Thymopoiesis-Associated Genetic Variant Correlates with Cancer Risk and Outcome
Authors: Kooshesh Kameron Allen , Gustafsson Karin , Foy Brody , Scadden David 
Published: December 2024

T cells are important to surveil for cancer, prevent its development, and control its spread. Although the thymus is the first organ to undergo age-related functional decline, it continues to produce T cells late into adult life and is essential to health. We recently demonstrated that adults who underwent surgical removal of their thymus have an increased risk of mortality, cancer, and autoimmunity that correlates with a reduction in T cell production and a pro-inflammatory cytokine environment (Kooshesh et al., NEJM, 2023). In line with this, there is mounting evidence to suggest that the reduction in thymopoiesis with age could contribute to the age-associated increased cancer incidence. Others have shown that a widespread genetic variant within the T cell receptor (TCR) gene, rs2204985, predicts high versus low thymopoiesis with age, depending on its genotype (GG versus AA, respectively). We tested whether the persistence of thymopoiesis rs2204985 GG genotype correlates with cancer development or cancer outcome.

5162 Mass General Brigham patients with a GG genotype (corresponding to high thymopoiesis) were compared with 5650 patients with an AA genotype (predicting low thymopoiesis) to calculate the incidence rate of all cancers and individual cancer subtypes. Manual chart review was also conducted to evaluate survival, relapse, risk of progression, and response to therapy among patients of different rs2204985 genotypes with myelodysplastic syndrome (N=68 patients), chronic lymphocytic leukemia (CLL; N=50 patients), gastroesophageal cancers (N=182 patients), lung cancers (N=57 patients), and melanoma (N=40 patients). Patients within the two groups had similar age, race, sex, smoking history, kidney function, and A1c.

Compared to patients with the high thymopoiesis genotype (GG), demographically-similar patients with the low thymopoiesis genotype (AA) had a higher risk of developing all cancers over a period of 10 years (incidence rate ratio, IRR [95% confidence interval]: 1.1 [1.05-1.14], p&lt;0.001). Patients with the AA genotype had a higher risk of developing a diverse host of cancers, including melanoma (1.14 [1.07-1.23], p&lt;0.001) and genitourinary cancers (1.16 [1.02-1.33], p=0.02) compared with patients with the GG genotype.

Clinical outcomes of demographically-similar patients with cancer also differed between groups. Among patients with low thymopoiesis, progression free survival was significantly inferior and the numbers of relapses were greater compared to patients with high thymopoiesis across myelodysplastic syndrome (2.1 vs 3.3 years, p=0.02; 1.0 vs 0.5 relapses per patient, p=0.03), CLL (4.3 vs 8.8 years, p&lt;0.001; 1.7 vs 0.3 relapses per patient, p=0.004), gastroesophageal cancers (2.6 vs 4.5 years, p&lt;0.001; 1.7 vs 0.8 relapses per patient, p=0.02), lung cancers (0.83 vs 1.24 years, p=0.01; 3.7 vs 2.2 relapses per patient, p=0.003), and melanoma (0.91 vs 2.1 years, p&lt;0.001; 6.4 vs 3.1 relapses per patient, p=0.004). Among patients with low thymopoiesis, the numbers of metastases and immune-related adverse events (irAEs) in response to therapy were greater compared with patients with high thymopoiesis across gastroesophageal cancers (5.2 vs 3.1 metastases, p=0.002; 0.81 vs 0.29 irAEs per patient, p=0.007), lung cancers (8.5 vs 2.7 metastases, p&lt;0.001; 1.9 vs 0.89 irAEs per patient, p=0.03), and melanoma (7.5 vs 2.5 metastases, p&lt;0.001; 5.4 vs 1.6 irAEs per patient, p&lt;0.001). Finally, progression of myelodysplastic syndrome to leukemia and transformation of CLL to lymphoma were also more frequent outcomes among patients with low thymopoiesis (50.0% vs 20.6% and 56.3% vs 9.7% of patients progressed to leukemia [p=0.02] and lymphoma [p&lt;0.001], respectively).

More robust thymopoiesis associated with the rs2204985 GG genotype correlates with both reduced development of cancer in adults and improved outcomes across a variety of hematologic and solid cancers. These data support the importance of sustained thymus function to health throughout adult life particularly in cancer control.