We analyzed the effect of anti-EGFR monoclonal antibodies (mAbs; cetuximab and panitumumab) in combination with chemotherapeutic agents (docetaxel, cisplatin, and epirubicin) on EGFR-expressing TNBC cell lines that have different mutation statuses for one oncogene (KRAS) and two tumor suppressor genes (PTEN and BRCA1).
Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.
Sequencing of BRCA1 amplified from genomic DNA of lymphocytes and microdissected ovarian tumor cells of a familial ovarian cancer patient revealed three, rare heterozygous DNA variations (2418delA, 233G-->A, and IVS1-10T-->C) in both tumor and constitutional (lymphocyte) DNA.
Intensive surveillance may not detect breast carcinoma at an early, curable stage in young women with BRCA1 or BRCA2 gene mutations because the growth rate of the tumors in these women most likely will be rapid and the density of the breast tissue may compromise detection.
The INK4a-ARF locus encodes two tumor suppressor proteins involved in cell-cycle regulation, p16INK4a and p14ARF, whose functions are inactivated in many human cancers.
<i>Atm</i>-mutant rats (<i>Atm<sup>L2262P/L2262P</sup></i> ) expressed low levels of ATM protein, suggesting a destabilizing effect of the mutation, and had a significantly reduced lifespan compared with <i>Atm<sup>+/+</sup></i> Whereas these rats did not show cerebellar atrophy, they succumbed to hind-limb paralysis (45%), and the remainder developed tumors.
This locus has been associated with frequent loss of heterozygosity (LOH) and allelic imbalance in breast cancers; however, BRCA1 mutations are rare events in sporadic breast cancer with LOH in the region, suggesting that another tumor suppressor gene resides in this area.
Consistent with earlier studies, TP53 mutations were present in the majority (96.6%) of the tumors studied, and mutations in BRCA1/2 that affect DNA repair were also detected frequently in 20.5% of the tumors.
In this review, we discuss how the discovery of BRCA1 and BRCA2 has not only provided an understanding of the molecular processes that drive tumourigenesis but also reignited an interest in therapeutically exploiting loss-of-function alterations in tumour suppressor genes.
Overexpression of epidermal growth factor receptor (EGF-R), K-ras gene mutations and c-myc gene amplification were studied in tumor and normal lung tissues from 100 patients with non-small cell lung cancer.
Tumors with ATM mutations only partially correlated with tumors with loss of an ATM allele through an 11q deletion and, interestingly, those 11q-deleted tumors with a second wild-type ATM allele had a preserved DNA damage response.
SETD2-mutated LUADs exhibited relatively poor recurrence- free survival (RFS) and mutations in STK11 and ATM were associated with poor RFS among KRAS-mutant tumors.
The recent approval of olaparib (Lynparza), the poly (ADP-ribose) polymerase (PARP) inhibitor for treating tumors harboring BRCA1 or BRCA2 mutations, represents the first medicine based on this principle, exploiting an underlying cause of tumor formation that also represents an Achilles' heel.
Furthermore, p53 mutation and EGFR overexpression occur similarly in BRCA1-mutated and basal-like cancers; these shared alterations provide very important information for understanding not only the genetic and epigenetic carcinogenic pathways in these tumors but also therapeutic strategies.
HDs were also noted for known tumor suppressor genes (TSG), including CDKN2A, CDKN2B, SMAD4, and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs.