title: Clinical and molecular relevance of mutant-allele tumor heterogeneity in breast cancer.
abstract: Intra-tumor heterogeneity (ITH) plays a pivotal role in driving breast cancer progression and therapeutic resistance. We used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters and multi-omics data.
  
  
  
  We assessed 916 female breast cancer patients from The Cancer Genome Atlas. We calculated the MATH values from whole-exome sequencing data and further investigated their correlation with clinical characteristics, somatic mutations, somatic copy number alterations (SCNAs), and gene enrichment.
  
  
  
  The patients were divided into low, intermediate, and high MATH groups. High T stage, African American race, and triple-negative or basal-like subtype were associated with a higher MATH level (all P < 0.001). In hormone receptor-positive and human epidermal growth factor receptor-negative patients, the high MATH group showed a tendency toward a worse overall survival (P = 0.052); Furthermore, the TP53 mutation rate increased as MATH was elevated (P < 0.001), whereas CDH1 mutations were correlated with a lower level of MATH (P = 0.002). Several focal and arm-level SCNA events were more common in the high MATH group (P < 0.05), including Chr8q24 with only the MYC gene in the "peak" region. Similarly, high MATH was associated with gene set enrichment related to the MYC pathway and proliferation.
  
  
  
  Our integrative analysis reveals the clinical and genetic relevance of ITH in breast cancer. These results also suggest the origin and natural history of clonal evolution and intra-tumor genetic heterogeneity, which warrant further investigation.
authors.affiliation: Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, 399 Ling-Ling Road, Shanghai, 200032, People's Republic of China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, People's Republic of China.
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, 399 Ling-Ling Road, Shanghai, 200032, People's Republic of China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, People's Republic of China.
authors.forename: Yi-Zhou
authors.initials: YZ
authors.lastname: Jiang
authors.affiliation: Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, 399 Ling-Ling Road, Shanghai, 200032, People's Republic of China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, People's Republic of China.
authors.forename: Xi-Yu
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, 399 Ling-Ling Road, Shanghai, 200032, People's Republic of China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, People's Republic of China.
authors.forename: Yi-Rong
authors.initials: YR
authors.lastname: Liu
authors.affiliation: Department of Breast Surgery, Cancer Institute, Fudan University Shanghai Cancer Center, 399 Ling-Ling Road, Shanghai, 200032, People's Republic of China. zhimingshao@yahoo.com.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, People's Republic of China. zhimingshao@yahoo.com.|Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China. zhimingshao@yahoo.com.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Shao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D005260:Female; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D000073359:Exome Sequencing; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor
keywords: Breast cancer; Intra-tumor genetic heterogeneity; MYC; Mutant-allele tumor heterogeneity; The Cancer Genome Atlas