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Genomic Profiling, Mutations and Deranged Signaling in Esophageal Cancer and Hereditary Colorectal Cancer

Isinger Ekstrand, Anna LU orcid (2010) In Lund University Faculty of Medicine Doctoral Dissertation Series 2010:46.
Abstract
Esophageal cancer and colorectal cancer represents two major types of gastrointestinal tumors. Though refined surgery and introduction of novel chemotherapeutics have improved outcome, more than 2500 Swedes die from these diseases every year. Novel markers for early diagnosis, prognosis and treatment prediction are therefore needed. This thesis aimed to genetically profile esophageal cancer with correlations to tumor location and prognosis, to explore the contribution of a low-risk allele, and to characterize involvement of signaling pathways in hereditary colorectal cancer.

In paper I, 32k array comparative genomic hybridization (aCGH) was used to genomically profile esophageal squamous cell cancer with correlations to prognosis.... (More)
Esophageal cancer and colorectal cancer represents two major types of gastrointestinal tumors. Though refined surgery and introduction of novel chemotherapeutics have improved outcome, more than 2500 Swedes die from these diseases every year. Novel markers for early diagnosis, prognosis and treatment prediction are therefore needed. This thesis aimed to genetically profile esophageal cancer with correlations to tumor location and prognosis, to explore the contribution of a low-risk allele, and to characterize involvement of signaling pathways in hereditary colorectal cancer.

In paper I, 32k array comparative genomic hybridization (aCGH) was used to genomically profile esophageal squamous cell cancer with correlations to prognosis. Copy number alterations affected median 19% of the genome and included frequent alterations of EGFR and CDKN2A. Gain of 7p22.3 predicted nodal metastasis and gain of 1p36.32 and 19p13.3 predicted poor survival.

In paper II, aCGH and gene expression profiling were used to identify genetic differences between adenocarcinomas arising at different locations – in the distal esophagus, the gastroesophageal junction and the proximal stomach. Within these genetically complex tumors, extensive similarities were detected in gains/losses and well as gene expression patterns between adenocarcinomas in the distal esophagus and the gastroesophageal junction, whereas gastric cancers showed different profiles. Upregulation of CDK6 and EGFR were found in approximately one quarter of the tumors, which provides molecular support for exploration of these markers as therapeutic targets in gastroesophageal adenocarcinoma.

In paper III, the low-risk CHEK2 1100delC allele was characterized in women with metachronous breast cancer and colorectal cancer. The 1100delC allele was identified in 2.5% of the women, compared to 1% in the population. Though alterations in low/moderate risk alleles are increasingly recognized to contribute to hereditary cancer, these findings exclude this CHEK2 variant as a major cause of metachronous breast and colorectal cancer in Swedish women.

In papers IV and V, alterations in the PI3K/AKT/mTOR and Wnt signaling pathways were studied in colorectal cancers linked to the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Frequent alterations in these pathways were demonstrated and included mutations of PIK3CA and KRAS and altered immunohistochemical expression of PIK3CA, p-AKT, PTEN, TCF4, ß-catenin and E-cadherin. Therapeutic strategies directed at these pathways are thus likely relevant also in HNPCC-associated cancers. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Varje år drabbas i världen ca 3 miljoner individer av cancer i mag-tarmkanalen. Stora skillnader finns i incidens med magsäckscancer och matstrupscancer särskilt vanliga i utvecklingsländer, medan tjock- och ändtarmscancer är en av de vanligaste tumörtyperna i västvärlden. Cancer i mag-tarmkanalen ger ofta diffusa symtom, vilket i många fall leder till att tumörerna upptäcks i sena stadier. Idag är 5-årsöverlevnaden 10-20% vid cancer i matstrupe och magsäck och 50% i tjock- och ändtarm. Cancer i mag-tarmkanalen är generellt genetiskt komplex med en rad förvärvade genetiska avvikelser. Kartläggning av dessa genetiska avvikelser och de förändringar i cellens signalvägar de leder till är av... (More)
Popular Abstract in Swedish

Varje år drabbas i världen ca 3 miljoner individer av cancer i mag-tarmkanalen. Stora skillnader finns i incidens med magsäckscancer och matstrupscancer särskilt vanliga i utvecklingsländer, medan tjock- och ändtarmscancer är en av de vanligaste tumörtyperna i västvärlden. Cancer i mag-tarmkanalen ger ofta diffusa symtom, vilket i många fall leder till att tumörerna upptäcks i sena stadier. Idag är 5-årsöverlevnaden 10-20% vid cancer i matstrupe och magsäck och 50% i tjock- och ändtarm. Cancer i mag-tarmkanalen är generellt genetiskt komplex med en rad förvärvade genetiska avvikelser. Kartläggning av dessa genetiska avvikelser och de förändringar i cellens signalvägar de leder till är av betydelse såväl för diagnostik som för att förutse patientens risk för återfall (prognostik) och för att välja bästa behandling (prediktion). Avhandlingen kan indelas i två delar; en som omfattar genetiska profiler i matstrupscancer och en som undersökt mutationer och påverkan på signalkedjor i ärftlig tjock- och ändtarmscancer. I studie I kartlades över- och underskott av genetiskt material i skivepitelcancer i matstrupen. Genetiska avvikelser på kromosomerna 1p36 och 19p13 kunde kopplas till prognos. I studie II undersöktes cancrar som uppkommit på olika platser i matstrupen och magsäcken med kartläggning av mängden genetiskt material och uttrycket av alla arvsmassans gener. Cancer i matstrupen och i övergången till magsäcken visade sig genetiskt lika, medan tumörer i magsäcken uppvisade delvis andra genetiska mönster. Studierna III-V handlar om ärftlig tjock- och ändtarmscancer. I studie III fastställdes att bärarskap av 1100delC mutationen i låg-risk genen CHEK2 var relativt ovanligt (2.5%) hos kvinnor som utvecklat både bröstcancer och tjock- och ändtarmscancer. I studierna IV och V undersöktes tarmscancrar från individer med det ärftliga syndromet hereditär nonpolypos kolorektalcancer (HNPCC). Förändringar i form av mutationer och ändrat uttryck i två olika signalvägar påvisades i en stor del av cancrarna. (Less)
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author
supervisor
opponent
  • Associate professor Melin, Beatrice, Department of Radiation Sciences, Umeå University, Umeå
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Esophageal cancer, hereditary cancer, HNPCC, copy number analysis, CGH, gene expression, Wnt, PIK3CA, CHEK2, gastric cancer, colorectal cancer
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2010:46
publisher
Lund University: Faculty of Medicine
defense location
Segerfalk lecture hall, Lund
defense date
2010-05-06 09:00:00
ISSN
1652-8220
ISBN
978-91-86443-61-0
language
English
LU publication?
yes
id
59c92caf-0055-4747-b7fe-bf7e153c6919 (old id 1584329)
date added to LUP
2016-04-01 14:42:17
date last changed
2025-04-04 14:35:13
@phdthesis{59c92caf-0055-4747-b7fe-bf7e153c6919,
  abstract     = {{Esophageal cancer and colorectal cancer represents two major types of gastrointestinal tumors. Though refined surgery and introduction of novel chemotherapeutics have improved outcome, more than 2500 Swedes die from these diseases every year. Novel markers for early diagnosis, prognosis and treatment prediction are therefore needed. This thesis aimed to genetically profile esophageal cancer with correlations to tumor location and prognosis, to explore the contribution of a low-risk allele, and to characterize involvement of signaling pathways in hereditary colorectal cancer.<br/><br>
In paper I, 32k array comparative genomic hybridization (aCGH) was used to genomically profile esophageal squamous cell cancer with correlations to prognosis. Copy number alterations affected median 19% of the genome and included frequent alterations of EGFR and CDKN2A. Gain of 7p22.3 predicted nodal metastasis and gain of 1p36.32 and 19p13.3 predicted poor survival. <br/><br>
In paper II, aCGH and gene expression profiling were used to identify genetic differences between adenocarcinomas arising at different locations – in the distal esophagus, the gastroesophageal junction and the proximal stomach. Within these genetically complex tumors, extensive similarities were detected in gains/losses and well as gene expression patterns between adenocarcinomas in the distal esophagus and the gastroesophageal junction, whereas gastric cancers showed different profiles. Upregulation of CDK6 and EGFR were found in approximately one quarter of the tumors, which provides molecular support for exploration of these markers as therapeutic targets in gastroesophageal adenocarcinoma.<br/><br>
In paper III, the low-risk CHEK2 1100delC allele was characterized in women with metachronous breast cancer and colorectal cancer. The 1100delC allele was identified in 2.5% of the women, compared to 1% in the population. Though alterations in low/moderate risk alleles are increasingly recognized to contribute to hereditary cancer, these findings exclude this CHEK2 variant as a major cause of metachronous breast and colorectal cancer in Swedish women. <br/><br>
In papers IV and V, alterations in the PI3K/AKT/mTOR and Wnt signaling pathways were studied in colorectal cancers linked to the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Frequent alterations in these pathways were demonstrated and included mutations of PIK3CA and KRAS and altered immunohistochemical expression of PIK3CA, p-AKT, PTEN, TCF4, ß-catenin and E-cadherin. Therapeutic strategies directed at these pathways are thus likely relevant also in HNPCC-associated cancers.}},
  author       = {{Isinger Ekstrand, Anna}},
  isbn         = {{978-91-86443-61-0}},
  issn         = {{1652-8220}},
  keywords     = {{Esophageal cancer; hereditary cancer; HNPCC; copy number analysis; CGH; gene expression; Wnt; PIK3CA; CHEK2; gastric cancer; colorectal cancer}},
  language     = {{eng}},
  publisher    = {{Lund University: Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Genomic Profiling, Mutations and Deranged Signaling in Esophageal Cancer and Hereditary Colorectal Cancer}},
  url          = {{https://lup.lub.lu.se/search/files/4120032/1584356.pdf}},
  volume       = {{2010:46}},
  year         = {{2010}},
}