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Tumors associated with Hereditary Nonpolyposis Colorectal Cancer: Defective Mismatch Repair and Familial Risk of Cancer

Ericson Lindquist, Kajsa LU (2005)
Abstract (Swedish)
Popular Abstract in Swedish

Defekt mismatch-reparation och familjär cancerrisk



Cancer är på cellnivå en genetisk sjukdom. Förändringar i cellens arvsmassa (DNA) drabbar tre huvudtyper av gener; onkgener, tumörsuppressorgener och DNA-reparationsgener. Onkgener är en grupp gener som befrämjar cellens tillväxt. Vid cancerutveckling aktiveras onkgener via mutation eller genom ökat uttryck, vilket leder till ökad tillväxt. Tumörsuppressorgener hämmar normalt celldelning, bromsar cellcykeln, styr defekta celler till programmerad celldöd och verkar för stabilitet i genomet. När båda kopiorna av en tumörsuppressorgen inaktiveras förloras dess funktion, vilket befrämjar tumörbildning. Normalt finns alla gener i... (More)
Popular Abstract in Swedish

Defekt mismatch-reparation och familjär cancerrisk



Cancer är på cellnivå en genetisk sjukdom. Förändringar i cellens arvsmassa (DNA) drabbar tre huvudtyper av gener; onkgener, tumörsuppressorgener och DNA-reparationsgener. Onkgener är en grupp gener som befrämjar cellens tillväxt. Vid cancerutveckling aktiveras onkgener via mutation eller genom ökat uttryck, vilket leder till ökad tillväxt. Tumörsuppressorgener hämmar normalt celldelning, bromsar cellcykeln, styr defekta celler till programmerad celldöd och verkar för stabilitet i genomet. När båda kopiorna av en tumörsuppressorgen inaktiveras förloras dess funktion, vilket befrämjar tumörbildning. Normalt finns alla gener i dubbel uppsättning, en kopia från vardera föräldern. Vid ärftlig cancer finns den första erforderliga DNA-förändringen (mutationen) i kroppens alla celler (konstitutionell mutation), medan icke-ärftlig (sporadisk) cancer uppkommer genom förvärvade (somatiska) mutationer av båda kopiorna. DNA-reparationsgener motverkar att förändringar i arvsmassan uppstår genom att ta hand om spontana mutationer vid celldelning via cellens olika DNA-reparationssystem.



Defekt DNA-reparation är en tumörbiologisk mekanism som styr utvecklingen i flera vanliga tumörtyper, bl. a. i en andel av tjocktarmscancer och livmodercancer. Dessutom karakteriserar defekt DNA-reparation av typen mismatch repair (MMR) specifikt de tumörer som uppkommer genom det ärftliga syndromet hereditär nonpolyposis colorektal cancer (HNPCC). I MMR-systemet samverkar sex olika proteiner och vid HNPCC är någon av MMR-generna MLH1, MSH2, MSH6 eller PMS2 defekta. Personer som bär en av mutation i någon av dessa gener löper ca 90% risk att drabbas av cancer, vanligast i tjock-/ändtarm och livmoder, men även i njurbäcken/urinledare, tunntarm eller äggstockar. Tumörer som uppkommit via defekt MMR karakteriseras av så kallad mikrosatellitinstabilitet (MSI) och immunhistokemisk förlust av det defekta MMR-proteinets uttryck.



Denna avhandlings fyra första delarbeten innefattar tumörbiologiska studier i vilka vi har undersökt förekomst av defekt MMR i olika tumörtyper associerade med HNPCC.



I arbete I studerades individer med fyra primära (separat uppkomna) tumörer varav minst två i tjocktarm eller ändtarm. Defekt MMR förekom i 41% av tumörerna. Hos 17/45 patienter (38%) var samma MMR protein förlorat i flera tumörer. Studien visade en ökad frekvens MMR-defekter vid multipla tumörer och HNPCC är en diagnos som bör övervägas hos patienter som drabbas av flera tumörer.



I arbete II undersöktes defekt MMR i tunntarmscancer, vilket förekom i 18% av fallen. MMR defekter var något vanligare bland de unga patienterna. Fynden visar att MMR-defekter i tunntarmscancer är ungefär lika vanliga som i tjocktarmscancer.



I arbete III studerades cancer i de övre urinvägarna, dvs. i njurbäcken och urinledare. MSI och/eller immunhistokemisk MMR-proteinförlust påvisades i cirka 5% av fallen. Trots en ökad risk för cancer i urinvägarna hos individer med HNPCC indikerar studien att endast en liten andel av tumörer i de övre urinvägarna uppkommer via defekt MMR.



I arbete IV påvisades att defekt MMR också kan förekomma i sarkom, en ovanlig tumörform som uppkommer i kroppens stödjevävnader. Denna tumörtyp är normalt inte associerad med ärftlighet, men en koppling mellan sarkom och HNPCC finns sannolikt.



I Sverige sker en rapportering av alla cancerdiagnoser till ett nationellt cancerregister. Det finns även ett familjeregister där individers barn kan identifieras. Genom att länka cancerregister och familjeregister till varandra kan cancerrisker hos barn till föräldrar med cancer räknas ut. Delarbete V är en epidemiologisk studie (en studie av samband och riskfaktorer i en befolkning) där vi beräknat cancerrisker hos individer vars föräldrar drabbats av de cancertyper som är vanligast vid HNPCC. Analyserna visade att barn till personer med någon HNPCC-associerad diagnos löper en förhöjd risk att själva drabbas av cancer, framför allt i samma organ som föräldern. Störst cancerrisk har de barn vars föräldrar fått sin tumör före 50 års ålder, barn som har både en förälder och ett syskon med cancer och barn vars förälder utvecklat flera primära tumörer. I studien påvisades ett starkt samband mellan canceruppkomst och HNPCC-associerad tumör hos en förälder och resultaten bekräftar vikten av att ta hänsyn till förekomst av flera olika tumörtyper när HNPCC övervägs som diagnos. Studien visade även att flera primära tumörer hos en individ är en stark riskfaktor för ärftlighet, jämförbar med tumörförekomst hos flera individer i familjen.



Sammanfattningsvis har vi i arbetena I-V



· påvisat defekt MMR i hög frekvens hos individer som utvecklat flera primära cancrar



· visat att defekt MMR förekommer i samma frekvens i tunntarmscancer som i tjocktarmscancer



· funnit låg andel defekt MMR i cancer i de övre urinvägarna



· visat att defekt MMR förekommer i mjukdelssarkom



samt



· beräknat cancerrisker hos individer vars föräldrar utvecklat HNPCC-relaterad cancer (Less)
Abstract
Inactivation of the DNA mismatch repair (MMR) system is a tumorigenic mechanism involved in 15-20% of tumor types such as colorectal and endometrial cancer and is specifically associated with the Hereditary Nonpolyposis Colorectal Cancer (HNPCC) syndrome. These MMR defective tumors are characterized by microsatellite instability (MSI), a phenomenon that reflects alterations in length of repeated sequences, and 90% of MSI tumors show loss of immunohistochemical expression for the MMR protein affected. HNPCC yields an increased risk for several tumor types; cancer of the colorectum (80-90% lifetime risk), endometrium (40-60%), ovary (5-15%), stomach (5-15%), urinary tract, small bowel, skin, and brain. The syndrome is characterized by an... (More)
Inactivation of the DNA mismatch repair (MMR) system is a tumorigenic mechanism involved in 15-20% of tumor types such as colorectal and endometrial cancer and is specifically associated with the Hereditary Nonpolyposis Colorectal Cancer (HNPCC) syndrome. These MMR defective tumors are characterized by microsatellite instability (MSI), a phenomenon that reflects alterations in length of repeated sequences, and 90% of MSI tumors show loss of immunohistochemical expression for the MMR protein affected. HNPCC yields an increased risk for several tumor types; cancer of the colorectum (80-90% lifetime risk), endometrium (40-60%), ovary (5-15%), stomach (5-15%), urinary tract, small bowel, skin, and brain. The syndrome is characterized by an early age (mean 45 years) at diagnosis and one third of the patients develop metachronous tumors. The major aims of this thesis were to assess the contribution of defective MMR to the development of the more rare tumor types associated with HNPCC and to assess cancer risks in children whose parents had developed HNPCC-associated tumors. In study I, patients who developed multiple (at least 4) primary tumors, including two colorectal cancers, were assessed for MSI and immunohistochemical expression of the MMR proteins MLH1 and MSH2. MSI was identified in 63/154 (40%) tumors, 55 of which also showed immunohistochemical loss of MMR protein expression. A concordant finding of MSI and loss of the same MMR protein, which strongly suggest HNPCC, was found in 17/45 (38%) patients, which suggests that a high fraction of such multiple tumors are caused by HNPCC. In studies II and III, the frequency of defective MMR was studied in adenocarcinomas of the small intestine and in upper urinary tract cancers (UUC). MSI was detected in 16/89 (18%) of cancers of the small intestine and in 9/194 (4%) UUC. MMR protein expression loss affected 11 cancers of the small intestine and 11 UUC. Malignant fibrous histiocytoma (MFH) represents one of the largest subsets of soft tissue sarcomas, and occasional MFHs have been described in HNPCC-families. In study IV, we assessed MMR expression in a series of 209 MFH and found loss of MSH2 and MSH6 in 2 MFH. Study V is based on the national Swedish cancer registry and analyses familial risk of HNPCC-associated tumors. Cancer risks were calculated in 204 358 offspring whose 102 814 parents had developed HNPCC-associated cancer and the risks were correlated to the age of the parent, metachronous tumors in the parent, and presence of several HNPCC-associated cancers in the family. Significantly increased risks were observed for several tumor types, including colon cancer, rectal cancer, endometrial cancer, gastric cancer, and ovarian cancer. The highest offspring risks were observed in the subgroup with multiple HNPCC-associated cancers in the parent. In summary, we have demonstrated that MMR defects are common in patients who develop multiple primary tumors, occur at similar frequencies in cancers of the small intestine and the colon, contribute to development of UUC and MFH at low frequencies, and that HNPCC-associated tumor in a parent confer an increased risk of several cancer types in the offspring, especially if the parent developed more than one cancer or cancer at a young age. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Grönberg, Henrik, Dept. of Oncology, Umeå University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
oncology, cancerology, Cytologi, onkologi, cancer, Multiple Tumors, Hereditary Nonpolyposis Colorectal Cancer, Cytology, Cohort study, Population based, Familial Risk of Cancer, Immunohistochemistry, MSH2, MSH6, MLH1, Microsatellite Instability, Soft Tissue Sarcomas, Cancer of the Upper Urinary Tract, Cancer of the Small Intestine, Colorectal Cancer
pages
120 pages
publisher
Department of Oncology, Clinical Sciences, Lund University
defense location
Segerfalksalen, Wallenberg Neurocentrum, BMC
defense date
2005-02-11 09:00
ISBN
91-628-6379-7
language
English
LU publication?
yes
id
57405178-9540-4d81-a92c-2f52ba3e8570 (old id 544243)
date added to LUP
2007-09-11 14:17:35
date last changed
2016-09-19 08:45:10
@misc{57405178-9540-4d81-a92c-2f52ba3e8570,
  abstract     = {Inactivation of the DNA mismatch repair (MMR) system is a tumorigenic mechanism involved in 15-20% of tumor types such as colorectal and endometrial cancer and is specifically associated with the Hereditary Nonpolyposis Colorectal Cancer (HNPCC) syndrome. These MMR defective tumors are characterized by microsatellite instability (MSI), a phenomenon that reflects alterations in length of repeated sequences, and 90% of MSI tumors show loss of immunohistochemical expression for the MMR protein affected. HNPCC yields an increased risk for several tumor types; cancer of the colorectum (80-90% lifetime risk), endometrium (40-60%), ovary (5-15%), stomach (5-15%), urinary tract, small bowel, skin, and brain. The syndrome is characterized by an early age (mean 45 years) at diagnosis and one third of the patients develop metachronous tumors. The major aims of this thesis were to assess the contribution of defective MMR to the development of the more rare tumor types associated with HNPCC and to assess cancer risks in children whose parents had developed HNPCC-associated tumors. In study I, patients who developed multiple (at least 4) primary tumors, including two colorectal cancers, were assessed for MSI and immunohistochemical expression of the MMR proteins MLH1 and MSH2. MSI was identified in 63/154 (40%) tumors, 55 of which also showed immunohistochemical loss of MMR protein expression. A concordant finding of MSI and loss of the same MMR protein, which strongly suggest HNPCC, was found in 17/45 (38%) patients, which suggests that a high fraction of such multiple tumors are caused by HNPCC. In studies II and III, the frequency of defective MMR was studied in adenocarcinomas of the small intestine and in upper urinary tract cancers (UUC). MSI was detected in 16/89 (18%) of cancers of the small intestine and in 9/194 (4%) UUC. MMR protein expression loss affected 11 cancers of the small intestine and 11 UUC. Malignant fibrous histiocytoma (MFH) represents one of the largest subsets of soft tissue sarcomas, and occasional MFHs have been described in HNPCC-families. In study IV, we assessed MMR expression in a series of 209 MFH and found loss of MSH2 and MSH6 in 2 MFH. Study V is based on the national Swedish cancer registry and analyses familial risk of HNPCC-associated tumors. Cancer risks were calculated in 204 358 offspring whose 102 814 parents had developed HNPCC-associated cancer and the risks were correlated to the age of the parent, metachronous tumors in the parent, and presence of several HNPCC-associated cancers in the family. Significantly increased risks were observed for several tumor types, including colon cancer, rectal cancer, endometrial cancer, gastric cancer, and ovarian cancer. The highest offspring risks were observed in the subgroup with multiple HNPCC-associated cancers in the parent. In summary, we have demonstrated that MMR defects are common in patients who develop multiple primary tumors, occur at similar frequencies in cancers of the small intestine and the colon, contribute to development of UUC and MFH at low frequencies, and that HNPCC-associated tumor in a parent confer an increased risk of several cancer types in the offspring, especially if the parent developed more than one cancer or cancer at a young age.},
  author       = {Ericson Lindquist, Kajsa},
  isbn         = {91-628-6379-7},
  keyword      = {oncology,cancerology,Cytologi,onkologi,cancer,Multiple Tumors,Hereditary Nonpolyposis Colorectal Cancer,Cytology,Cohort study,Population based,Familial Risk of Cancer,Immunohistochemistry,MSH2,MSH6,MLH1,Microsatellite Instability,Soft Tissue Sarcomas,Cancer of the Upper Urinary Tract,Cancer of the Small Intestine,Colorectal Cancer},
  language     = {eng},
  pages        = {120},
  publisher    = {ARRAY(0x97cefc0)},
  title        = {Tumors associated with Hereditary Nonpolyposis Colorectal Cancer: Defective Mismatch Repair and Familial Risk of Cancer},
  year         = {2005},
}