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Nature Reviews. Cancer Feb 2021Although much work has focused on the elucidation of somatic alterations that drive the development of acute leukaemias and other haematopoietic diseases, it has become... (Review)
Review
Although much work has focused on the elucidation of somatic alterations that drive the development of acute leukaemias and other haematopoietic diseases, it has become increasingly recognized that germline mutations are common in many of these neoplasms. In this Review, we highlight the different genetic pathways impacted by germline mutations that can ultimately lead to the development of familial and sporadic haematological malignancies, including acute lymphoblastic leukaemia, acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Many of the genes disrupted by somatic mutations in these diseases (for example, TP53, RUNX1, IKZF1 and ETV6) are the same as those that harbour germline mutations in children and adolescents who develop these malignancies. Moreover, the presumption that familial leukaemias only present in childhood is no longer true, in large part due to the numerous studies demonstrating germline DDX41 mutations in adults with MDS and AML. Lastly, we highlight how different cooperating events can influence the ultimate phenotype in these different familial leukaemia syndromes.
Topics: Disease Progression; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 33328584
DOI: 10.1038/s41568-020-00315-z -
Cells Dec 2020Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as... (Review)
Review
Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. The ATM-CHEK2-p53 axis has been documented as a backbone for DDR and hypothesized as a barrier against cancer initiation. However, although CHK2 kinase coded by the gene expedites the DDR signal, its function in activation of p53-dependent cell cycle arrest is dispensable. mutations rank among the most frequent germline alterations revealed by germline genetic testing for various hereditary cancer predispositions, but their interpretation is not trivial. From the perspective of interpretation of germline variants, we review the current knowledge related to the structure of the gene, the function of CHK2 kinase, and the clinical significance of germline mutations in patients with hereditary breast, prostate, kidney, thyroid, and colon cancers.
Topics: Animals; Checkpoint Kinase 2; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Mutation Rate; Neoplasms; Substrate Specificity
PubMed: 33322746
DOI: 10.3390/cells9122675 -
PloS One 2014Technological advances coupled with decreasing costs are bringing whole genome and whole exome sequencing closer to routine clinical use. One of the hurdles to clinical...
Technological advances coupled with decreasing costs are bringing whole genome and whole exome sequencing closer to routine clinical use. One of the hurdles to clinical implementation is the high number of variants of unknown significance. For cancer-susceptibility genes, the difficulty in interpreting the clinical relevance of the genomic variants is compounded by the fact that most of what is known about these variants comes from the study of highly selected populations, such as cancer patients or individuals with a family history of cancer. The genetic variation in known cancer-susceptibility genes in the general population has not been well characterized to date. To address this gap, we profiled the nonsynonymous genomic variation in 158 genes causally implicated in carcinogenesis using high-quality whole genome sequences from an ancestrally diverse cohort of 681 healthy individuals. We found that all individuals carry multiple variants that may impact cancer susceptibility, with an average of 68 variants per individual. Of the 2,688 allelic variants identified within the cohort, most are very rare, with 75% found in only 1 or 2 individuals in our population. Allele frequencies vary between ancestral groups, and there are 21 variants for which the minor allele in one population is the major allele in another. Detailed analysis of a selected subset of 5 clinically important cancer genes, BRCA1, BRCA2, KRAS, TP53, and PTEN, highlights differences between germline variants and reported somatic mutations. The dataset can serve a resource of genetic variation in cancer-susceptibility genes in 6 ancestry groups, an important foundation for the interpretation of cancer risk from personal genome sequences.
Topics: Adolescent; Adult; Alleles; Cohort Studies; Female; Gene Frequency; Gene Pool; Genes, Neoplasm; Genetic Predisposition to Disease; Genome, Human; Germ-Line Mutation; Health; Humans; Male; Middle Aged; Models, Molecular; Neoplasms; Open Reading Frames; Phylogeny; Sequence Analysis, DNA; Young Adult
PubMed: 24728327
DOI: 10.1371/journal.pone.0094554 -
International Journal of Molecular... Dec 2021Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as , , ,... (Review)
Review
Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as , , , , , , (), , , and , lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. The penetrance of germline pathogenic variants of each gene varies, whereas all their associated protein products are indispensable for maintaining a high-fidelity DNA repair system by HR. The present review summarizes the basic molecular mechanisms and components that collectively play a role in maintaining genomic integrity against DNA double-strand damage and their clinical implications on each type of hereditary tumor.
Topics: Genetic Predisposition to Disease; Genetic Testing; Germ-Line Mutation; Homologous Recombination; Humans; Neoplasms; Precision Medicine
PubMed: 35008774
DOI: 10.3390/ijms23010348 -
Nature Reviews. Clinical Oncology Mar 2010Microsatellite instability (MSI) is the molecular fingerprint of a deficient mismatch repair system. Approximately 15% of colorectal cancers (CRC) display MSI owing... (Review)
Review
Microsatellite instability (MSI) is the molecular fingerprint of a deficient mismatch repair system. Approximately 15% of colorectal cancers (CRC) display MSI owing either to epigenetic silencing of MLH1 or a germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2. Methods to detect MSI are well established and routinely incorporated into clinical practice. A clinical and molecular profile of MSI tumors has been described, leading to the concept of an MSI phenotype in CRC. Studies have confirmed that MSI tumors have a better prognosis than microsatellite stable CRC, but MSI cancers do not necessarily have the same response to the chemotherapeutic strategies used to treat microsatellite stable tumors. Specifically, stage II MSI tumors might not benefit from 5-fluorouracil-based adjuvant chemotherapy regimens. New data suggest possible advantages of irinotecan-based regimens, but these findings require further clarification. Characterization of the molecular basis of MSI in CRC is underway and initial results show that mutations in genes encoding kinases and candidate genes with microsatellite tracts are over-represented in MSI tumors. Transcriptome expression profiles of MSI tumors and systems biology approaches are providing the opportunity to develop targeted therapeutics for MSI CRC.
Topics: Colorectal Neoplasms; DNA Repair; DNA Repair Enzymes; Germ-Line Mutation; Humans; Microsatellite Instability
PubMed: 20142816
DOI: 10.1038/nrclinonc.2009.237 -
Leukemia Jun 2020
Topics: Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Myelodysplastic Syndromes; Myeloproliferative Disorders
PubMed: 31911633
DOI: 10.1038/s41375-019-0701-8 -
Modern Pathology : An Official Journal... Nov 2016Hereditary endometrial carcinoma is associated with germline mutations in Lynch syndrome genes. The role of other cancer predisposition genes is unclear. We aimed to...
Hereditary endometrial carcinoma is associated with germline mutations in Lynch syndrome genes. The role of other cancer predisposition genes is unclear. We aimed to determine the prevalence of cancer predisposition gene mutations in an unselected endometrial carcinoma patient cohort. Mutations in 25 genes were identified using a next-generation sequencing-based panel applied in 381 endometrial carcinoma patients who had undergone tumor testing to screen for Lynch syndrome. Thirty-five patients (9.2%) had a deleterious mutation: 22 (5.8%) in Lynch syndrome genes (three MLH1, five MSH2, two EPCAM-MSH2, six MSH6, and six PMS2) and 13 (3.4%) in 10 non-Lynch syndrome genes (four CHEK2, one each in APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, NBN, PTEN, and RAD51C). Of 21 patients with deleterious mutations in Lynch syndrome genes with tumor testing, 2 (9.5%) had tumor testing results suggestive of sporadic cancer. Of 12 patients with deleterious mutations in MSH6 and PMS2, 10 were diagnosed at age >50 and 8 did not have a family history of Lynch syndrome-associated cancers. Patients with deleterious mutations in non-Lynch syndrome genes were more likely to have serous tumor histology (23.1 vs 6.4%, P=0.02). The three patients with non-Lynch syndrome deleterious mutations and serous histology had mutations in BRCA2, BRIP1, and RAD51C. Current clinical criteria fail to identify a portion of actionable mutations in Lynch syndrome and other hereditary cancer syndromes. Performance characteristics of tumor testing are sufficiently robust to implement universal tumor testing to identify patients with Lynch syndrome. Germline multi-gene panel testing is feasible and informative, leading to the identification of additional actionable mutations.
Topics: Aged; DNA Mutational Analysis; Endometrial Neoplasms; Female; Genetic Predisposition to Disease; Genetic Testing; Germ-Line Mutation; Humans; Middle Aged
PubMed: 27443514
DOI: 10.1038/modpathol.2016.135 -
The Journal of Molecular Diagnostics :... Jan 2018Authors' Reply to the Letter to the Editor by Montgomery et al (Identification of Germline Variants in Tumor Genomic Sequencing Analysis. J Mol Diagn 2017, 19:XXXX-XXXX).
Authors' Reply to the Letter to the Editor by Montgomery et al (Identification of Germline Variants in Tumor Genomic Sequencing Analysis. J Mol Diagn 2017, 19:XXXX-XXXX).
Topics: Germ-Line Mutation; Guidelines as Topic; Humans; Sequence Analysis, DNA
PubMed: 29249244
DOI: 10.1016/j.jmoldx.2017.11.002 -
Genetics in Medicine : Official Journal... Aug 2018Blood/saliva DNA is thought to represent the germ line in genetic cancer-risk assessment. Cases with pathogenic TP53 variants detected by multigene panel testing are...
PURPOSE
Blood/saliva DNA is thought to represent the germ line in genetic cancer-risk assessment. Cases with pathogenic TP53 variants detected by multigene panel testing are often discordant with Li-Fraumeni syndrome, raising concern about misinterpretation of acquired aberrant clonal expansions (ACEs) with TP53 variants as germ-line results.
METHODS
Pathogenic TP53 variants with abnormal next-generation sequencing metrics (e.g., decreased ratio (<25%) of mutant to wild-type allele, more than two detected alleles) were selected from a CLIA laboratory testing cohort. Alternate tissues and/or close relatives were tested to distinguish between ACE and germ-line status. Clinical data and Li-Fraumeni syndrome testing criteria were examined.
RESULTS
Among 114,630 multigene panel tests and 1,454 TP53 gene-specific analyses, abnormal next-generation sequencing metrics were observed in 20% of 353 TP53-positive results, and ACE was confirmed for 91% of cases with ancillary materials, most of these due to clonal hematopoiesis. Only four met Chompret criteria. Individuals with ACE were older (50 years vs. 33.7; P = 0.02) and were identified more frequently in multigene panel tests (66/285; 23.2%) than in TP53 gene-specific tests (6/68; 8.8%, P = 0.005).
CONCLUSION
ACE confounds germ-line diagnosis, may portend hematologic malignancy, and may provoke unwarranted clinical interventions. Ancillary testing to confirm germ-line status should precede Li-Fraumeni syndrome management.
Topics: Genes, p53; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Germ Cells; Germ-Line Mutation; Humans; Li-Fraumeni Syndrome; Mutation; Pedigree; Tumor Suppressor Protein p53
PubMed: 29189820
DOI: 10.1038/gim.2017.196 -
Cold Spring Harbor Perspectives in... Apr 2020Germline pathogenic phosphatase and tensin homolog () mutations cause hamartoma tumor syndrome (PHTS), characterized by various benign and malignant tumors of the... (Review)
Review
Germline pathogenic phosphatase and tensin homolog () mutations cause hamartoma tumor syndrome (PHTS), characterized by various benign and malignant tumors of the thyroid, breast, endometrium, and other organs. Patients with PHTS may present with other clinical features such as macrocephaly, intestinal polyposis, cognitive changes, and pathognomonic skin changes. Clinically, deregulation of PTEN function is implicated in other human diseases in addition to many types of human cancer. PTEN is an important phosphatase that counteracts one of the most critical cancer pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways. Although PTEN can dephosphorylate lipids and proteins, it also has functions independent of phosphatase activity in normal and pathological states. It is positively and negatively regulated at the transcriptional level as well as posttranslationally by phosphorylation, ubiquitylation, oxidation, and acetylation. Although most of its tumor-suppressor activity is likely to be caused by lipid dephosphorylation at the plasma membrane, PTEN also resides in the cytoplasm and nucleus, and its subcellular distribution is under strict control. In this review, we highlight our current knowledge of PTEN function and recent discoveries in understanding PTEN function regulation and how this can be exploited therapeutically for cancer treatment.
Topics: Animals; Disease Management; Genetic Predisposition to Disease; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Humans; Neoplasms; PTEN Phosphohydrolase; Phosphatidylinositol 3-Kinases; Signal Transduction
PubMed: 31570378
DOI: 10.1101/cshperspect.a036087