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

Research output: ThesisDoctoral Thesis (compilation)

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. 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.

Details

Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • Esophageal cancer, hereditary cancer, HNPCC, copy number analysis, CGH, gene expression, Wnt, PIK3CA, CHEK2, gastric cancer, colorectal cancer
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2010 May 6
Publisher
  • Lund University: Faculty of Medicine
Print ISBNs978-91-86443-61-0
Publication statusPublished - 2010
Publication categoryResearch

Bibliographic note

Defence details Date: 2010-05-06 Time: 09:00 Place: Segerfalk lecture hall, Lund External reviewer(s) Name: Melin, Beatrice Title: Associate professor Affiliation: Department of Radiation Sciences, Umeå University, Umeå ---

Related activities

Johansson, M. C. (Second supervisor)
2010 → …

Activity: Examination and supervisionSupervision of PhD students

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