China
Africa
Explore chapters and articles related to this topic
Clinical Cancer Genetics
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Rosalind A. Eeles, Lisa J. Walker
Whole-exome sequencing has started to enter the arena of diagnosis for pediatric conditions in intensive care and in developmental delay (the DDD project) to make diagnoses. It is likely that the technology of whole-genome sequencing will transfer itself to routine clinical practice in the next few years. Panels of genes are already being developed for parallel testing, so that instead of a clinician opting to test one gene in the first instance, and then move on to testing another gene if the first yields normal results, a patient’s sample would be tested simultaneously for mutations in all the genes known to pre-dispose individuals to the development of cancers. This new approach does however raise issues of consent and incidental findings. Many people would not, for example, choose to know that they have a mutation in the TP53 gene, which causes Li–Fraumeni syndrome, because this syndrome can cause cancer to develop anywhere throughout the body, and there are few proven prevention strategies. Conversely, the use of next-generation sequencing will lower costs of tests, enabling more people to be tested with the same healthcare budget; this will enable more cancer patients to be offered a genetic test for potential susceptibility to their particular cancer which may impact on their care as some are amenable to targeted treatments, e.g. PARP inhibitors in BRCA1/2 mutation carriers.
Pediatric Central Nervous System Tumors as Phenotypic Manifestation of Cancer Predisposition Syndromes
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Giorgio Perilongo, Irene Toldo, Stefano Sartori
Li–Fraumeni syndrome is a well-known autosomal-dominant disorder predisposing to a lifelong high risk of developing a variety of malignant tumors, with an estimated prevalence of 1 in 20,000 individuals. A loss-of-function germline mutation in the p53 gene is documented in roughly 70% of affected families.57,58 The gene alteration is identified at locus 17p13 and encodes the tumor suppressor gene TP53, which can promote cell cycle arrest, DNA damage repair, and apoptosis. As the “guardian of the genome,” mutations in TP53 can have deleterious effects on DNA integrity and lead to tumorigenesis. Notably, germline mutations in TP53 have been identified in a high percentage of children affected by CPCs even in the absence of another malignancy or of a positive family history.26–29 Other than malignant gliomas, patients affected by Li–Fraumeni syndrome are at higher risk of developing a wide range of primary CNS tumors, such as ependymoma, medulloblastoma, and primitive neuroectodermal tumors.
Pathogenesis of cancer
Published in Peter Hoskin, Peter Ostler, Clinical Oncology, 2020
The best known example of a tumour-suppressor gene is the P53 gene, which has been called ‘the guardian of the genome’ and is found to be mutated in the majority of sporadic cancers. It is also mutated in Li–Fraumeni syndrome, characterized by cancers of the breast, adrenal glands, leukaemia, gliomas and soft-tissue sarcomas. This gene induces cell cycle arrest, which allows cells with DNA damage to repair these mutations before entering mitosis. The mutation of P53 therefore makes the cell susceptible to carcinogenic mutations. Other examples include the retinoblastoma gene which is located on chromosome 13, breast cancer susceptibility genes BRCA1 (chromosome 17) and BRCA2 (chromosome 13), the Wilms’ tumour gene on chromosome 11, and the familial polyposis coli gene on chromosome 5.
Impact of TP53 gene variants on prognosis and survival of childhood acute lymphoblastic leukemia
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2023
Sinem Firtina, Yucel Erbilgin, Ozden Hatirnaz Ng, Serap Karaman, Zeynep Karakas, Tulin Tiraje Celkan, Sema Aylan Gelen, Yildiz Yildirmak, Ugur Ozbek, Muge Sayitoglu
Recent studies demonstrated the importance of heterozygous TP53 variants and the tp53 haploinsufficiency. The heterozygous forms of rare TP53 variants were previously reported in acute and chronic leukemia patients [30–33]. Monoallelic missense TP53 variants that were identified in this study, were located in the DNA-binding domain which was associated with decreased p53 activity [34]. The most common variant was p.(E298*) in our cohort, found as clonal and subclonal in eight (six T-ALL, two B-ALL) ALL patients. The p.(E298*) variant was classified as pathogenic and predicted to lead to a loss of TP53 protein function. The p.(E298*) was observed in Li-Fraumeni syndrome, several types of carcinomas and cancer tissues. Even though, there is no functional evidence for p.(E298*) in ClinVar, ovarian cancer tissues with this variant showed an intermediate tp53 expression level [35,36].
“I need to know if I’m going to die young”: Adolescent and young adult experiences of genetic testing for Li–Fraumeni syndrome
Published in Journal of Psychosocial Oncology, 2021
Rowan Forbes Shepherd, Allison Werner-Lin, Louise A. Keogh, Martin B. Delatycki, Laura E. Forrest
Li–Fraumeni syndrome (LFS; OMIM #151623) is a rare cancer predisposition syndrome caused by heterozygous germline mutations in TP53. LFS is characterized by increased incidence of a wide spectrum of cancers from childhood, including soft-tissue sarcoma and osteosarcoma, central nervous systems tumors, hematological malignancies, and premenopausal breast cancer, among others.7 While LFS confers nearly 100% cancer risk by age 70,7 the potential for early onset profoundly affects AYAs. Estimates suggest females by age 31 and males by age 46 with LFS have a 50% chance of developing cancer,7 with a mean age at first tumor diagnosis of 25 years.8 In addition to the risk of recurrence, nearly half of individuals with LFS develop a second primary malignancy.7
The Inherited Cancer Registry (ICARE) Initiative: An Academic-Community Partnership for Patients and Providers
Published in Oncology Issues, 2018
Tuya Pal, Cristi Radford, Anne Weidner, Ann Louise Tezak, Deborah Cragun, Georgia Lowrey Wiesner
In addition to efforts among BRCA carriers, it has become increasingly important to study patients who are carriers of other inherited cancer genes, including genes with moderate or uncertain levels of cancer risk and that lack evidence-based management options. These individuals have been increasingly identified with the expanded use of multigene cancer panels, which has also raised the complexity of testing and results interpretation.53 There are currently almost 500 registry participants with mutations (i.e., pathogenic or likely pathogenic variants) in inherited cancer predisposing genes other than BRCA1 or BRCA2 (Figure 2), with ongoing efforts to study cancer risks and management practices among these individuals. These include focused efforts to study breast cancer outcomes among PALB2 carriers in collaboration with colleagues from the University of Toronto (inheritedcancer.net/palb2-study), which has resulted in the recruitment of more than 100 PALB2 carriers to ICARE. We have also recently reported on TP53 carriers in ICARE identified through multigene panel tests.54 Our findings indicated that many of these individuals did not meet clinical diagnostic criteria for Li-Fraumeni syndrome, highlighting the substantial variations in clinical phenotypes among TP53 carriers that may be taken into account when making cancer risk management recommendations.