Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 7 uppssatser.

Diffuse gliomas, the most common primary brain cancer, are classified into astrocytomas, oligodendrogliomas and oligoastrocytomas according to morphological similarity to glial cell, and categorized into grade II to IV according to histological features. While standard-of-care of surgery followed by chemo-radiotherapy exists for grade IV glioblastomas, lower grade gliomas (grades II and III) remain as a heterogeneous entity with variable treatment and outcome. The current WHO classification of lower grade glioma is purely based on histology and subject to interobserver variation, which can be aggravated by sampling error or small tissue biopsy. Objective prognostic biomarker guiding patient risk stratification is also relatively inadequate in lower grade gliomas. Since molecular markers will be supplemented into the future classification system of gliomas in order to facilitate clinico-pathological prediction and therapeutic planning in patient management and clinical trials, identification of clinically relevant biomarker is of paramount importance in neuro-oncology. In this study, we evaluated the clinical significance of several important molecular markers in a very large cohort of 453 lower grade gliomas (including 244 diffuse astrocytomas, 73 anaplastic astrocytomas, 31 oligodendrogliomas, 17 anaplastic oligodendrogliomas, 76 oligoastrocytomas and 12 anaplastic oligoastrocytomas) from Prince of Wales Hospital (Hong Kong) and Huashan Hospital (Shanghai). Mutational analysis was conducted in IDH, CIC, FUBP1 and TERT promoter by direct sequencing and 1p/19q codeletion and EGFR amplification were evaluated by fluorescent in-situ hybridization. Protein expressions of IDH1-R132H, CIC, FUBP1, EGFR, INA, p53 and PDGFRA were examined by immunohistochemistry. IDH mutation, detected in 69% of lower grade gliomas, represented a crucial marker in classifying the tumors into two groups with distinct prognosis, the favorable IDH mutated group and unfavorable IDH wild type group. 1p/19q codeletion, present in 20% of lower grade gliomas, identified tumors with oligodendroglial histology and favorable prognosis within the IDH mutated group. This IDH mutated-1p/19q codeleted genetic signature was frequently found in incidentally-discovered low grade gliomas, a clinical subgroup of tumors with excellent prognosis. CIC and FUBP1 mutations, detected in 47% and 16% of oligodendroglial tumors respectively, were oligodendroglial markers which conferred unfavorable prognosis to patients within IDH mutated-1p/19q codeleted oligodendroglial tumors. Among IDH mutated-1p/19q intact gliomas, p53 positive expressing tumors exhibited worse prognosis and PDGFRA positive expressing tumors showed better prognosis. TERT promoter mutation, identified in 28% of lower grade gliomas, exhibited as an oligodendroglial marker and favorable prognostic factor within the IDH mutated group and highlighted a subgroup of aggressive astrocytic tumors with short survival within the IDH wild type group. EGFR amplification, observed in 7% of lower grade gliomas, occurred exclusively in IDH wild type tumors, correlated with TERT promoter mutation and contributed a subset of tumors with fatal prognosis. Taken together, this study identifies objective and clinically relevant biomarkers which define lower grade gliomas into molecular subgroups with distinct clinico-pathological features. The biomarkers not only provide adjuncts to tumor classification beyond histology but potentially facilitate standardization of treatment strategy. With continuous efforts, I believe that this information will ultimately contribute to patient care in neuro-oncology in the era of personalized medicine. / 瀰漫性腦膠質瘤是最常見的原發性腦癌，可根據形態學分為星形細胞瘤、少枝膠質細胞瘤和少枝星形細胞瘤，並根據惡性特徵分為II至IV級。雖然膠質母細胞瘤(Ⅳ級)有標準的手術和術後化放療方案，低級別膠質瘤(Ⅱ和Ⅲ級)在治療方案和臨床結果上仍有很大的變異。目前世界衛生組織就膠質瘤的分類是純基於組織學，因此存在著觀察者間的變異，而抽樣誤差和活檢組織樣本太小亦加劇此問題。客觀和俱臨床價值的標誌物在低級別膠質瘤亦相對缺乏。為了改善腫瘤診斷和治療，未來膠質瘤分類將會加入分子標誌物，因此探討預後標誌物在神經腫瘤研究領域極為重要。我們從香港威爾斯親王醫院和上海華山醫院採集了453例低級別膠質瘤樣本，並對幾個重要的分子標誌物的臨床意義進行評估。我們以直接測序分析IDH，CIC，FUBP1和TERT啟動子突變，以熒光原位雜交技術檢測染色體1p/19q雜合性缺失和EGFR基因擴增，並以免疫組化檢測IDH1-R132H，CIC，FUBP1，EGFR，INA，p53和PDGFRA蛋白表達。IDH的突變率為69%，它把膠質瘤分成兩組: 預後好的IDH突變型組和預後差的IDH野生型組。1p/19q雜合性缺失的發生率為20%，主要是IDH突變型組內的少枝膠質細胞瘤，有較好的預後。IDH突變-1p/19q雜合性缺失這個基因特徵經常出現在偶發低級別膠質瘤，是一組預後良好的臨床亞組。CIC和FUBP1在少枝膠質腫瘤的突變率分別為47%和16%，在IDH突變-1p/19q雜合性缺失的少枝膠質腫瘤有不良的預後。在IDH突變-1p/19q完整的膠質瘤，p53陽性表達的腫瘤預後較差，PDGFRA陽性表達的腫瘤則預後較好。TERT啟動子的突變率為28%。在IDH突變型組，TERT啟動子突變表現為少枝膠質標誌物，出現在預後良好的腫瘤;在IDH野生型組，TERT啟動子突變則出現在一組生存期很短的星形細胞腫瘤亞組。EGFR基因擴增的發生率為7%，只出現在IDH野生型腫瘤，與TERT啟動子突變有相關性，並有致命性的預後。綜上所述，本研究確定了客觀的臨床標誌物，為膠質瘤分類提供組織學以外的參考，更為制定標準治療方案奠定基礎。在這個體化醫療時代，本人相信這些資訊最終將有助於神經腫瘤病人的治理。 / Chan, Ka Yin. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 159-186). / Abstracts also in Chinese. / Title from PDF title page (viewed on 02, December, 2016). / Detailed summary in vernacular field only.

A number of major crop species, such as allohexaploid wheat and autotetraploid potato are polyploid. Potato is the fourth most important crop in terms of production and has become an important food source in many countries. Therefore, the molecular analysis was directed towards investigating ways to develop markers to assist the potato breeding process; for example breeding for powdery scab disease resistance, and tolerance to cold induced sweetening. Polyploids have more possible genotypes per population, allele dosage effects and increased marker complexity compared to diploids. Potato is also outcrossing and therefore highly heterozygous. Various methods for detecting marker-trait associations including, linkage, quantitative trait locus (QTL) and association mapping were studied and protocols developed. A mapping population was produced and a number of traits were measured including powdery scab resistance. Powdery scab disease assays were carried out over six seasons and markers associated with disease resistance were identified. Markers associated with resistance to powdery scab were identified on chromosomes I, IV, V, VI, VIII and IX using analysis of variance (ANOVA). Linkage maps were produced for each parent of the population and QTL associated with resistance and susceptibility to disease were identified using interval mapping, which revealed QTL on chromosomes II, V, VII , VIII, IX and an unanchored linkage group. QTL were detected across years on regions of chromosomes VIII and IX. These QTL results had some overlap with the marker-trait associations that were identified using ANOVA analysis. Another marker identification technique was tested, known as association or linkage disequilibrium mapping. Alleles of candidate genes were tested for association with cold-induced sweetening using a germplasm collection. The alleles identified as important were of the apoplastic invertase and UGPase genes and a unique interaction between alleles of the apoplastic invertase and apoplastic invertase inhibitor was also detected. This thesis describes the first study into the genetics of powdery scab resistance and the markers identified as associated with resistance will be validated for use in a marker-assisted selection (MAS) programme. The tools and resources developed as part of this thesis are vital to the potato breeding programme that requires the identification of associated molecular markers.

Colorectal cancer (CRC) is one of the most common causes of death from malignant disease. Nevertheless, no ideal screening method exists and there is a lack of prognostic and predictive factors to support clinical decisions and to aid the development of a more individualized treatment for patients with CRC. The aim of this thesis was to investigate early detection, prognostic and predictive factors of CRC. In the first paper, a novel method to collect cells for DNA quantification from the rectal mucosa was investigated. The sensitivity and specificity of this test to detect CRC or any pathology in colon and rectum were ultimately too low to be acceptable. In the second paper, the prognostic value of growth differentiation factor 15 (GDF 15) was evaluated in patients curatively operated for colorectal cancer. GDF 15 expression was demonstrated to be associated with a negative prognosis in patients with stages I-III and III disease. In the third paper, the prognostic value of BRAF, PIK3CA KRAS and MSI was evaluated in a cohort of patients with CRC stratified by disease and recurrence. The results indicated that patients with CRC stage III without recurrence have a higher frequency of BRAF mutation compared to stage III patients with recurrence. In the fourth paper, histopathological predictors of pathologic complete response (pCR) as well as the association between pre-treatment carcinoembryonic antigen (CEA) levels and pCR in non-smoking and smoking patients receiving preoperative chemo-radiotherapy for rectal cancer were evaluated. Only in non-smokers was a low CEA level significantly associated with pCR, suggesting that the predictive value of CEA for pCR in rectal cancer in smokers can be limited. In sum, this research has investigated a new method for CRC detection and further evaluated the clinical use of prognostic and predictive markers in CRC.

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