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Circulating Tumor Cells in Individualizing Breast Cancer Therapy
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
James M. Reuben, Massimo Cristofanilli
Using an immunomagnetic detection approach, Austrup et al. reported the prognostic significance of genomic alterations (e.g., c-erbB-2 overexpression) present in CTCs purified from the blood of patients with breast cancer (27). The authors investigated genomic imbalances, such as mutation, amplification, and loss of heterozygosity, of 13 tumor suppressor genes and 2 proto-oncogenes using DNA isolated from minimal residual cancer cells. The presence and the number of genomic imbalances measured in disseminated tumor cells were significantly associated with a worse prognosis (27).
Future perspectives in peritoneal malignancy
Published in Tom Cecil, John Bunni, Akash Mehta, A Practical Guide to Peritoneal Malignancy, 2019
Ioanna Panagiotopoulou, Alexios Tzivanakis, Tom Cecil
Finally, we include SMAD4 in this snapshot review of molecular markers as its loss of function was seen in 16.5% of appendiceal tumours in the study by Borazanci et al. [28] and is also implicated in colorectal carcinogenesis [15]. SMAD4 is a component of the TGFβ signalling pathway that is located on chromosome 18q21. Most commonly, its function is lost by homozygous deletion [15]. In a study by Davison et al., loss of SMAD4 was associated with high-grade histological features in disseminated appendiceal mucinous neoplasms and worse overall survival [44]. The authors conclude that SMAD4 may be a useful adjunct in cases where discrimination between low-grade and high-grade is difficult [44]. Also, loss of heterozygosity at 18q21 has been shown to be a predictor of shortened survival in colorectal cancer patients [45]. In addition, loss of function of SMAD4 in patients with colorectal cancer induces resistance to 5-FU chemotherapy [46].
Cancer as a genetic disorder
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
It has long been recognised that chromosomal changes are seen in many cancers and that, while these are not completely specific in most cases, neither are they random. Molecular analysis has brought added precision to these findings, with the result that a number of tumour types can be associated with somatic changes in specific chromosomal regions. Loss of heterozygosity is the most important finding, as measured by comparing the DNA of the tumour with DNA of blood (i.e. leucocytes) from the same individual.
Personalizing tamoxifen therapy in adjuvant therapy: a brief summary of the ongoing discussion
Published in Expert Review of Clinical Pharmacology, 2023
Anabel Sanchez-Spitman, Henk-Jan Guchelaar
In 2014, the International Tamoxifen Pharmacogenomics Consortium carried out a meta-analysis as an attempt to give a definitive answer to this topic [16]. In this study, 4973 breast cancer patients who received adjuvant endocrine therapy with tamoxifen were studied by testing three predefined inclusion criteria. Of the three analysis, only in the most limited and restricted criterion a significantly poorer survival result in PM was observed (HR: 1.25, 95% CI: 1.06–1.47, p-value: 0.009). While for many researchers this meta-analysis was accepted as a conclusive proof of the association between improved clinical outcomes and the role of CYP2D6 polymorphisms in breast cancer patients treated with tamoxifen, many other authors have been highly critical with these conclusions. An important and relevant limitation was the exclusion of studies such as ATAC [17], TEAM [18] or BIG1-98 [19], mainly due to loss of heterozygosity as observed in these studies. In theory, patients might be categorized in the ‘incorrect’ predicted phenotype due to the loss of heterozygosity. However, a meta-analysis by Ahern et al. evaluated the clinical relevance of the loss of heterozygosity in tamoxifen-treated patients [20]. Authors concluded that, despite the strong arguments for the relevance of loss of heterozygosity, it might lack clinical relevance. In any case, since this putative association between tamoxifen efficacy, CYP2D6 genotyping, and clinical outcomes still remains unclear, many other approaches have been suggested as alternatives for potentially guiding tamoxifen efficacy.
MYCN amplification levels in primary retinoblastoma tumors analyzed by Multiple Ligation-dependent Probe Amplification
Published in Ophthalmic Genetics, 2021
Elizabeth A. Price, Roopal Patel, Irene Scheimberg, Esin Kotiloglu Karaa, Mandeep S. Sagoo, M. Ashwin Reddy, Zerrin Onadim
A broad spectrum of RB1 variants is distributed across the gene. The most common are single base substitutions (50–60%) giving rise to missense, nonsense, splice site changes, and small length pathogenic variants (30%) which mostly generate premature stop codons. These variants are usually associated with highly penetrant and expressive (bilateral, multifocal) Rb. Missense variants, in frame deletions/insertions, promoter and some splicing changes are associated with a low penetrance phenotype (2). About 60–70% of tumors display loss of heterozygosity (LOH) (3). Promoter hypermethylation is present in up to 15% of retinoblastomas (4). Whole genome sequencing (WGS) added chromothripsis to the list of RB1 pathogenic variants in around 3% of Rb tumors (5). Around 2% of sporadic, unilateral cases characterised by early onset of large, invasive tumors, display over-amplification of MYCN (MYCNA; 28–121 copies) in the absence of an RB1 pathogenic variant (6).
Investigational PARP inhibitors for the treatment of biliary tract cancer: spotlight on preclinical and clinical studies
Published in Expert Opinion on Investigational Drugs, 2021
Rutika Mehta, Anthony C Wood, James Yu, Richard Kim
Through extensive genome sequencing, multiple other genes have now been identified that play a role in DDR and specifically HRR. These have been identified in different tumor types and while this list is not absolute; some version of this list is being increasingly used to define DDR or HR deficiency (HRD) or BRCAness in cancers. These genes include ATM, ATR, BAP1, BRCA1, BRCA2, CDK12, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, PALB2, NBS1, WRN, RAD51C, RAD51D, MRE11A, CHEK1, BLM, RAD51B, and BRIP1 [21]. But with the vast number of genes involved in the DDR pathway, it can be difficult to predict which mutations are clinically significant and potentially targetable [31,32]. Additionally, epigenetic phenomena that influence gene expression are not routinely accounted for [33]. To get around these dilemma alternative detection methods have been developed to identify tumors that may possess a BRCA-like HRD phenotype. Loss of heterozygosity (LOH) is an allelic imbalance in which a previously heterozygous locus becomes homozygous as the result of the genetic loss of one allele. This type of chromosomal damage is commonly seen in HRD tumors as error-prone repair processes play a more prominent role in the DDR [34].