Malignant Neoplasms of the Colon
Philip H. Gordon, Santhat Nivatvongs, Lee E. Smith, Scott Thorn Barrows, Carla Gunn, Gregory Blew, David Ehlert, Craig Kiefer, Kim Martens in Neoplasms of the Colon, Rectum, and Anus, 2007
The sequence of nucleotides within cellular chromosomes is reproduced faithfully and is passed down from generation to generation during cell division. A “normal” rate of mutation is estimated to be one mistake in every 10 billion base pairs copied. To correct replication errors, a repair mechanism is dependent on genes called mismatch repair genes. Malignant transformation appears to result from the accumulation of mutations within genes that are critical to cell growth and differentiation caused either by an increase in the mutational rate or because the DNA repair process is compromised. A carcinoma is the end result of four to 12 genetic changes that convey a growth advantage to the mutated cells. During the initiation phase, there is an increase in the mutational rate of DNA. Mutations in some genes become incorporated into an individual’s genome and are passed from generation to generation. These “germline mutations” may occur in genes related to carcinoma and, as a result, cause hereditary carcinoma. Other mutations, termed “somatic,” cause a sporadic carcinoma. Knudson (37) proposed that inherited carcinomas arise in individuals with germline mutations of one allele of a recessively acting carcinoma gene, after which only one additional somatic alteration is needed to inactivate the gene and initiate carcinogenesis. Sporadic carcinomas require two somatic mutations (or allelic loss).
Cancer Susceptibility Genes and Common Gene Variants That Increase Cancer Risk
Peter G. Shields in Cancer Risk Assessment, 2005
Many of the genes involved in these cancer syndromes have been identified (Table 1a–c) and they are referred to as “inherited cancer genes” or “susceptibility genes.” Germline mutations in some of these genes approach a 100% risk of cancer during a lifetime. If a gene has incomplete penetrance, some mutation carriers will not develop the expected cancer. Environmental factors and/or other modifying genes (see below) may cause this reduced penetrance. In addition, non-carriers within a hereditary cancer family may develop sporadic cancer of the same type as the mutation carriers. These are termed phenocopies. Thus, accumulation of rare cancers in a family is more likely to be caused by an inherited predisposition than is the case for accumulation of common cancers.
Cancer genomics in clinics
Shirley Sun in Socio-economics of Personalized Medicine in Asia, 2016
Genetic testing for preventive purposes seems to have more adverse implications than benefits based on these doctors’ accounts. First of all, such data are not easily comprehensible. Second, these tests only indicate the likelihood of disease but provide no definitive answers. This could potentially cause much distress for individuals, and even for family members, particularly since the germline mutations in question are heritable and would affect future generations. Lastly, there are limited measures that individuals can adopt to reduce biological risks and prevent the diseases in question. Thus, doctors generally agreed that these genetic tests in relation to preventive medicine should be done in the context of a strong family history.
Germline mosaicism in a DMD family: incidental identification in prenatal diagnosis
Published in Journal of Obstetrics and Gynaecology, 2018
Yu Yang, Ping He, Dong-Zhi Li
Germline mosaicism can occur with any inheritance pattern, but it is most commonly observed in autosomal dominant and X-linked disorders (Edwards 1989). A mosaic germline mutation is significant because it can be obscurely passed to offspring. Most individuals are unaware of a naturally occurring germline mutation until they have a child who is affected. Duchenne Muscular Dystrophy (DMD) is a severe X-linked neuromuscular disease with an incidence of approximately 1 in 3500 newborn boys. The DMD locus has a high mutation frequency: one-third of mutations are de novo, and two-thirds are inherited from carrier mothers (Lee et al. 2014). Instances of germinal mosaicism have been elucidated in DMD families on the basis of more than one affected offspring born to an apparently non-carrier parent (Bermúdez-López et al. 2014). Here we report on germline mosaicism in a DMD family incidentally identified in prenatal diagnosis by using chromosomal microarray analysis (CMA).
The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities
Published in Expert Review of Anticancer Therapy, 2018
Anteneh A. Tesfaye, Mandana Kamgar, Asfar Azmi, Philip A. Philip
The use of targeted next-generation sequencing (NGS) has been proposed to improve the diagnostic value of fine needle aspiration-derived material by detecting key somatic and germline genetic alterations that are unique to pancreatic cancer [80,81]. The findings of germline mutations may also have implication for unaffected family members. It can also help identify patients at risk of developing pancreatic adenocarcinoma and help define future therapeutic options [82]. NGS in exceptional responders may identify subset of patients that might benefit from specific treatments. Furthermore, NGS may identify potential targets that may help tailor treatments to a specific mutation. However, NGS has not been prospectively validated for clinical use in patients with pancreatic cancer and remains experimental at this point. There is currently no available drug that can directly target the four most common mutations, KRAS, CDKN2A, TP53, and SMAD4 in pancreatic cancer. All the mutations that can be therapeutically exploited in pancreatic cancer have an exceedingly low prevalence [83] and as such are not interrogated in clinical practice unless enrolled in a clinical trial that is enriched for a particular molecular abnormality [84]. NGS results can also be used to risk stratify patients. In a recent study, a composite of 25-gene signature from NGS in pancreas cancer patients has been shown to identify patients with short- and long-term survival benefits after surgical resection of the primary tumor [85].
Histopathology of the Conduction System in Long QT Syndrome
Published in Fetal and Pediatric Pathology, 2022
Alexandra Rogers, Rachel Taylor, Janet Poulik, Bahig M. Shehata
At least 16 genotypically different subtypes of Long QT Syndrome (LQTS) have been identified to date (ex: LQT1, LQT2, LQT3). About 75% of these cases are caused by mutations in one of three major genes, 5% are attributable to mutations in one of 10 minor genes, 5–10% are caused by de novo germline mutations, and the remaining 10–15% of diagnoses are due to unidentified causes [2]. Most cases of LQTS are inherited in an autosomal dominant pattern, underlying the importance of a thorough family history in the evaluation of presenting patients. Most of the mutations are single nucleotide substitutions or insertions/deletions [2]. While a majority of patients harbor only a single mutation in one of the three major genes, a small percentage, roughly 5% to 10%, show multiple mutations. These patients tend to demonstrate a more severe disease phenotype with an earlier age of onset [2].