Молекулярная биология рака молочной железы

Введение

Рак считается генетическим заболеванием, и его можно лучше понять, изучив изменения ДНК, которые ведут к развитию рака. Однако более глубокое понимание канцерогенеза требует понимания того, как эти генетические альтерации изменяют клеточные программы, которые приводят к росту, инвазии и метастазированию. Эта глава представлена в виде логической прогрессии от ДНК к РНК и к протеину, и она описывает повреждения, которые способствуют канцерогенезу в молочной железе на каждом этапе. В этой главе также представлены концепции эпигенетики и анализ экспрессии генов, показывающие, как новые биологические открытия и новые технологии оказывают глубокое влияние на наше понимание патогенеза рака молочной железы и влияют на лечение пациентов.

Генетика рака молочной железы

Рак молочной железы является гетерогенным заболеванием, вызываемым прогрессирующей аккумуляцией генетических аберраций, включая точечные мутации, хромосомные амплификации, делеции, перестройки, транслокации и дупликации. Подавляющее большинство случаев рака молочной железы возникают спорадически и связаны с соматическими генетическими изменениями. Герменативные мутации составляют примерно 10% всех случаев рака молочной железы и связаны с несколькими наследственными синдромами рака молочной железы.

Наследственный рак молочной железы

Семейная история представляет один из наиболее важных факторов риска развития рака молочной железы. Хотя семейные формы составляют почти 20% всех случаев рака молочной железы, большинство генов, ответственных за семейный рак молочной железы, не идентифицированны. Гены восприимчивости к раку молочной железы можно разделить на три класса в зависимости от их частоты и уровня риска: редкие высоко-пенетрантные гены, редкие гены с промежуточной пенетрантностью и частые низко-пенетрантные гены и локусы (Таблица 78.1).

Редкие высокопенетрантные гены

BRCA1 и BRCA2. BRCA1 and BRCA2 mutations account for approximately half of all dominantly inherited hereditary breast cancers. These mutations confer a relative risk of breast cancer 10 to 30 times that of women in the general population, resulting in a nearly 85% lifetime risk of breast cancer development.5 BRCA1 and BRCA2 mutation carriers are quite rare among the general population; however, the prevalence is substantially higher in certain founder populations, most notably in the Ashkenazi Jewish population, where the carrier frequency is 1 in 40.

More than a thousand germline mutations have been identified in BRCA1 and BRCA2. Pathogenic mutations most often result in truncated protein products, although mutations that interfere with protein function also exist.4,5 Interestingly, the penetrance of pathogenic BRCA1 and BRCA2 mutations and age of cancer onset appear to vary both within and among family members. Specific BRCA mutations as well as gene–gene and gene–environment interactions as potential modifiers of BRCA-related cancer risk are areas of active investigation.6,7 Risk variation may be explained by different genetic modifiers in BRCA1 and BRCA2 mutation carriers. These alleles have been primarily identified from studies of the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).8 The commonly identified single nucleotide polymorphisms (SNPs) that modify BRCA1/2 are listed in Table 78.2 with their gene location, associated risks, and frequency. These modifying SNPs combine multiplicatively and, therefore, may significantly alter a mutation carrier’s risk depending on the number of risk alleles present.9

Features of BRCA1-related breast cancers distinguish them from both BRCA2-related and sporadic breast cancers.4 BRCA1-related tumors typically occur in younger women and have more aggressive features, including high histologic grade; high proliferative rate; aneuploidy; and absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This triple-negative phenotype of BRCA1- related breast cancers is further characterized by a basal-like gene expression profile of cytokeratins 5/6, 14, and 17; epidermal growth factor; and P-cadherin.10 Although BRCA1 and BRCA2 genes encode large proteins with multiple functions, they primarily act as classic tumor suppressor genes, maintaining genomic stability by facilitating double-strand DNA repair through homologous recombination.10,11 When loss of heterozygosity (LOH) occurs via loss, mutation, or silencing of the wild-type BRCA1 or BRCA2 allele, the resultant defective DNA repair leads to rapid acquisition of additional mutations, particularly during DNA replication, and ultimately sets the stage for cancer development.

The integral role of BRCA1 and BRCA2 in double-strand DNA repair holds potential as a therapeutic target for BRCA-related breast cancers. For example, platinum agents cause interstrand cross-links, thereby blocking DNA replication and leading to stalled replication forks.

Poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) inhibitors additionally show promise as specific therapy for BRCA-related tumors. PARP1 is a cellular enzyme that functions in single-strand DNA repair through base excision and represents a major cellular alternative DNA repair pathway. When PARP inhibition is applied to tumor cells deficient in double-strand DNA repair, as is the case in BRCA mutants, the cells are left without adequate DNA repair mechanisms and ultimately undergo cell cycle arrest, chromosome instability, and cell death.4 Given their phenotypic similarities to BRCA1-related breast cancers, sporadic basal-like breast tumors may display sensitivity to PARP inhibition as well.12 Phase II and III studies are currently under way to explore the use of PARP inhibitors in both BRCA-related and basal-like, non– BRCA-related breast tumors. PARP inhibitors in late clinical development include olaparib, niraparib, rucaparib, talazoparib, and veliparib. Olaparib is the first-in-class PARP inhibitor and was recently approved by the U.S. Food and Drug Administration (FDA) for treatment of germline BRCA-positive, HER2-negative metastatic breast cancer in patients who previously received chemotherapy in the neoadjuvant, adjuvant, or metastatic settings. This application is based on results from the phase III OlympiAD trial, demonstrating a 42% reduced risk of disease progression or death from olaparib and a 2.3-month improved progression-free survival (PFS) versus standard chemotherapy in previous treated patients with BRCA-positive, HER2-negative breast cancer.13 Of note, olaparib is additionally approved for the treatment of BRCA-positive advanced ovarian cancer after treatment with three or more lines of chemotherapy and as maintenance treatment for ovarian cancer patients following response to platinum-based chemotherapy, regardless of BRCA mutation status. Beyond olaparib, veliparib has demonstrated promise in BRCA-positive patients. Phase II data have shown that adding veliparib to carboplatin and paclitaxel chemotherapy induced a response rate of 77.8% in patients with advanced BRCA-positive breast cancer.14 Although the PFS was not statistically significantly improved, there was a numeric improvement in the veliparib-containing arm (PFS, 12.3 versus 14.1 months with and without veliparib, respectively), and a larger randomized phase III trial (BROCADE-3) is under way to determine if this combination provides superior outcomes. Other ongoing phase III trials with PARP inhibitors in BRCA mutated breast cancer include EMBRACA which is a study evaluating the PARP inhibitor, talazoparib, compared to physician’s choice of chemotherapy and BRAVO which is a phase III trial of Niraparib compared to physicians choice of therapy. Much remains to be understood about the optimal use of PARP inhibitors. Challenges include identifying robust predictive biomarkers that can guide patient selection (e.g., measures of platinum sensitivity and homologous recombination repair) and understanding variations among PARP inhibitors in clinical development to name but a few. Differences in potency and the mechanism of action have been well elucidated in preclinical studies,15 and the results of ongoing clinical trials need to be interpreted in this context. Of note, several studies have identified mechanisms of resistance to PARP inhibitors such as the development of reversion mutations in the BRCA1 or BRCA2 genes that can restore the open reading frame and hence DNA repair activity.

Таблица 78.1. Гены и локусы восприимчивости к раку молочной железы