细胞期刊(Cell)2013-10-28 8:41 PM

Hypermutation of the Inactive X Chromosome Is a Frequent Event in Cancer

Highlights
- X chromosome has up to 4× more mutations than the autosomes in female cancer genomes
- Hypermutations only affect the inactive X chromosome
- X hypermutation involves somatic point mutations and indels, but not germline mutations
- No X hypermutation is found in clonal expansions of normal or premalignant cells
Summary Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising a diverse set of childhood and adult tumors, including both solid and hematopoietic malignancies. Surprisingly, we found that the inactive X chromosome of many female cancer genomes accumulates on average twice and up to four times as many somatic mutations per megabase, as compared to the individual autosomes. Whole-genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals and a premalignant myelodysplastic syndrome (MDS) sample revealed no X chromosome hypermutation. Our data suggest that hypermutation of the inactive X chromosome is an early and frequent feature of tumorigenesis resulting from DNA replication stress in aberrantly proliferating cells.

KEYWORDS

SHARE & LIKE

COMMENTS

ABOUT THE AUTHOR

细胞期刊(Cell)

0 Following 3 Fans 0 Projects 125 Articles

SIMILAR ARTICLES

Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To

Read More

Summary Replenishing insulin-producing pancreatic β cell mass will benefit both type I and type II diabetics. In adults, pancreatic β cells are gene

Read More

Summary Replenishing insulin-producing pancreatic β cell mass will benefit both type I and type II diabetics. In adults, pancreatic β cells are gene

Read More

Summary 5-methylcytosine is a major epigenetic modification that is sometimes called “the fifth nucleotide.” However, our knowledge of how offspring

Read More

Summary 5-methylcytosine is a major epigenetic modification that is sometimes called “the fifth nucleotide.” However, our knowledge of how offspring

Read More

Summary All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathog

Read More

Summary All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathog

Read More

Summary Alterations of symbiosis between microbiota and intestinal epithelial cells (IEC) are associated with intestinal and systemic pathologies. I

Read More

Summary Alterations of symbiosis between microbiota and intestinal epithelial cells (IEC) are associated with intestinal and systemic pathologies. I

Read More

Summary The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify

Read More