The landscape of cancer genes and mutational processes in breast cancer

Abstract

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis1, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

“…Activating PIK3CA point mutations are among the most common genetic aberrations in invasive breast cancer, [1][2][3][4][5][6][7][8][9][10] and several studies have shown that these mutations exist at nearly the same frequency in DCIS. [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.…”

“…Our data on PIK3CA mutations in DCIS (48% in this study and 45% combined) and invasive mammary carcinoma (35% in this study and 34% combined) matches the literature. [1][2][3][4][5][6][7][8] We identified point mutations in other genes in invasive carcinomas, but not in 'earlier' lesions, including TP53, FBXW7, FGFR2, and HRAS.…”

“…Activating mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are present in B25% of invasive carcinomas and are present in an even higher percentage (on the order of 40%) of low-grade estrogen receptorpositive carcinomas (luminal A intrinsic subtype). [1][2][3][4][5][6][7][8][9][10] PIK3CA mutations cluster in 'hotspots' in exon 9 (helical domain, E542K and E545K) and exon 20 (kinase domain, H1047R/L). [1][2][3][4][5][6][7][8][9][10] In addition, this pathway is activated by mutations in the plekstrinhomology domain of AKT1 in B5% of breast carcinomas, by the loss of the phosphatase PTEN (phosphatase and tensin homolog on chromosome 10), or rarely by amplification or alterations in other regulatory subunits, and is a target of active drug development.…”

“…[1][2][3][4][5][6][7][8][9][10] PIK3CA mutations cluster in 'hotspots' in exon 9 (helical domain, E542K and E545K) and exon 20 (kinase domain, H1047R/L). [1][2][3][4][5][6][7][8][9][10] In addition, this pathway is activated by mutations in the plekstrinhomology domain of AKT1 in B5% of breast carcinomas, by the loss of the phosphatase PTEN (phosphatase and tensin homolog on chromosome 10), or rarely by amplification or alterations in other regulatory subunits, and is a target of active drug development. [8][9][10][11] In recent large studies of estrogen receptor-positive tumors, the presence of activating PIK3CA hotspot point mutations has been paradoxically associated with more favorable outcome as compared with breast carcinomas with wild-type PIK3CA.…”

Myoepithelial Cell Differentiation Markers in Ductal Carcinoma in Situ Progression

“…Clinical evidence is compelling for histologic progression of breast cancer through atypical hyperplasia, ductal carcinoma in situ (DCIS), invasive ductal carcinoma, and metastatic stages. 1 Such histopathologic progression studies and mutational profiling of epithelial cancers 2,3 suggest that acquisition of invasive potential is a relatively late event. However, genomic data analyses have revealed that most tumor cell gene expression changes occur at the transition from normal to DCIS, with few additional changes in expression occurring at the transition from DCIS to overt invasive disease.…”