Human Y chromosome pan-organ mapping reveals progressive mosaic loss from normal to cancer
Arkadiusz Gertych, Huihui Ye, Xingyu Chen, Eric Vail, V. Krishnan Ramanujan, Lauren Brady, Lawrence D. True, Peter S. Nelson, Peter R. Carroll, Dan Theodorescu
Arkadiusz Gertych, Huihui Ye, Xingyu Chen, Eric Vail, V. Krishnan Ramanujan, Lauren Brady, Lawrence D. True, Peter S. Nelson, Peter R. Carroll, Dan Theodorescu
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Research Article Clinical Research Genetics Oncology

Human Y chromosome pan-organ mapping reveals progressive mosaic loss from normal to cancer

Abstract

BACKGROUND. Loss of the Y chromosome (LOY) is a frequent event in male tumors and has been linked to cancer progression. However, the degree of mosaic LOY (mLOY) within normal tissues from men with or without cancer remains uncharacterized. METHODS. Here we used a FISH-based assay targeting X- and Y-chromosome centromeres to perform a pan-organ analysis of mLOY in 1,000 male tissue samples from 405 individuals representing 11 organs. Automated image processing generated a quantitative FISH-based mLOY score (YchrFISH) that we validated against a transcriptomic surrogate of Y-chromosome dosage from RNA-seq data. RESULTS. mLOY burden varied by tumor type, with highest degree in colorectal carcinoma. Across tissue groups, YchrFISH scores declined progressively from normal tissues of cancer-free men to histologically normal tissues adjacent to cancer and carcinoma (P < 0.0001). Paired analyses confirmed consistently greater mLOY in malignant compared with tumor-adjacent histologically normal tissue in different organs. Spatially resolved RNA-seq maps of bladders removed for cancer demonstrated a transcriptional gradient of Y-chromosome loss from normal urothelium through intraepithelial neoplasia to invasive carcinoma. CONCLUSION. mLOY gradients exist across histologically normal and malignant tissues, consistent with the concept of field cancerization. Our findings support epithelial mLOY as a biomarker of early malignant transformation and, to our knowledge, a previously unrecognized hallmark of male oncogenesis. FUNDING. NIH grants R35CA294022, P01CA163227, and P50CA97186 (the Pacific Northwest Prostate Cancer SPORE) and the Institute for Prostate Cancer Research.

Authors

Arkadiusz Gertych, Huihui Ye, Xingyu Chen, Eric Vail, V. Krishnan Ramanujan, Lauren Brady, Lawrence D. True, Peter S. Nelson, Peter R. Carroll, Dan Theodorescu

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Figure 3

LOY increases progressively from normal to adjacent to malignant epithelium.

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LOY increases progressively from normal to adjacent to malignant epithel...
(A) Distribution of organ-level FISH-derived LOY (YchrFISH) scores obtained from analysis of 1,000 TMA cores from 405 individuals (Table 1). One circle represents 1 organ-level YchrFISH score. Tissues are stratified into 5 types: fetal tissue (FT), histologically normal tissue from cancer-free individuals [NM(noCA)], histologically normal tissue from cancer patients sampled from a non-malignant organ [NM(inCA)], histologically normal epithelium adjacent to carcinoma [NM(adCA)], and carcinoma (CA). Statistical analysis was carried out using the Wilcoxon rank-sum test. (B) YchrFISH scores in NM(noCA) and NM(inCA) derived from colon and rectum (n = 18 and n = 8 individuals, respectively) juxtaposed with YchrFISH scores from 10 other organs (n = 69 and n = 45 individuals, respectively). The organ-level YchrFISH scores in NM(noCA) tissue and NM(inCA) tissue originate from 53 and 10 individuals, respectively. A summary of the number of analyzed samples, stratified by organ, tissue type and match status can be found in Supplemental Table 1. Statistical analysis was carried out using the Wilcoxon rank-sum test. (C) Venn diagram showing the distribution of tissue types across individuals (n = 405). FT, NM(noCA), NM(inCA), NM(adCA), and CA samples spanned major organs and included tissues from multiple organs obtained from the same individual. Among 321 men with cancer, 49 contributed paired same-organ CA and NM(adCA) tissue samples. Three of the 321 cancer-bearing men had cancer in 2 major organs resulting in 324 organ-level CA YchrFISH scores presented in Figure 3A. Additional paired NM(adCA) and CA samples (i.e., without paired tissue from the same organ) originated from 18 and 267 men, respectively. Fetal tissues from multiple organs (FT; n = 9 donors) served as reference groups in the analysis.