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 ... -  《-》

Predictors of mosaic chromosome Y loss and associations with mortality in the UK Biobank.

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

Particulate matter pollution, polygenic risk score and mosaic loss of chromosome Y in middle-aged and older men from the Dongfeng-Tongji cohort study.

Mosaic loss of chromosome Y (mLOY) is the most common somatic alteration as men aging and may reflect genome instability. PM exposure is a major health concern worldwide, but its effects with genetic factors on mLOY has never been investigated. Here we explored the associations of PM2.5 and PM10 exposure with mLOY of 10,158 males measured via signal intensity of 2186 probes in male-specific chromosome-Y region from Illumina array data. The interactive and joint effects of PM2.5 and PM10 with genetic factors and smoking on mLOY were further evaluated. Compared with the lowest tertiles of PM2.5 levels in each exposure window, the highest tertiles in the same day, 7-, 14-, 21-, and 28-day showed a 0.005, 0.006, 0.007, 0.007, and 0.006 decrease in mLRR-Y, respectively (all P < 0.05), with adjustment for age, BMI, smoking pack-years, alcohol drinking status, physical activity, education levels, season of blood draw, and experimental batch. Such adverse effects were also observed in PM10-mLOY associations. Moreover, the unweighted and weighted PRS presented significant negative associations with mLRR-Y (both P < 0.001). Participants with high PRS and high PM2.5 or PM10 exposure in the 28-day separately showed a 0.018 or 0.019 lower mLRR-Y level [β (95 %CI) = -0.018 (-0.023, -0.012) and - 0.019 (-0.025, -0.014), respectively, both P < 0.001], when compared to those with low PRS and low PM2.5 or PM10 exposure. We also observed joint effects of PM with smoking on exacerbated mLOY. This large study is the first to elucidate the impacts of PM2.5 exposure on mLOY, and provides key evidence regarding the interactive and joint effects of PM with genetic factors on mLOY, which may promote understanding of mLOY development, further modifying and increasing healthy aging in males.

Guan X ，Meng X ，Zhong G ，Zhang Z ，Wang C ，Xiao Y ，Fu M ，Zhao H ，Zhou Y ，Hong S ，Xu X ，Bai Y ，Kan H ，Chen R ，Wu T ，Guo 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 ... -  《-》

Mosaic chromosome Y loss is associated with alterations in blood cell counts in UK Biobank men.

Lin SH ，Loftfield E ，Sampson JN ，Zhou W ，Yeager M ，Freedman ND ，Chanock SJ ，Machiela MJ ... -  《Scientific Reports》