Date of Award

2019

Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy in Biological Sciences (PhD)

Administrative Home Department

Department of Biological Sciences

Advisor 1

Lanrong Bi

Advisor 2

Jingfang Ju

Committee Member 1

Chandrashekhar Joshi

Committee Member 2

Mark Tang

Committee Member 3

Feng Zhao

Abstract

As the third most commonly diagnosed malignancy and second leading cause of cancer-related death, colorectal cancer remains a major global healthcare concern. Despite numerous studies to elucidate the mutations involved in tumorigenesis and assist with the prognostic stratification of patients, individual outcomes and therapeutic responses remain unpredictable. In this study, we performed a retrospective analysis of the clinical and pathological features of colorectal cancers diagnosed in the Upper Peninsula of Michigan. We then characterized the frequency and diversity of six molecular markers (MMR, BRAF, NRAS, KRAS, PIK3CA, PD-L1) in matched samples belonging to 120 patients in our cohort and correlated the findings with cancer registry data.

PCR-based assays were performed to identify point mutations in the RAS, RAF and PIK3CA pathways using zinc formalin-fixed, paraffin-embedded blocks belonging to the patients in our cohort. Additionally, immunohistochemical stains were prepared to assess DNA mismatch repair protein expression and PD-L1 status in the tumor cells. Individual mutations were correlated with the clinical -pathological features of CRC in patients. We noted a higher frequency of primary tumors arising in the proximal colon, as well as a potential prognostic value in KRAS and PIK3CA mutation testing. We believe this is the first population-based study to characterize and correlate mutations with clinicopathological variables in colorectal cancer patients from the Upper Peninsula of Michigan. The findings presented here provide additional insight regarding the tumor microenvironment at various stages of disease and may lead to more effective patient management strategies as well as the development of new companion diagnostics.

Available for download on Monday, December 14, 2020

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