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Dissertation
Multi-omic analysis of gastroenteropancreatic and lung neuroendocrine tumors to elucidate risk factors and treatment-related outcomes
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2024
DOI: 10.25820/etd.007695
Abstract
Background: Neuroendocrine tumors (NETs) are a heterogeneous group of uncommon neoplasms arising from neuroendocrine cells throughout the body. The incidence of NETs continues to increase worldwide with a 6.4-fold increase between 1973 and 2012 in the USA. The 1-, 3-, 5-, and 10-year overall survival rates for patients with NETs are 72.8%, 52.7%, 39.4%, and 18.1%, respectively. Gastroenteropancreatic (GEP) NETs are the most common NETs site comprising 55-70 % of all NET patients. Lung NETs are the second most common NET diagnosis, accounting for 30% of all NETs. The etiology of NETs remains inconclusive. Nonmodifiable risk factors, such as age, sex and race/ethnicity, have been considered as potential risk factors for NET development. In addition, other risk factors, including the family history of cancer, cigarette smoking, alcohol consumption, obesity and other chronic conditions (e.g., type 2 diabetes) may be related to the risk of developing NETs. In addition to several inherited genetic factors (e.g., MEN1, CDKN1B, VHL, TSC2, and NF1) and pathway-related genetic factors (e.g., PTEN and NOTCH1), emerging genes and variants (i.e., ATRX, DAXX, OTP and CD44) have been identified as genetic risk factors of developing NETs. Further investigations are needed to replicate and confirm these novel genetic risks and protective factors. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs has been a therapeutic option in patients with progressive metastatic neuroendocrine tumors. 90-yttrium (90Y)-DOTATOC and 177-lutetium (177Lu)-DOTATATE have been the most commonly used forms of PRRT over the past two decades. Renal and hematological toxicity are side effects and dose-limiting factors of PRRT.
Objectives: This dissertation had three aims: 1) examine potential risk factors for developing GEP and lung NETs, 2) evaluate genetic associations between selected genes and the risk of developing GEP and lung NET, and 3) assess the changes in renal and hematological function and associations with survival in NET patients treated with PRRT.
Methods: Aims 1 and 2 were addressed using phenotypic and genotypic data from the All of Us Research program. We applied a nested case-control study of 366 NET cases and 1814 healthy controls to compare the odds of GEP and lung NETs in the presence or absence of various potential risk factors in Aim 1. Piecewise structural equation modeling was used for generating effect estimates of these risk factors. Aim 2 utilized a nested case-control study of 257 NET cases and 2567 healthy controls to compare the odds of developing NETs in the presence or absence of selected genetic risk factors. Logistic regression was applied to produce effect estimates of each genetic variant. In Aim 3, we conducted a retrospective cohort study of 448 NET patients treated at two large academic medical centers with either 177Lu-DOTATATE or 90Y-DOTATOC and followed for up to 15 years for changes of renal (i.e., serum creatinine, blood urea nitrogen and estimated glomerular filtration rate) and hematological function (i.e., white blood cell counts, platelet counts, and hemoglobin concentrations). Piecewise linear mixed effect models with a random intercept and two random slopes were applied to model the longitudinal repeated measurements of renal and hematological function. Overall survival (OS) and progression-free survival (PFS) were modelled using Cox proportional hazard regressions. Bonferroni correction and the Benjamini-Hochberg procedure were used to account for multiple comparisons and adjust the significance levels for all three aims.
Results: In risk factor analyses of all individuals, a family history of any cancer in a first-degree relative, a past medical history of type 2 diabetes or any immune-mediated disease were associated with an increased risk of developing GEP or lung NETs (P<0.05). In sex-specific analyses, male individuals with obesity were more likely to develop GEP and lung NETs(P<0.05). In addition, a family history of any cancer, pre-existing type 2 diabetes and a past medical history of immune-mediated diseases were associated with an increased risk of developing GEP and lung NETs in females (P<0.05). Females from racial groups other than non-Hispanic White, non-Hispanic Black, and Hispanic or Latino tended to have a lower risk of developing NETs. Individuals with pre-existing type 2 diabetes and having a first-degree relative of any cancer had higher risk of developing GEP NETs. Individuals with immune-mediated diseases were more likely to develop lung NETs.
In the candidate gene analysis, we identified ten intron variants in gene KIF16B and one intron variant in gene SEMA6A significantly associated with the risk of developing NETs (P<5E-4). In addition, we observed that rs1360210 and rs7269190 were significantly associated with the risk of lung NETs and rs7269190 was associated with the risk of GEP NETs (P<5E-4).
In treatment-related outcome analyses, comparing patients treated with 177Lu-DOTATATE to those treated with 90Y-DOTATOC, renal function did not differ significantly prior to, during or after PRRT (P>0.05). Compared with patients treated with 90Y-DOTATOC, significantly decreased indicators of hematological function were observed in those treated with 177Lu-DOTATATE prior to and during PRRT (P<0.001), and no significant recovery was observed in hematological function post PRRT. Further analysis of the monthly rate of change in hematological markers supported these primary models. Individuals who received PRRT with 177Lu-DOTATATE tended to have a higher PFS (hazard ratio, 0.47, 95%CI: 0.28-0.79) compared with 90Y-DOTATOC, but there was no difference in OS.
Conclusions: A first-degree family history of any cancer and pre-existing type 2 diabetes and immune-mediated diseases were the strongest risk factors for developing GEP or lung NETs. Genetic variants in KIF16B and SEMA6A were reaffirmed to affect the development of GEP or lung NETs and could be useful biomarkers of disease. Our evidence indicates that NET development can be attributed to both inheritable and environmental risk factors. Future studies of large-scale replication and functional validations are needed to confirm the findings. A statistically significant albeit physiologically minor hematological toxicity was observed in patients treated with 177Lu-DOTATATE compared with 90Y-DOTATOC. Conversely, compared to 90Y-DOTATOC, 177Lu-DOTATATE appears to enhance PFS but not OS. Treatment with 177Lu-DOTATATE may necessitate follow-up for hematological toxicity irrespective of other therapies before PRRT. This dissertation sheds light on and raises novel hypotheses regarding the etiology of NETs and treatment assessments, laying a foundation for improved disease control and prevention strategies at both individual and population levels.
Details
- Title: Subtitle
- Multi-omic analysis of gastroenteropancreatic and lung neuroendocrine tumors to elucidate risk factors and treatment-related outcomes
- Creators
- Tao Xu
- Contributors
- Michael O'Rorke (Advisor)Hyunkeun Cho (Committee Member)Joseph Dillon (Committee Member)Sarah Nash (Committee Member)Dawn Quelle (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Epidemiology
- Date degree season
- Summer 2024
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.007695
- Number of pages
- xiii, 123 pages
- Copyright
- Copyright 2024 Tao Xu
- Language
- English
- Date submitted
- 07/21/2024
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 101-115).
- Public Abstract (ETD)
Neuroendocrine tumors (NETs), formerly known as “carcinoid tumors,” are rare tumors found in organs throughout the body. NETs commonly occur in the bronchial and gastrointestinal tracts. Despite the nature of their slow growth, the increasing incidence and disease burden of NETs attracts the interest of researchers to explore the etiology and prognosis of NETs.
My dissertation investigated the traditional and genetic risk factors of NETs and assessed treatment-related toxicities and outcomes in NET patients. Using data from a large cohort involving around 800,000 participants and another multi-institutional dataset, my thesis has shown that presence of a positive family history (first-degree) of any cancer, a past medical history of type 2 diabetes or immune-mediated disease could increase the risk of developing NETs. We also found some novel genetic variants in two genes, including KIF16B and SEMA6A, associated with the risk of NETs. In the assessment of resulting toxicity from a widely accepted peptide receptor radionuclide therapy called 177Lu-DOTATATE, we found that this therapy may cause minor blood marker toxicities during treatment but could effectively slow the progression of NETs.
These findings underscore the importance of both inheritable and environmental risk factors in NET development, and the necessity of follow-up for NET patients who are receiving treatment with 177Lu-DOTATATE. By examining the risk factors of NETs and assessing treatment toxicities, we could identify individuals at a higher risk of disease, implement effective interventions to reduce their risks, and improve prognosis for diagnosed patients.
- Academic Unit
- Epidemiology
- Record Identifier
- 9984698352202771
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