File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

postgraduate thesis: Characterisation of methylator phenotype of colorectal cancer in young patients

TitleCharacterisation of methylator phenotype of colorectal cancer in young patients
Authors
Advisors
Issue Date2013
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Li, C. [李嘉敏]. (2013). Characterisation of methylator phenotype of colorectal cancer in young patients. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5334853
AbstractThe majority of sporadic colorectal cancer (CRC) cases affects individuals over the age of 50, but about 10% of cases occur in young adults under 50 in Hong Kong. Apart from germline mutation of the DNA mismatch repair genes that predisposes to early-onset CRC with a high-level of microsatellite instability (MSI-H), it is unknown if the mechanisms that give rise to CRC in other young adults differ from those in older individuals. In an effort to understand the genetic and epigenetic basis of early and late-onset CRC outside the Lynch Syndrome setting, we performed a detailed characterization of 36 MSI-H and 198 non-MSI-H tumours from patients of varying ages. This characterization was based primarily on the presence of the CpG island methylator phenotype (CIMP), as measured by the level of DNA methylation; and presence of genetic instability, as measured by DNA copy number aberrations, as well as mutations in BRAF, KRAS, or TP53. Our findings revealed that early (≤50) and late-onset (>50) CRCs have different genetic and epigenetic features. In non-MSI-H cancers, CIMP-H was associated with early-onset, while CIMP-L and KRAS mutation was associated with late-onset. However, in MSI-H tumours, late-onset disease was associated with CIMP-H and BRAF mutation. In addition, promoter methylation of MLH1 in early-onset MSI-H patients had a higher frequency of occurring in the germline that was locus specific, whereas nearly all late-onset MSI-H patients showed somatic regional methylation at the MLH1 locus, as well as regional methylation on other chromosomes. This is the first study to show regional methylation at chromosome 9p21 and 7p14, which encompass the CIMP markers P16 and ELMO1, respectively. We also observed an association between regional methylation and CIMP-H, but in MSI-H cases it was linked with late-onset, whereas in non-MSI-H cases it was irrespective of age. This suggests that mechanisms of methylation seeding and spreading may be different in early and late-onset disease. Moreover, CIMP-H non-MSI-H cases had significantly worse prognosis (p=0.021 for overall survival, p=0.004 for disease-free survival) and poor response to chemotherapy compared to CIMP-L or CIMP-Neg cases. Lastly, a methylation score assigned to non-MSI-H patients based on the degree of methylation of known CIMP markers was a significant prognostic factor of disease-free survival (p=0.004), and patients with a high methylation score showed a poor response to chemotherapy. Thus, our results suggest that different genetic and epigenetic mechanisms may drive tumourigenesis in early and late-onset disease. Although further research will be needed to elucidate the exact nature of these mechanisms, our findings should help to improve current classification of CRC patients with a goal towards personalized treatment.
DegreeDoctor of Philosophy
SubjectRectum - Cancer - Genetic aspects
Colon (Anatomy) - Cancer - Genetic aspects
Dept/ProgramPathology
Persistent Identifierhttp://hdl.handle.net/10722/207182

 

DC FieldValueLanguage
dc.contributor.advisorChan, TL-
dc.contributor.advisorLeung, SY-
dc.contributor.authorLi, Carmen-
dc.contributor.author李嘉敏-
dc.date.accessioned2014-12-18T23:17:53Z-
dc.date.available2014-12-18T23:17:53Z-
dc.date.issued2013-
dc.identifier.citationLi, C. [李嘉敏]. (2013). Characterisation of methylator phenotype of colorectal cancer in young patients. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5334853-
dc.identifier.urihttp://hdl.handle.net/10722/207182-
dc.description.abstractThe majority of sporadic colorectal cancer (CRC) cases affects individuals over the age of 50, but about 10% of cases occur in young adults under 50 in Hong Kong. Apart from germline mutation of the DNA mismatch repair genes that predisposes to early-onset CRC with a high-level of microsatellite instability (MSI-H), it is unknown if the mechanisms that give rise to CRC in other young adults differ from those in older individuals. In an effort to understand the genetic and epigenetic basis of early and late-onset CRC outside the Lynch Syndrome setting, we performed a detailed characterization of 36 MSI-H and 198 non-MSI-H tumours from patients of varying ages. This characterization was based primarily on the presence of the CpG island methylator phenotype (CIMP), as measured by the level of DNA methylation; and presence of genetic instability, as measured by DNA copy number aberrations, as well as mutations in BRAF, KRAS, or TP53. Our findings revealed that early (≤50) and late-onset (>50) CRCs have different genetic and epigenetic features. In non-MSI-H cancers, CIMP-H was associated with early-onset, while CIMP-L and KRAS mutation was associated with late-onset. However, in MSI-H tumours, late-onset disease was associated with CIMP-H and BRAF mutation. In addition, promoter methylation of MLH1 in early-onset MSI-H patients had a higher frequency of occurring in the germline that was locus specific, whereas nearly all late-onset MSI-H patients showed somatic regional methylation at the MLH1 locus, as well as regional methylation on other chromosomes. This is the first study to show regional methylation at chromosome 9p21 and 7p14, which encompass the CIMP markers P16 and ELMO1, respectively. We also observed an association between regional methylation and CIMP-H, but in MSI-H cases it was linked with late-onset, whereas in non-MSI-H cases it was irrespective of age. This suggests that mechanisms of methylation seeding and spreading may be different in early and late-onset disease. Moreover, CIMP-H non-MSI-H cases had significantly worse prognosis (p=0.021 for overall survival, p=0.004 for disease-free survival) and poor response to chemotherapy compared to CIMP-L or CIMP-Neg cases. Lastly, a methylation score assigned to non-MSI-H patients based on the degree of methylation of known CIMP markers was a significant prognostic factor of disease-free survival (p=0.004), and patients with a high methylation score showed a poor response to chemotherapy. Thus, our results suggest that different genetic and epigenetic mechanisms may drive tumourigenesis in early and late-onset disease. Although further research will be needed to elucidate the exact nature of these mechanisms, our findings should help to improve current classification of CRC patients with a goal towards personalized treatment.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.subject.lcshRectum - Cancer - Genetic aspects-
dc.subject.lcshColon (Anatomy) - Cancer - Genetic aspects-
dc.titleCharacterisation of methylator phenotype of colorectal cancer in young patients-
dc.typePG_Thesis-
dc.identifier.hkulb5334853-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePathology-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5334853-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats