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Investigating Thymic Function in Human Papillomavirus (HPV)-Related Cancer Risk and Survival

Principal Investigator
Name
Eric Engels
Degrees
MD, MPH
Institution
National Cancer Institute, National Institutes of Health
Position Title
Senior Investigator
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
PLCO-1991
Initial CDAS Request Approval
Sep 29, 2025
Title
Investigating Thymic Function in Human Papillomavirus (HPV)-Related Cancer Risk and Survival
Summary
Although the thymus atrophies with age, it continues to support immune function by producing new T-cells throughout the lifespan. In aging adults, reduced thymic output leads to a less diverse T-cell repertoire, potentially impairing immune surveillance and increasing the risk of infections, cancer, and autoimmune diseases. Research has shown that adults undergoing thymectomy and individuals with compromised immune status have a higher risk of cancer and overall mortality. However, it remains unclear whether the subclinical immunosuppression resulting from age-related thymus dysfunction affects cancer risk and survival in adults.
The functional single nucleotide polymorphism (SNP) rs2204985, located in the TCRA-TCRD locus encoding the T-cell receptor, influences thymus function and T-cell diversity. Circulating signal-joint T-cell receptor excision circles (sjTRECs) provide a direct molecular measure of recent thymic emigrants and reflect immune competence. We hypothesize that individuals with the rs2204985 GG genotype have higher sjTREC levels, leading to enhanced immune surveillance, which may result in a lower risk of human papillomavirus (HPV)-related cancers and improved overall survival. This proposal prioritizes HPV-related cancers, including anogenital and oropharyngeal cancers, due to their established connection with HPV infection and preliminary evidence from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.
Using a nested case-control design within the PLCO Trial, we will evaluate the association between sjTREC levels and the risk of HPV-related cancers. We will also assess the association of SNP rs2204985 genotype and sjTREC levels with overall survival among both cancer cases and controls. Additionally, we will validate the relationship between SNP rs2204985 genotype and circulating sjTREC levels among cancer-free controls. By integrating molecular epidemiologic data, this study aims to clarify how natural variation in thymus function influences both the development and progression of HPV-related cancers, potentially uncovering new avenues for cancer prevention targeting thymus function in aging populations.
Aims

Aim 1. Evaluate the association between the rs2204985 genotype and circulating sjTREC levels. The circulating sjTREC levels will be compared across rs2204985 genotypes among controls in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We hypothesize that individuals with the rs2204985 GG genotype exhibit higher sjTREC levels than those with the AA genotype.
Aim 2. Assess the relationship between circulating sjTREC levels and risk of HPV-related cancers. We will examine the association between circulating sjTREC levels and HPV-related cancer risk in a case-control study nested in the PLCO Trial. We hypothesize that circulating sjTREC levels are inversely associated with the risk of HPV-related cancers.
Aim 3. Investigate the association between rs2204985 genotype, sjTREC levels, and overall survival among patients with HPV-related cancers and controls. We will analyze overall survival among participants in the PLCO Trial, separately for the cases and controls. We hypothesize that individuals with cancer who have better thymus function (i.e., the presence of rs2204985 GG genotype or higher circulating sjTREC levels) will have improved overall survival, reflecting in part their better control of their cancer after diagnosis.

Collaborators

Eric Engels National Cancer Institute, National Institutes of Health
Jun Tao National Cancer Institute, National Institutes of Health
Mitchell Machiela National Cancer Institute, National Institutes of Health