Breast cancer (referring to mammary carcinoma, not mammary sarcoma) is histopathologically and almost certainly etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement.
Cady (1970) described a family in which 3 sisters had bilateral breast cancer. Together with reports in the literature, this suggested to him the existence of families with a particular tendency to early-onset, bilateral breast cancer. The genetic ... Cady (1970) described a family in which 3 sisters had bilateral breast cancer. Together with reports in the literature, this suggested to him the existence of families with a particular tendency to early-onset, bilateral breast cancer. The genetic basis might, of course, be multifactorial. Anderson (1974) concluded that the sisters of women with breast cancer whose mothers also had breast cancer have a risk 47 to 51 times that in control women; a revised estimate was 39 times (Anderson, 1976). The disease in these women usually developed before menopause, was often bilateral, and seemed to be associated with ovarian function. About 30% of daughters with early-onset, bilateral breast cancer inherited the susceptibility. The risk of breast cancer to women with affected relatives is higher when the diagnosis is made at an early age and when the disease is bilateral. Ottman et al. (1983) provided tables that give the cumulative risk of breast cancer to mothers and sisters at various ages. The highest risk group is sisters of premenstrual probands with bilateral disease. Among the sisters of women with breast cancer, Anderson and Badzioch (1985) found the highest lifetime risks when the proband had bilateral disease, an affected mother (25 +/- 7.2%), or an affected sister (28 +/- 11%). The risks were reduced to 18 +/- 3.3% and 14 +/- 2.6%, respectively, with unilateral disease. An early example of familial breast cancer was provided by Broca (1866). According to the pedigree drawn by Lynch (1976), 10 women in 4 generations of the family of Broca's wife died of breast cancer. Eisinger et al. (1998) called attention to an even earlier report of hereditary breast cancer by Le Dran (1757), who related the experience of a colleague in Avignon who had diagnosed a 19-year-old nun with cancer of the right breast. The patient refused a mastectomy not only because of the pain of surgery, but also because of a belief that the operation would be futile. Her grandmother and a grandmaternal uncle died with breast cancer, and she was convinced that this malady was hereditary and that 'her blood was corrupted by a cancerous ferment natural to her family.' Two families with an extraordinary incidence of male breast cancer and father-to-son transmission of same was reported by Everson et al. (1976). They found a suggestion of elevated urinary estrogen in 3 of the affected males. Teasdale et al. (1976) described breast cancer in 2 brothers and in a daughter of 1 brother. Kozak et al. (1986) reported breast cancer in 2 related males, an uncle and nephew. In this family and in several reported families with male breast cancer, Kozak et al. (1986) found women in the same family with breast cancer. Soft tissue sarcomas are associated with breast cancer in Li-Fraumeni syndrome. Mulvihill (1982) used the term cancer family syndrome of Lynch (120435) for the association of colon and endometrial carcinoma and other neoplasms including breast cancer. Seltzer et al. (1990) concluded that dermatoglyphics can help in the identification of women either with or at risk for breast cancer. They found that the presence of 6 or more whorls is associated in a statistically significant manner with breast cancer. Marger et al. (1975) presented the cases of 2 brothers with breast cancer and reviewed the courses of 28 other previously unreported male patients. In one of the brothers, breast cancer was preceded by prostate cancer and estrogen administration, raising the possibility that the breast cancer was a metastatic deposit. The possibility of prostatic metastases was raised in 2 other patients. Demeter et al. (1990) reported breast cancer in a 64-year-old man who had had bilateral gynecomastia since childhood. His maternal grandfather had been found to have adenocarcinoma of the breast at the age of 65. His maternal grandmother had radical mastectomy for breast cancer at the age of 66 and 2 years later underwent radiation therapy for rib metastases. The proband's sister developed breast cancer at the age of 31 years and despite aggressive therapy died 1 year later with extensive metastases. Hauser et al. (1992) reported a family in which 2 females and 2 males in 2 generations had breast cancer. Two females in the family had prophylactic bilateral mastectomy at a young age. One male developed a left breast mass and axillary node at age 59 and died of metastatic disease at age 62. His paternal uncle presented at age 57 years with bleeding from his right breast. Biopsy suggested Paget disease of the breast and he underwent mastectomy. He subsequently died at age 75 years of prostatic carcinoma. He had a daughter who developed breast cancer at age 27 years and died at age 30 with disseminated disease, and a son who developed infiltrating grade 4 adenocarcinoma of the breast at age 54.
A previously reported loss of alleles at the HRAS locus, located at 11p14, in about 20% of breast cancer tumors was confirmed by Mackay et al. (1988). Comparing tumor and blood leukocyte DNA ... - Somatic Changes A previously reported loss of alleles at the HRAS locus, located at 11p14, in about 20% of breast cancer tumors was confirmed by Mackay et al. (1988). Comparing tumor and blood leukocyte DNA from a consecutive series of patients with primary breast cancer, Mackay et al. (1988) found that 61% of the tumors had allele loss demonstrated with a probe located at 17p13.3. Coles et al. (1990) mapped regions of LOH on chromosome 17 by comparing DNA of paired tumor and blood leukocyte samples. They confirmed a high frequency of LOH on 17p, where 2 distinct regions of LOH were identified in bands p13.3 and p13.1. The latter probably involves the structural gene TP53 (191170). The frequency of LOH was higher, however, at 17p13.3, and there was no correlation between allele loss at the 2 sites. Since LOH at 17p13.3 was associated with overexpression of p53 mRNA, Coles et al. (1990) suggested the existence of a gene some 20 megabases telomeric of TP53 that regulates its expression; see 113721. They concluded that lesions of this regulatory gene are involved in the majority of breast cancers. Devilee et al. (1991) reported LOH data. Davidoff et al. (1991) found that in 11 (22%) of 49 primary invasive human breast cancers, widespread overexpression of p53 was indicated by immunohistochemical staining. The p53 gene was directly sequenced in 7 of the tumors with elevated levels of protein, and in each case a mutation that altered the coding sequence for p53 was found in a highly conserved region of the gene. Whereas 4 of these tumors contained only a mutant p53 allele, the other 3 exhibited coding sequences from both a mutant and a wildtype allele. Six tumors that were deleted at or near the p53 locus but did not express high levels of the protein were sequenced and all retained a wildtype p53 allele. This was interpreted as indicating that overexpression of the p53 protein, not allelic loss, was associated with mutation of the p53 gene. The ARHGEF5 (600888) oncogene belongs to the DBL family of guanine nucleotide exchange factors (GEFs) for RHO GTPases. Debily et al. (2004) identified 5 novel ARHGEF5 alternative transcripts specifically expressed in breast tumors, which were predicted to generate modified or truncated proteins. Histologic features suggested that ARHGEF5 may activate RAC1 (602048), CDC42 (116952), or ARHG (179505) rather than ARHA (165390). The authors hypothesized that activation of the ARHGEF5 oncogene, possibly by variant isoforms, may play a role in proliferative breast disease. By examining DNA copy number in 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2; 606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types. Sjoblom et al. (2006) determined the sequence of well-annotated human protein-coding genes in 2 common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of about 90 mutant genes, but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, Sjoblom et al. (2006) identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these were not known to be genetically altered in tumors and were predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. Sjoblom et al. (2006) concluded that their data defined the genetic landscape of 2 human cancer types, provided new targets for diagnostic and therapeutic intervention, and opened fertile avenues for basic research in tumor biology. Forrest and Cavet (2007), Getz et al. (2007), and Rubin and Green (2007) commented on the article by Sjoblom et al. (2006), citing statistical problems that, if addressed, would result in the identification of far fewer genes with significantly elevated mutation rates. Parmigiani et al. (2007) responded that the conclusions of the above authors were inaccurate because they were based on analyses that did not fully take into account the experimental design and other critical features of the Sjoblom et al. (2006) study. By array CGH, Yang et al. (2006) analyzed the copy number and expression level of genes in the 8p12-p11 amplicon in 22 human breast cancer specimens and 7 breast cancer cell lines. Of the 21 potential genes identified, PCR analysis and functional analysis indicated that 3 genes, LSM1 (607281), BAG4 (603884), and C8ORF4 (607702), are breast cancer oncogenes that could work in combination to influence a transformed phenotype in human mammary epithelial cells. To catalog the genetic changes that occur during tumorigenesis, Wood et al. (2007) isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, Wood et al. (2007) concluded that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene 'mountains' and a much larger number of gene 'hills' that are mutated at low frequency. Wood et al. (2007) described statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. The gene mountains were comprised of well-known cancer genes such as APC (611731), KRAS (190070), and TP53 (191170). Furthermore, Wood et al. (2007) observed that most tumors accumulated approximately 80 mutations, and that the majority of these were harmless. Fewer than 15 mutations are likely to be responsible for driving the initiation progression or maintenance of the tumor. Srivastava et al. (2008) found an alteration of the H2AFX (601772) gene copy number in 25 (37%) of 65 breast cancer tissues derived from patients with sporadic forms of the disorder. Gene deletion accounted for 19 (29%) of total cases and gene amplification for 6 (9%). Patients with estrogen and progesterone receptor (PGR; 607311)-positive tumors had more significantly altered copy numbers of H2AFX compared to those with ER/PR-negative tumors. None of the tissues contained H2AFX sequence alterations. Sotiriou and Pusztai (2009) reviewed gene expression signatures in breast cancer. Stephens et al. (2009) used a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by nonhomologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. Stephens et al. (2009) concluded that their study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development. Kan et al. (2010) reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Kan et al. (2010) found that mutation rates and the sets of mutated genes varied substantially across tumor types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G protein-coupled receptors such as GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS (see 139320), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335) in oncogenesis. Curtis et al. (2012) presented an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumors, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single-nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in approximately 40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, Curtis et al. (2012) identified putative cancer genes, including deletions in PPP2R2A (604941), MTAP (156540), and MAP2K4 (601335). Unsupervised analysis of paired DNA-RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, estrogen-receptor-positive 11q13/14 cis-acting subgroup and a favorable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 'CNA-devoid' subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Curtis et al. (2012) concluded that their results provided a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome. To correlate the variable clinical features of estrogen-receptor-positive breast cancer with somatic alterations, Ellis et al. (2012) studied pretreatment tumor biopsies accrued from patients in 2 studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including 5 genes (RUNX1, 151385; CBFB, 121360; MYH9, 160775; MLL3, 606833; and SF3B1, 605590) previously linked to hematopoietic disorders. Mutant MAP3K1 (600982) was associated with luminal A status, low-grade histology, and low proliferation rates, whereas mutant TP53 (191170) was associated with the opposite pattern. Moreover, mutant GATA3 (131320) correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in estrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumor biology, but most recurrent mutations are relatively infrequent. Ellis et al. (2012) suggested that prospective clinical trials based on these findings will require comprehensive genome sequencing. Primary triple-negative breast cancers (TNBCs), a tumor type defined by lack of estrogen receptor (133430), progesterone receptor (607311), and ERBB2 (611223) gene amplification, represent approximately 16% of all breast cancers. Shah et al. (2012) showed in 104 TNBC cases that at the time of diagnosis these cancers exhibited a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing revealed that only approximately 36% of mutations are expressed. Using deep resequencing measurements of allelic abundance for 2,414 somatic mutations, Shah et al. (2012) determined in an epithelial tumor subtype the relative abundance of clonal frequencies among cases representative of the population. They showed that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than nonbasal TNBC. Although p53, PIK3CA (171834), and PTEN (601728) somatic mutations seem to be clonally dominant compared to other genes, in some tumors their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape, and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumor progression. Shah et al. (2012) concluded that their results showed that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumor clonal genotypes. Banerji et al. (2012) reported the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1 (164730), GATA3, and MAP3K1, Banerji et al. (2012) discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, they identified a recurrent MAGI3-AKT3 (611223) fusion enriched in TNBC, lacking estrogen and progesterone receptors, and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor. The Cancer Genome Atlas Network (2012) analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing, and reverse-phase protein arrays. They demonstrated the existence of 4 main breast cancer classes (luminal A, luminal B, HER2 (164870)-enriched, and basal-like) when combining data from 5 platforms, each of which showed significant molecular heterogeneity. Somatic mutations in only 3 genes (TP53, PIK3CA, and GATA3) occurred at greater than 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA, and MAP3K1 with the luminal A subtype. The Cancer Genome Atlas Network (2012) identified 2 novel protein expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR (131550)/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumors with high-grade serous ovarian tumors showed many molecular commonalities, indicating a related etiology and similar therapeutic opportunities. The biologic finding of the 4 main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raised the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer. Employing a new methodology that combines cistromics, epigenomics, and genotype imputation, Cowper-Sal-lari et al. (2012) annotated the noncoding regions of the genome in breast cancer cells and systematically identified the functional nature of SNPs associated with breast cancer risk. Their results showed that breast cancer risk-associated SNPs are enriched in the cistromes of FOXA1 (602294) and ESR1 (133430) and the epigenome of histone H3 lysine-4 monomethylation (H3K4me1) in a cancer- and cell type-specific manner. Furthermore, the majority of the risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, thereby resulting in allele-specific gene expression, which is exemplified by the effect of the dbSNP rs4784227 SNP in the TOX3 gene (611416) within the 16q12.1 risk locus. - Mutation in the BARD1 Gene on Chromosome 2q34-q35 In 7 of 126 (5.6%) index cases from Finnish families with breast and/or ovarian cancer, Karppinen et al. (2004) identified a cys557-to-ser substitution in the BARD1 gene (C557S; 601593.0001) at elevated frequency compared to healthy controls (5.6% vs 1.4%, p = 0.005). The highest prevalence of C557S was found among a subgroup of 94 patients with breast cancer whose family history did not include ovarian cancer (7.4% vs 1.4%, p = 0.001). Karppinen et al. (2004) concluded that C557S may be a commonly occurring and mainly breast cancer-predisposing allele. - Mutation in the CYP17A1 Gene on Chromosome 10q24.3 In 3 sisters with early-onset breast cancer (diagnosed at ages 34, 38, and 42 years, respectively) who did not have mutations in BRCA1 or BRCA2, Hopper et al. (2005) identified a germline R239X mutation in the CYP17A1 gene (609300.0006). A sister who was cancer-free at age 58 did not have the R239X mutation; the mutation was not found in 788 controls. Hopper et al. (2005) suggested that there may be rare mutations in steroid hormone metabolism genes associated with a high dominantly inherited breast cancer risk. Although Haiman et al. (2003) presented initial evidence that haplotypes in the CYP19A1 (107910) gene, which encodes the enzyme aromatase, were associated with increased risk for breast cancer, Haiman et al. (2007) did not find an association between haplotypes or SNPs in the CYP19A1 gene among 5,356 patients with invasive breast cancer and 7,129 controls composed primarily of white women of European descent. Haiman et al. (2007) found that common haplotypes spanning the coding and proximal 5-prime region of the CYP19A1 gene were significantly associated with a 10 to 20% increase in endogenous estrogen levels in postmenopausal women, but not with breast cancer. - Mutation in the PALB2 Gene on Chromosome 16p12 Mutations in the PALB2 gene (610355), which encodes a BRCA2-interacting protein, cause Fanconi anemia of complementation group N (FANCN; 610832). To investigate whether monoallelic PALB2 mutations confer susceptibility to breast cancer, Rahman et al. (2007) sequenced the PALB2 gene in individuals with breast cancer from familial breast cancer pedigrees in which mutations in BRCA1 or BRCA2 had not been found, and in 1,084 controls. They identified monoallelic truncating PALB2 mutations in 10 of 923 individuals with familial breast cancer and in none of the controls (P = 0.0004), and showed that such mutations confer a 2.3-fold higher risk of breast cancer. The results established PALB2 as a breast cancer susceptibility gene and further demonstrated the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition. By screening the PALB2 gene, Tischkowitz et al. (2012) identified 5 pathogenic truncating mutations in 0.9% of 559 patients with contralateral breast cancer compared to no PALB2 mutations among 565 women with unilateral breast cancer, who were used as controls (p = 0.04). Among the mutation carriers, the median ages of the first and second breast cancers were 46 and 55 years, respectively, and all probands had at least 1 first-degree relative with breast cancer, yielding a relative risk of 5.3 for carriers of a pathogenic PALB2 mutation. The frequency of rare missense mutations was similar in both groups, suggesting that rare PALB2 missense mutations do not strongly influence breast cancer risk. - Association with the NQO2 Gene on Chromosome 6p25 In a hospital-based study of 893 Chinese breast cancer patients and 711 Chinese cancer-free controls, Yu et al. (2009) genotyped 11 polymorphisms of the NQO2 (160998) gene, which encodes NRH:quinone oxidoreductase-2 and has enzymatic activity on estrogen-derived quinones and is able to stabilize p53 (TP53; 191170). The authors identified significant association between the incidence of breast cancer and a 29-bp insertion/deletion polymorphism (29-bp I/D; p = 0.0027; OR, 0.76) and the dbSNP rs2071002 SNP (+237A-C; p = 0.0031; OR, 0.80), both of which are within the NQO2 promoter region. The findings were replicated in a second Chinese population of 403 familial/early-onset breast cancer patients and 1,039 controls. Decreased risk was associated with the D allele of 29 bp-I/D and the +237C allele of dbSNP rs2071002. The susceptibility variants within NQO2 were notably associated with breast carcinomas with wildtype p53. The 29-bp insertion allele introduced a transcriptional repressor Sp3 binding sites, and the authors demonstrated that the 237A allele of dbSNP rs2071002 abolished a transcriptional activator Sp1 binding site. Real-time PCR assay showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of NQO2 mRNA than those in normal breast tissues harboring risk genotypes. Yu et al. (2009) suggested that NQO2 is a susceptibility gene for breast carcinogenesis.