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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.
Molecular Mediator of Prostate Cancer Progression and Its Implication in Therapy
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam, Kaustubh Datta
Family history of prostate cancer is a known risk factor. Familial prostate cancer is often defined as having one first degree relative with prostate cancer. Sometimes, the term hereditary prostate cancer is also used especially when a family with either three affected generations, three affected first-degree relatives or two affected relatives before 55 years of age develops prostate cancer. The factors responsible for familial or heritable prostate cancer can be either single nucleotide polymorphisms identified through genome-wide association studies which are usually associated with modest increased risk of prostate cancer or some rare mutants that can substantially increase the risk [98, 184–186]. The genome wide association studies indicated chromosomal loci such as 8q24, 17p with familial risk of prostate cancer [98, 184–186]. On the other hand, rare pathogenic germline mutations such as mutations in DNA repair genes such as BRCA2 and BRCA1 not only increase the risk of developing prostate cancer and earlier onset, but also lead to aggressive cancers with higher rate of recurrence following primary therapy. These mutations therefore are responsible for cancer-associated mortality [98, 185, 187]. Recent whole exome sequencing of autosomal dominant cancer risk genes isolated from tumor tissues of mCRPC indicated 11.8% of men were detected to have germline mutations in one of the 16 DNA repair genes in addition to BRAC2 and BRCA1 (ATM , CHEK2, PALB2, RAD51C, RAD51D); as a result, multigene cancer screening panels have been increasingly suggested [178, 188, 189]. These screenings would help identify men with advanced prostate cancer harboring deficiency in somatic homologous recombination DNA repair, as these patients would be benefitted from PARP inhibitor and platinum chemotherapy [179, 190, 191]. However, elaborate studies in this area should be performed to link the genetic testing with the identification of familial prostate cancer predisposition and design specific treatment strategies to treat this high-risk prostate cancer patient. High-risk prostate cancer predisposition genes other than DNA repair genes also exist. One such gene is HOXB13, which carries a rare missense mutation (G84E). This mutation is specifically found in young prostate cancer patient with a family history [192–194]. RNaseL, MSR1 and ELAC2/HPC2 are tumor suppressor genes and have been identified in hereditary prostate cancer [195, 196].
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].