Approved Research

M6A-associated genetic variants in pancreatic cancer and pre-cursor lesions, and associations with telomere maintenance and prognosis: a population-based study

Lay summary

Pancreatic cancer remains one of the deadliest cancers. Surgery may be the only curative treatment, but only a small minority with early-stage disease are eligible, confirming the need for earlier diagnosis and alternative therapies.

Although most people understand that our DNA (subunits of which are called chromosomes) contains the 'code' or genes to produce proteins that fulfil a particular function or need in the human body, many do not realize that the role of these genes can be changed by factors in our environment (both within and outside our bodies), so called 'epigenetics'. We intend to study the role that small genetic changes in the genes that code for some of the epigenetic regulators associated with pancreatic cancer initiation and progression have upon pancreatic cancer survival - we will study this among cancer patients, patients with conditions predisposing to cancer (cancer pre-cursors), and healthy patients. In addition, we intend to examine the length of the 'ends' of the chromosomes ('teleomeres'), of these patient groups. Telomeres these are like the plastic caps at the end of your laces which stop your thread (your chromosomes) from fraying, which would destroy our genetic information. We will determine if there are any associations between these genetic changes, telomere length and pancreatic cancer survival, as well as the relevance of these genetic variations to the prediction of pancreatic cancer. We expect work on the UK Biobank dataset will begin in early 2022 and end no later than mid-2024.

While the direct public health impact of this project will be minimal, any prospective findings could lead to additional research into the epigenetic regulation of pancreatic cancer and a potential therapeutic target (i.e., a METTL3 inhibitor) in the future. The downstream impact of this research could lead to a decrease in disease burden and mortality amongst the afflicted to the point where a diagnosis is no longer synonymous with death.

Scope extension:

Pancreatic ductal adenocarcinoma (PDAC) is a disease with a formidable prognosis and notoriously poor survival, which has not markedly changed in decades. N6-methyladenosine (methylation of nitrogen of carbon six of adenosine), or m6A, is an important epitranscriptomic modification that controls cancer self-renewal, differentiation and cell fate. Dysregulation of m6A-related processes are likely involved in pancreatic carcinogenesis and m6A modification may have a profound impact on telomere homeostasis and genomic stability. The overarching goal of this study is to investigate the role of variation in several m6A regulators and telomere length on the prognosis and survival of PDAC for therapeutic integration, and/or reduction in PDAC mortality via earlier detection.

Aims:

1) Assess the association between variations in SNPs of several unexploited m6A regulators (i.e., METTL3, METTL14, YTHDF2, ALKBH5, IGF2BP1, and IGF2BP2) and cancer-specific/overall mortality.

2) Leverage UK Biobank primary care data to incorporate analyses that include PDAC precursors such as chronic pancreatitis and pancreatic intraepithelial neoplasia.

3) Assess the relationship between telomere length, disease status and survival in PDAC patients (pending tumor stage/grade release)

1. i) If a relationship is observed, assess the predictive utility of these biomarkers in discriminating incident PDAC from healthy controls.

Additionally, these three aims intend to leverage the newly available proteomic data from UKB as additional covariates.