Association of Mosaic Loss of Chromosome Y with Lung Cancer Risk and Prognosis in a Chinese Population.

Mosaic loss of chromosome Y (mLOY) is the most commonly detectable mosaic chromosomal event in cancers; however, its underlying relationship with tumorigenesis is still unclear. We conducted a mendelian randomization study to systematically investigate the effect of mLOY on lung cancer based on a published genome-wide association study and inferred the causal relationship between mLOY and lung cancer. Kaplan-Meier and Cox regression analyses were used to evaluate the effect of mLOY on lung cancer prognosis. We discovered that genetically defined mLOY was a protective factor against lung cancer development in nonsmokers but not in smokers (lifelong nonsmokers: OR = 0.80, 95% confidence interval [CI]: 0.69-0.93, p = 4.03×10-3; smokers: OR = 0.96, 95% CI: 0.89-1.04, p =2.90 × 10-1, pHeterogeneity = 3.83 × 10-2). A U-shaped curve between the copy number level of chromosome Y and lung cancer risk was fitted (p for linearity Wald = 8.81 × 10-10) to support the idea that heavy mLOY caused by acquired damaging environmental factors may have effects on lung cancer that are different from those of genetically defined mLOY, whereas genetically predicted mLOY was linearly associated with a decreased lung cancer risk (p for linearity Wald = 0.15). In addition, increased genetically defined mLOY was also significantly associated with a better outcome of lung cancer (HR = 0.86, 95% CI: 0.75-0.98, p = 2.03 × 10-2). In summary, we propose a "two-sides" model: "natural" mLOY reduces the risk and ensures a better prognosis of lung cancer, although the effect can be abolished by an aberrant loss of chromosome Y caused by environmental risk factors. Our results reveal a complex relationship between mLOY and lung cancer and provide important implications for the prevention of lung cancer.

Qin N ，Li N ，Wang C ，Pu Z ，Ma Z ，Jin G ，Zhu M ，Dai M ，Hu Z ，Ma H ，Shen H ... -  《-》

[Epidemiological distribution of mosaic loss of chromosome Y in adult men in 10 areas in China and its prospective association with lung cancer].

Zhao YX ，Song MY ，Lyu J ，Yu CQ ，Pei P ，Du HD ，Chen JS ，Chen ZM ，Li LM ，Sun DJY ... -  《-》

Genetic association of mosaic loss of chromosome Y with prostate cancer in men of European and East Asian ancestries: a Mendelian randomization study.

Background: Genomic instability is a significant hallmark of aging and has a major impact on aging biology. Mosaic loss of chromosome Y (mLOY) in blood cells is a common chromosomal abnormality in aging men and is considered an indicator of genomic instability. Previous studies have indicated a connection between mLOY and prostate cancer risk, but the causal relationship has not been fully established. Methods: To determine the causal effect of mLOY on prostate cancer, we conducted a Mendelian Randomization (MR) study in two ancestral groups. We utilized 125 and 42 mLOY-associated variants as instrumental variables (IVs) in European and East Asian GWAS of prostate cancer, respectively. Summary-level data on prostate cancer was obtained from the PRACTICAL consortium (79,148 cases and 61,106 controls of European ancestry) and the Biobank Japan consortium (5,408 cases and 103,939 controls of East Asian ancestry). A single population was used to assess the causal relationship in East Asian ancestry. Our main method for obtaining MR results was inverse-variance weighted (IVW), and we conducted sensitivity analyses to confirm the robustness of our results. Finally, we combined the estimates from both sources using a fixed-effects meta-analysis. Results: Our MR analysis using the IVW method showed that a one-unit increase in genetically predicted mLOY was associated with an increased risk of prostate cancer in the PRACTICAL consortium (OR = 1.09%, 95% CI: 1.05-1.13, p = 1.2 × 10-5), but not in the Biobank Japan consortium (OR = 1.13%, 95% CI: 0.88-1.45, p = 0.34). Sensitivity analyses robustly indicated increased odds ratios for prostate cancer with every one-unit increase in genetically predicted mLOY for the PRACTICAL consortium. Furthermore, mLOY was found to be associated with prostate cancer risk in a meta-analysis of both sources (OR = 1.09%, 95% CI: 1.05-1.13, p = 8.0 × 10-6). Conclusion: Our MR study provides strong evidence that higher mLOY increases the risk of prostate cancer. Preventing mLOY may be a means of reducing the risk of developing prostate cancer.

Kobayashi T ，Hachiya T ，Ikehata Y ，Horie S ... -  《-》

Mosaic Y Loss Is Moderately Associated with Solid Tumor Risk.

Mosaic loss of the Y chromosome (mLOY) in peripheral leukocytes is a somatic event in which a fraction of leukocytes have lost the entire Y chromosome. The frequency of mLOY increases with age and may reflect poor genomic maintenance as well as clonal imbalances in normal immune function, making mLOY an attractive candidate marker for cancer risk. Here, we investigated the relationship between mLOY and incident cancer in a large sample of 207,603 cancer-free men from the UK Biobank, in which 13,895 men developed an incident solid tumor during follow-up. We identified mLOY by scanning for deviations in genotyping array log R intensity ratios across the male-specific chromosome Y region. Overall, we detected low proportions of cells with mLOY in 3,358 (1.6%) men and high proportions of mLOY in 524 (0.3%) men. We found an association of mLOY with overall solid tumor incidence using both low and high mLOY thresholds [HRlow = 1.18; 95% confidence interval (CI)low, 1.07-1.30; P low = 0.001; HRhigh = 1.36; 95% CIhigh, 1.09-1.71; P high = 0.007] and more specifically we observed an association with lung cancer (HRhigh = 2.25; 95% CIhigh, 1.36-3.71; P high = 0.002). Stronger associations were observed without adjustment for smoking, suggesting that smoking is an important confounder of tumor incidence. It is unlikely that mLOY is a major mediator of the effect of cigarette smoking on cancer risk, as mLOY was observed in only a small fraction of smokers who developed cancer. In summary, mLOY was modestly associated with incidence of solid tumors in the UK Biobank, although for some cancer subtypes these findings may reflect residual confounding by smoking. SIGNIFICANCE: Evidence from the UK Biobank indicates mosaic chromosome Y loss in leukocytes is moderately associated with increased incidence of select solid tumors.

Loftfield E ，Zhou W ，Yeager M ，Chanock SJ ，Freedman ND ，Machiela MJ ... -  《-》

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer's Disease Aetiopathogenesis in Men.

García-González P ，de Rojas I ，Moreno-Grau S ，Montrreal L ，Puerta R ，Alarcón-Martín E ，Quintela I ，Orellana A ，Andrade V ，Adami PVM ，Heilmann-Heimbach S ，Gomez-Garre P ，Periñán MT ，Alvarez I ，Diez-Fairen M ，Nuñez Llaves R ，Olivé Roig C ，Garcia-Ribas G ，Menéndez-González M ，Martínez C ，Aguilar M ，Buongiorno M ，Franco-Macías E ，Saez ME ，Cano A ，Bullido MJ ，Real LM ，Rodríguez-Rodríguez E ，Royo JL ，Álvarez V ，Pastor P ，Piñol-Ripoll G ，Mir P ，Lara MC ，Padilla MM ，Sánchez-Juan P ，Carracedo A ，Valero S ，Hernandez I ，Tàrraga L ，Ramirez A ，Boada M ，Ruiz A ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》