Genome evolution during progression to breast cancer

Abstract

Cancer evolution involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype. Early neoplasias, which are often found concurrently with carcinomas and are histologically distinguishable from normal breast tissue, are less advanced in phenotype than carcinomas and are thought to represent precursor stages. To elucidate their role in cancer evolution we performed comparative wholegenome sequencing of early neoplasias, matched normal tissue, and carcinomas from six patients, for a total of 31 samples. By using somatic mutations as lineage markers we built trees that relate the tissue samples within each patient. On the basis of these lineage trees we inferred the order, timing, and rates of genomic events. In four out of six cases, an early neoplasia and the carcinoma share a mutated common ancestor with recurring aneuploidies, and in all six cases evolution accelerated in the carcinoma lineage. Transition spectra of somatic mutations are stable and consistent across cases, suggesting that accumulation of somatic mutations is a result of increased ancestral cell division rather than specific mutational mechanisms. In contrast to highly advanced tumors that are the focus of much of the current cancer genome sequencing, neither the early neoplasia genomes nor the carcinomas are enriched with potentially functional somatic point mutations. Aneuploidies that occur in common ancestors of neoplastic and tumor cells are the earliest events that affect a large number of genes and may predispose breast tissue to eventual development of invasive carcinoma.[Supplemental material is available for this article.]

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

“…[14][15][16][17] Accumulating evidence suggests that PIK3CA point mutations may also be common in other proliferative breast lesions such as benign papillomas and columnar cell lesions. [18][19][20][21][22][23] Prior studies have failed to identify PIK3CA mutations in histologically normal breast tissue, even with the same sensitive methods employed here. 1,8,16,19 In this study, we demonstrated a 50% frequency of PIK3CA point mutations in usual ductal hyperplasia and columnar cell lesions across 62 lesions, representing the largest series to date.…”

“…(43) Li et al 16 studied PIK3CA mutations in usual ductal hyperplasia and found no mutations in 16 lesions, in contrast to our results; the differences may be due to sample size and methodologic sensitivity, as they used less-sensitive direct Sanger sequencing. 16 The activating PIK3CA hotspot mutations seen frequently in breast cancers and proliferative lesions, most notably H1047R, E542K and, E545K, have transforming potential when overexpressed in a variety of cell culture models, [8][9][10] which arise before the most common ancestor in the genomic history of several breast carcinomas 23,44 and have thus been logically viewed as drivers of carcinogenesis. Interestingly, expression of the PIK3CA H1047R mutation at physiologic or inducible supraphysiologic levels in the mouse mammary gland leads to increased branching, duct dilation, and luminal epithelial hyperplasia.…”

“…[14][15][16][17] However, several small studies suggest that pre-neoplastic or benign breast lesions, such as papillomas, radial scars, or columnar cell lesions, may also very frequently harbor PIK3CA mutations. [18][19][20][21][22][23] The goal of this study was to systematically screen a large number of hyperplastic and putative precursor breast lesions, along with accompanying carcinomas for known activating mutations in PIK3CA and other key signaling molecules.…”

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

“…S14). Evolutionary phylogenies were constructed using the somatic mutation hierarchy algorithm (20,47) in 22 patients for whom multiple tumors were interrogated by exome sequencing, using all detected somatic mutations. Enrichment of mutations within EIPs was tested using a Fisher exact test with a Bonferroni correction for multiple hypothesis testing.…”

Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis

“…With fractions of mutated alleles evolving over time, the study of the exact mutated allele fractions, of their subclonal distribution and possible role in clonal evolution gains more importance (7)(8)(9).…”