Chimeric autosomal variants and polygenic genetic risk scores synergistically increase the pathogenesis of lung cancer

On October 17, 2022, Hongbing Shen and Zhibin Hu's research group from the School of Public Health of our university published a study entitled "Association of the interaction" in the international top oncology journal "The Lancet Oncology" between mosaic chromosomal alterations and polygenic risk score with the risk of lung cancer: an array-based case-control association and prospective cohort study
).

Mosaic chromosomal alterations (mCAs) are a type of genomic alteration caused by DNA replication errors not being properly repaired during the differentiation of hematopoietic stem cells, which accumulate in the body with the age of organisms since embryonic development, and are imprinted on the genome by internal and external environmental
exposures.
In recent years, many studies have confirmed the association between mCAs and the risk of solid tumors, cardiovascular diseases and other chronic diseases, but no studies have explored the association
between mCAs and the risk of lung cancer.
Therefore, depicting the characteristic spectrum of mCAs, clarifying their association with the risk of lung cancer, and revealing their interaction with genetic factors is helpful to explore the "genomic instability" and related biological mechanisms in the process of lung cancer progression, and further optimize the secondary prevention
of lung cancer.

Using genome-wide genotyping chip data from large-scale populations, the team of Shen Hongbing and Hu Zhibin found for the first time that mCAs, especially chimeric copy loss variants, were significantly associated with an increased risk of lung cancer and had a synergistic effect with polygenic risk scores (PRS), and the combined effect of the two on the risk of lung cancer was dose-response
。 These conclusions were confirmed
in both the Nanjing Lung Cancer Cohort (NJLCC) cohort from the Han Chinese population and the European population from the UK Biobank (UKB).
The authors believe that mCAs, as a novel genomic marker, can be synergistic with PRS for predicting the risk of lung cancer, thereby improving the effect of early screening, prevention and intervention of
lung cancer.

First, the authors recruited 10,248 lung cancer patients and 9,298 controls from the southern, central and northern regions of China, as well as 450821 European population samples
from the UKB cohort.
By comparison, individuals carrying mCAs in Chinese and European populations had an increased risk of lung cancer by 19% and 24%,
respectively, compared with individuals without mCAs.
Further subtype analysis found that the association effect of mCAs and lung cancer was mainly due to chimeric copy loss variants: individuals carrying chimeric copy loss variants had an increased risk of lung cancer by 81% and 40%, respectively, compared with individuals without mCAs, and the effect was stronger
in individuals carrying clonal expansion (cell ratio ≥ 10%) chimeric copy loss variant events.

Subsequently, the authors further investigated the interaction between mCAs and PRS, and found that there was a significant multiplication and additive interaction between chimeric copy loss variants and PRS in both Han Chinese and European populations, and the combined effect of the two on lung cancer risk was dose-response (Figure 1): compared with people with low genetic risk and no chimeric copy loss variants, People at high genetic risk and carrying chimeric copy loss variants have an increased risk of lung cancer by 5.
05-fold (NJLCC) and 2.
75-fold (UKB),
respectively 。 In addition, there was a positive additive interaction between chimeric copy loss variants and PRS: in the NJLCC study, the Relative Excess Risk of Interaction (RERI) caused by the additive interaction between high genetic risk and chimeric copy loss variants was 3.
67, accounting for about 61% of the risk effect of lung cancer in this group.
In the UKB study, the RERI caused by the additive interaction between high genetic risk and chimeric copy loss variants was 2.
15, accounting for approximately 67%
of the risk effect of lung cancer in this group.

Figure 1.
Chimeric copy loss variants and polygenic genetic risk scores synergize to increase the risk of lung cancer (NJLCC study results above, UKB study results below)

In summary, this study is the first to propose that mCAs can be used as a new class of genomic markers to predict the risk of lung cancer, and can be used in combination with PRS to optimize the individualized risk assessment
of lung cancer.
Since the detection of mCAs requires only low-cost genotyping chips and can be dynamically monitored throughout the life cycle, incorporating mCAs into existing lung cancer risk prediction models will help improve the identification strategy of high-risk groups of lung cancer and provide an important theoretical basis
for the precise prevention and diagnosis and treatment of lung cancer.
However, existing population-based association studies of mCAs and disease risk are mostly case-control designs and cannot distinguish between chimeric variants that occur after zygote formation and genetic variants
transmitted from parents.
At the same time, we also note that mCAs can occur since embryonic development, and their sources and specific biological mechanisms affecting the occurrence of lung cancer have not been systematically studied
.
Therefore, large-scale birth cohort studies based on core family lines (parent-mother-offspring) will help optimize the detection of mCAs, and at the same time, mCAs can be tracked and dynamically monitored for a long time from birth, which is helpful to deeply analyze the causes and natural history of mCAs and their biological mechanisms
affecting the occurrence of complex diseases.