cancers of primarily the colorectum and the endometrium. The aim of our study was to identify persons at a high risk of hereditary colorectal cancer and to estimate their risk of colon and other HNPCC-associated tumours. Family histories of cancer were obtained on 89 persons with double primary (DP) cancers of the colon and the endometrium. The cancer risks in their 649 first-degree-relatives (FDR) were analysed. The microsatellite instability (MSI) status of the tumour of the proband was also analysed and the cancer risks were estimated in relation to MSI status and age at diagnosis in the proband (over or under 50 years). The overall standardised incidence ratio (SIR) was 1.69 (95% CI; 1.39-2.03). In the =50-year-old cohort the SIR was 2.67 (95% CI; 2.08-3.38). Colon, rectal and uterus cancer exhibited significantly increased risks. This risk was further increased in the =50-year-old MSI positive families. Several =50-year-old MSI negative HNPCC-like families with increased risks were also identified. In conclusion a FDR to a person with a DP cancer of the colorectum or the colon/endometrium have a significantly increased risk of having a colorectal or other HNPCC-associated cancers if the proband is diagnosed with one of the cancers before age 50. These families are candidates for genetic counselling and colorectal screening programmes. Mutations in mismatch repair genes can explain some of the increased risk in these families, but mutations in MSI negative families are probably due to other colon cancer susceptibility genes not yet described. Copyright 2001 Wiley-Liss, Inc.

Nyckelord
HNPCC; MSI; double primary tumour; mismatch repair genes; cancer risk
Identifikatorer
urn:nbn:se:umu:diva-4760 (URN)10.1002/1097-0215(200002)9999:9999<::AID-IJC1093>3.0.CO;2-P (DOI)11251970 (PubMedID)
Tillgänglig från: 2005-10-19 Skapad: 2005-10-19 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
2. Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden
Öppna denna publikation i ny flik eller fönster >>Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden
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2004 (Engelska)Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 109, nr 3, s. 370-376Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder that predisposes to predominantly colorectal and endometrial cancers due to germline mutations in DNA mismatch repair genes, mainly MLH1, MSH2 and in families with excess endometrial cancer also MSH6. In this population-based study, we analysed the mutation spectrum of the MLH1, MSH2 and MSH6 genes in a cohort of patients with microsatellite unstable double primary tumours of the colorectum and the endometrium by PCR, DHPLC and sequencing. Fourteen of the 23 patients (61%) had sequence variants in MLH1, MSH2 or MSH6 that likely affect the protein function. A majority (10/14) of the mutations was found among probands diagnosed before age 50. Five of the mutations (36%) were located in MLH1, 3 (21%) in MSH2 and 6 (43%) in MSH6. MSH6 seem to have larger impact in our population than in other populations, due to a founder effect since all of the MSH6 families originate from the same geographical area. MSH6 mutation carriers have later age of onset of both colorectal cancer (62 vs. 51 years) and endometrial cancer (58 vs. 48 years) and a larger proportion of endometrial cancer than MLH1 or MSH2 mutation carriers. We can conclude that patients with microsatellite unstable double primary cancers of the colorectum and the endometrium have a very high risk of carrying a mutation not only in MLH1 or MSH2 but also in MSH6, especially if they get their first cancer diagnosis before the age of 50. Copyright 2004 Wiley-Liss, Inc.

Nyckelord
HNPCC, DHPLC, double primary tumours, colorectal cancer, endometrial cancer, population based, mismatch repair genes
Identifikatorer
urn:nbn:se:umu:diva-15020 (URN)10.1002/ijc.11718 (DOI)14961575 (PubMedID)
Tillgänglig från: 2007-09-13 Skapad: 2007-09-13 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
3. Retained immunohistochemical staining in a large Swedish HNPCC family with a pathogenic MLH1 missense mutation
Öppna denna publikation i ny flik eller fönster >>Retained immunohistochemical staining in a large Swedish HNPCC family with a pathogenic MLH1 missense mutation
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Medicinsk biovetenskap
Identifikatorer
urn:nbn:se:umu:diva-4762 (URN)
Tillgänglig från: 2005-10-19 Skapad: 2005-10-19 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
4. Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome.
Öppna denna publikation i ny flik eller fönster >>Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome.
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2005 (Engelska)Ingår i: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 68, nr 6, s. 533-541Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a cancer susceptibility syndrome caused by germline mutations in mismatch-repair genes, predominantly MLH1, MSH2 and MSH6. A majority of the mutations reported are truncating, but for MSH6, missense mutations constitute over one third. Few have been proven pathogenic in functional studies or shown to segregate in families. In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree. Another large family with the MSH6 nonsense c.2931C>G, p.Tyr977X mutation is similar in tumour spectra, age of onset and cumulative risk. These MSH6 families, despite their late age of onset, have a high lifetime risk of all Lynch syndrome-related cancers, significantly higher in women (89% by age 80) than in men (69%). The gender differences are in part explained by high endometrial (70%) and ovarian (33%) cancer risks added upon the high colorectal cancer risk (60%). The several occurrences of breast cancer are not due to the MSH6 mutations. These findings are of great importance for counselling, management and surveillance of families with MSH6 mutations.

Nyckelord
Colorectal neoplasms, founder effect, hereditary non-polyposis, MSH6, missense mutation, nonsense mutation, risk assessment
Identifikatorer
urn:nbn:se:umu:diva-14301 (URN)doi:10.1111/j.1399-0004.2005.00537.x (DOI)16283884 (PubMedID)
Tillgänglig från: 2007-09-14 Skapad: 2007-09-14 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
5. Genome-wide scan in a large Swedish family with hereditary colorectal cancer, suggestive evidence of linkage to chromosome 7
Öppna denna publikation i ny flik eller fönster >>Genome-wide scan in a large Swedish family with hereditary colorectal cancer, suggestive evidence of linkage to chromosome 7
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Manuskript (Övrigt vetenskapligt)
Identifikatorer
urn:nbn:se:umu:diva-4764 (URN)
Tillgänglig från: 2005-10-19 Skapad: 2005-10-19 Senast uppdaterad: 2010-01-13Bibliografiskt granskad

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