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Rare Mendelian cancer syndromes and other cancers
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Prostate cancer has been a relatively neglected field of research in comparison with breast cancer, although recent studies have made considerable progress. Problems are created by the late age at onset, making recognition of a Mendelian pattern difficult, and by the high proportion of tumours that are not relentlessly aggressive. The most clinically significant genetic loci for prostate cancer are the BRCA1 and BRCA2 genes, but specific mutations of the HOXB13 gene have also recently been shown to confer a significantly increased risk. The prostate cancers associated with the BRCA2 and HOXB13 genes tend to have a poorer prognosis. Monitoring for prostate-specific antigen (PSA) levels may be helpful for men with a strong family history although there is no formal screening programme for prostate cancer.
Precision medicine in prostate cancer
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
While the evidence for these three genes is conflicting, the more recent discovery of the prostate cancer susceptibility gene HOXB13 seems to be more clear-cut. More than 200 genes from the chromosomal region 17q21–22 were sequenced from families with hereditary prostate cancer. Probands from four families were found to have a rare but recurrent mutation (G84E) in HOXB13, a homeobox transcription factor important in prostate development (Ewing et al., 2012). The mutation was found in all men with prostate cancer within these four families. In population studies, the heterozygous carrier state in sporadic prostate cancer is increased by a factor of 20. The G84E mutation in a prescreened white Canadian population was more frequent in men with a prostate biopsy positive for cancer, 0.7% versus those with a biopsy negative for cancer 0.1% (Akbari et al., 2012). This signifies that the mutation cosegregates with prostate cancer in hereditary prostate cancer families and is associated with prostate cancer risk in unrelated cases and controls. In the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial, all 3508 men had an initial negative prostate biopsy and were biopsied after 2 and 4 years of treatment or placebo. The G84E mutation was only detected in Caucasians, with the highest frequency in Northern Europe (1.06%), followed by Western Europe (0.60%) and North America (0.31%). No mutation carrier was observed in Southern or Eastern Europe, Latin America, Australia, and South Africa, which highlights the importance of differences in the genetic load of differing populations. In Caucasians the detected mutation frequency was 0.99% and 0.24% in men with a biopsy positive and negative for cancer, respectively. In those men with a biopsy positive for cancer, the detection frequency was higher in those with a family history of prostate cancer, 4.31% versus 0.34% in those without a family history.
Hereditary Prostate Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Veda N. Giri, Jennifer Beebe-Dimmer, Kathleen A. Cooney
The only prostate cancer susceptibility gene identified through linkage studies is HOXB13 on the long arm of chromosome 17 (i.e., 17q21.32). In 2003, a genome-wide linkage scan conducted on 175 prostate cancer pedigrees from the University of Michigan (UM) identified a novel linkage region on chromosome 17q near BRCA1 [17]. Through mutation screening, BRCA1 mutations were excluded as the cause of this linkage signal [18]. Our investigative team subsequently narrowed the candidate region to a 10 cM interval using a large number of pedigrees from UM and Johns Hopkins University (JHU) by focusing on the 147 families with ≥4 cases of prostate cancer AND early age of prostate cancer diagnosis (LOD = 5.49) [19]. Using emerging next-generation sequencing technologies, targeted sequencing of all 202 genes in the candidate region was performed and only the youngest family member from 94 UM and JHU multiplex prostate cancer families with evidence for linkage to the candidate region was tested [20]. A recurrent HOXB13 missense mutation (G84E) was identified that was predicted to be damaging by bioinformatic prediction algorithms in 4 families, and perfect segregation of the mutation in 14 additional men with prostate cancer in their respective families was observed. The G84E mutation was only identified in individuals of European descent, although other mutations have been identified in African American [20] and Chinese men with prostate cancer [21]; notably all observed mutations are in functional domains of the molecule. Importantly, the carrier frequency observed in men with a positive family history (2.2%) was identical to men with an early age of prostate cancer diagnosis (2.2%), and the highest carrier frequency was observed in the subset of men with BOTH a positive family history and EO disease (3.1%). In contrast, the carrier frequency in men diagnosed with prostate cancer above the age of 65 was only 0.65%. These results emphasize the enrichment of contributing genetic factors to EO familial prostate cancer and highlight the challenges of using unselected prostate cancer cases in gene discovery studies. Over a dozen studies have confirmed our HOXB13 findings, including a study by Karlsson et al., who found that almost 10% of men in Sweden with EO familial prostate cancer are carriers of the G84E mutation [22]. There is evidence that G84E mutation occurs on a common haplotype consistent with a founder effect [23]. Finally, extensive pathological studies revealed evidence of pseudohyperplastic-type features and a markedly low prevalence of ERG+ tumors in men carrying the HOXB13 mutation [24]. This suggests that cancers arising in HOXB13 G84E carriers may have unique molecular pathways implicated in the development of prostate cancer (Figure 33.1).
ZNF503 combined with GATA3 is a prognostic factor in triple-negative breast cancer
Published in Biomarkers, 2023
Siyu Liu, Xiaobin Cao, Jing Li, Jingjing Liu
Various traditional molecular prognostic markers and prognostic gene expression signatures for patients with breast cancer have been identified (Lal et al.2017). Gene signatures are sets of genes that together have predictive power to predict the clinical outcomes. The 21-gene OncotypeDx assay was defined to detect early-stage ER + breast cancer (Paik et al.2004). A two-gene expression ratio of HOXB13 and IL17BR, HOXB13:IL17BR ratio, was associated with a high risk of recurrence in patients with primary breast cancer (Jansen et al.2007, Ma et al.2004). The continuous identification of relevant prognostic biomarkers and signatures has improved the prediction of prognosis and guided the use of anti-cancer therapy in breast cancer. In this study, since GATA3 and ZNF503 alone were not effective prognostic biomarkers, we combined the two genes to predict the breast cancer prognosis.
Cell-Biomaterial constructs for wound healing and skin regeneration
Published in Drug Metabolism Reviews, 2022
Ingrid Safina, Luke T. Childress, Srinivas R. Myneni, Kieng Bao Vang, Alexandru S. Biris
Several other studies on gene expression showed eight specific subtypes of homeobox (HOX) genes―transcription factors that direct pattern formation during developmental events―expressed during fetal skin development: HOX-A4, HOX-A5, HOX-A7, HOX-B13, MSX-1 (Msh homeobox 1), MSX-2, MOX-1 (mesenchyme homeobox 1), and PRX-2 (peroxidase gene 2) (Stelnicki et al. 1997; Stelnicki, Arbeit, et al. 1998). HOX-B13 and PRX-2, two genes that correlate with fetal healing, exhibited a change in level of expression after healing (Bullard et al. 2003). However, those same genes are not expressed in adult skin nor in adult wound healing (Bullard et al. 2003). Furthermore, HOXB13 and PRX-2 are indirectly connected to the scarring pathway, as their activation or deactivation could turn ‘on’ or ‘off’ the expression of TGF-β through the promoter regions of TGF-β, which are downstream targets of these two homeobox genes (Stelnicki, Kömüves, et al. 1998; Bullard et al. 2003). Moreover, the same homeobox gene of the PRX family was found to be expressed in regenerative species such as the Xenopus froglet as the PRX-1 gene but not in non-regenerative species such as adult mice (Yokoyama et al. 2011).
Available and emerging molecular markers in the clinical management of breast cancer
Published in Expert Review of Molecular Diagnostics, 2019
Karthik V. Giridhar, Minetta C. Liu
BCI analyzes expression of 7 target and 4 control genes to derive both a molecular grade index and a ratio of HOXB13:IL17BR (H/I) [42]. The latter component focuses on genes identified as both predictive and prognostic for endocrine therapy [43,44]. Multiple retrospective evaluations showcase the ability of the BCI to discriminate between those at low or high risk for distant recurrence [42,45,46]. BCI is the only multigene tissue biomarker to evaluate the benefit of extending adjuvant hormonal therapy beyond 5 years. In the MA.17 trial, which compared 5 years of letrozole versus placebo after approximately 5 years of tamoxifen, an improvement in relapse-free survival was seen with extended endocrine therapy in patients with a high H/I index, compared to no improvement observed in patients with a low H/I index [47].