bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023–06–18
nine papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. TP53 germline pathogenic variants in modern humans were likely originated during recent human history.
  2. Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.
  3. Investigating the prevalence of pathogenic variants in Saudi Arabian patients with familial cancer using a multigene next generation sequencing panel.
  4. Do All Patients Diagnosed With Cancer Deserve Germline Testing?
  5. The clinical phenotype of germline RUNX1 mutations in relation to the accompanying somatic variants and RUNX1 isoform expression.
  6. CDH1 and hereditary diffuse gastric cancer: a narrative review.
  7. Fumarate Hydratase-Deficient Leiomyoma of the Uterine Corpus: Comparative Morphologic Analysis of Protein-Deficient Tumors With and Without Pathogenic Germline Fumarate Hydratase Gene Mutations.
  8. Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing.
  9. Molecular reclassification reveals low prevalence of germline predisposition in children with ependymoma.
  1. NAR Cancer. 2023 Sep;5(3): zcad025
    TP53 germline pathogenic variants in modern humans were likely originated during recent human history.
    Si Hoi Kou, Jiaheng Li, Benjamin Tam, Huijun Lei, Bojin Zhao, Fengxia Xiao, San Ming Wang.
      TP53 is crucial for maintaining genome stability and preventing oncogenesis. Germline pathogenic variation in TP53 damages its function, causing genome instability and increased cancer risk. Despite extensive study in TP53, the evolutionary origin of the human TP53 germline pathogenic variants remains largely unclear. In this study, we applied phylogenetic and archaeological approaches to identify the evolutionary origin of TP53 germline pathogenic variants in modern humans. In the phylogenic analysis, we searched 406 human TP53 germline pathogenic variants in 99 vertebrates distributed in eight clades of Primate, Euarchontoglires, Laurasiatheria, Afrotheria, Mammal, Aves, Sarcopterygii and Fish, but we observed no direct evidence for the cross-species conservation as the origin; in the archaeological analysis, we searched the variants in 5031 ancient human genomes dated between 45045 and 100 years before present, and identified 45 pathogenic variants in 62 ancient humans dated mostly within the last 8000 years; we also identified 6 pathogenic variants in 3 Neanderthals dated 44000 to 38515 years before present and 1 Denisovan dated 158 550 years before present. Our study reveals that TP53 germline pathogenic variants in modern humans were likely originated in recent human history and partially inherited from the extinct Neanderthals and Denisovans.
    DOI:  https://doi.org/10.1093/narcan/zcad025
  2. J Clin Oncol. 2023 Jun 15. JCO2202378
    Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.
    Hannah M Seagle, Samantha R Keller, Sean V Tavtigian, Carolyn Horton, Andreana N Holowatyj.
       PURPOSE: The early-onset colorectal cancer (EOCRC) burden differs across racial/ethnic groups, yet the role of germline genetic predisposition in EOCRC disparities remains uncharacterized. We defined the prevalence and spectrum of inherited colorectal cancer (CRC) susceptibility gene variations among patients with EOCRC by race and ethnicity.
    PATIENTS AND METHODS: We included individuals diagnosed with a first primary CRC between age 15 and 49 years who identified as Ashkenazi Jewish, Asian, Black, Hispanic, or White and underwent germline genetic testing of 14 CRC susceptibility genes performed by a clinical testing laboratory. Variant comparisons by racial and ethnic groups were evaluated using chi-square tests and multivariable logistic regression adjusted for sex, age, CRC site, and number of primary colorectal tumors.
    RESULTS: Among 3,980 patients with EOCRC, a total of 530 germline pathogenic or likely pathogenic variants were identified in 485 individuals (12.2%). By race/ethnicity, 12.7% of Ashkenazim patients, 9.5% of Asian patients, 10.3% of Black patients, 14.0% of Hispanic patients, and 12.4% of White patients carried a germline variant. The prevalence of Lynch syndrome (P = .037), as well as APC, CHEK2, MLH1, monoallelic MUTYH, and PTEN variants, varied by race/ethnicity among patients with EOCRC (all P < .026). Ashkenazim and Hispanic patients had significantly higher odds of presenting with a pathogenic APC variant, which included p.I1307K (odds ratio [OR], 2.67; 95% CI, 1.30 to 5.49; P = .007) and MLH1 variant (OR, 8.69; 95% CI, 2.68 to 28.20; P = .0003), respectively, versus White patients in adjusted models.
    CONCLUSION: Germline genetic features differed by race/ethnicity in young patients with CRC, suggesting that current multigene panel tests may not be representative of EOCRC risk in diverse populations. Further study is needed to optimize genes selected for genetic testing in EOCRC via ancestry-specific gene and variant discovery to yield equitable clinical benefits for all patients and to mitigate inequities in disease burden.
    DOI:  https://doi.org/10.1200/JCO.22.02378
  3. Oncotarget. 2023 Jun 12. 14 580-594
    Investigating the prevalence of pathogenic variants in Saudi Arabian patients with familial cancer using a multigene next generation sequencing panel.
    Musa AlHarbi, Nahla Ali Mobark, Wael Abdel Rahman AlJabarat, Hadeel ElBardis, Ebtehal AlSolme, Abdullah Bany Hamdan, Ali H AlFakeeh, Fatimah AlMushawah, Fawz AlHarthi, Abdullah A AlSharm, Ali Abdullah O Balbaid, Naji AlJohani, Alicia Y Zhou, Heather A Robinson, Saleh A Alqahtani, Malak Abedalthagafi.
      Family history is an important factor in determining hereditary cancer risk for many cancer types. The emergence of next-generation sequencing (NGS) has expedited the discovery of many hereditary cancer susceptibility genes and the development of rapid, affordable testing kits. Here, a 30-gene targeted NGS panel for hereditary cancer risk assessment was tested and validated in a Saudi Arabian population. A total of 310 subjects were screened, including 57 non-cancer patients, 110 index patients with cancer and 143 of the cancer patients' family members, 16 of which also had cancer. Of the 310 subjects, 119 (38.4%) were carriers of pathogenic or likely pathogenic variants (PVs) affecting one or more of the following genes: TP53, ATM, CHEK2, CDH1, CDKN2A, BRCA1, BRCA2, PALB2, BRIP1, RAD51D, APC, MLH1, MSH2, MSH6, PMS2, PTEN, NBN/NBS1 and MUTYH. Among 126 patients and relatives with a history of cancer, 49 (38.9%) were carriers of PVs or likely PVs. Two variants in particular were significantly associated with the occurrence of a specific cancer in this population (APC c.3920T>A - colorectal cancer/Lynch syndrome (p = 0.026); TP53 c.868C>T; - multiple colon polyposis (p = 0.048)). Diverse variants in BRCA2, the majority of which have not previously been reported as pathogenic, were found at higher frequency in those with a history of cancer than in the general patient population. There was a higher background prevalence of genetic variants linked to familial cancers in this cohort than expected based on prevalence in other populations.
    Keywords:  NGS; cancer; cancer screening; genetic counseling; hereditary cancer syndrome
    DOI:  https://doi.org/10.18632/oncotarget.28457
  4. J Clin Oncol. 2023 Jun 13. JCO2300710
    Do All Patients Diagnosed With Cancer Deserve Germline Testing?
    Steven Sorscher.
      
    DOI:  https://doi.org/10.1200/JCO.23.00710
  5. Genes Chromosomes Cancer. 2023 Jun 12.
    The clinical phenotype of germline RUNX1 mutations in relation to the accompanying somatic variants and RUNX1 isoform expression.
    David Cabrerizo Granados, Indira Barbosa, Panagiotis Baliakas, Eva Hellström-Lindberg, Vanessa Lundin.
      Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, abnormal bleeding, and an elevated risk of developing myelodysplastic neoplasia (MDS) and acute myeloid leukemia (AML) at young age. However, it is not known why or how germline carriers of RUNX1 mutations have a particular propensity to develop myeloid hematologic malignancies, but the acquisition and composition of somatic mutations are believed to initiate and determine disease progression. We present a novel family pedigree that shares a common germline RUNX1R204* variant and exhibits a spectrum of somatic mutations and related myeloid malignancies (MM). RUNX1 mutations are associated with inferior clinical outcome; however, the proband of this family developed MDS with ring sideroblasts (MDS-RS), classified as a low-risk MDS subgroup. His relatively indolent clinical course is likely due to a specific somatic mutation in the SF3B1 gene. While the three main RUNX1 isoforms have been ascribed various roles in normal hematopoiesis, they are now being increasingly recognized as involved in myeloid disease. We investigated the RUNX1 transcript isoform patterns in the proband and his sister, who carries the same germline RUNX1R204* variant, and has FPDMM but no MM. We demonstrate a RUNX1a increase in MDS-RS, as previously reported in MM. Interestingly, we identify a striking unbalance of RUNX1b and -c in FPDMM. In conclusion, this report reinforces the relevance of somatic variants on the clinical phenotypic heterogeneity in families with germline RUNX1 deficiency and investigates a potential new role for RUNX1 isoform disequilibrium as a mechanism for development of MM.
    Keywords:  FPDMM; MDS; RUNX1; RUNX1 isoforms; germline mutations; myeloid malignancies
    DOI:  https://doi.org/10.1002/gcc.23184
  6. Chin Clin Oncol. 2023 Jun 05. pii: cco-23-36. [Epub ahead of print]
    CDH1 and hereditary diffuse gastric cancer: a narrative review.
    Stephanie N Gregory, Jeremy L Davis.
       BACKGROUND AND OBJECTIVE: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that increases lifetime risk of diffuse-type gastric cancer which carries a dismal overall survival. Due to the high prevalence of cancer in patients with CDH1 variants, early screening and prophylactic total gastrectomy (PTG) are recommended. This review aims to summarize the current understanding of CDH1 and HDGC, highlighting its molecular and cellular implications as well as its clinical management and research efforts.
    METHODS: A review of PubMed and ClinicalTrials.gov was conducted. Articles published in English and with full text were considered. PubMed was searched using the terms 'CDH1' AND 'Hereditary Diffuse Gastric Cancer'.
    KEY CONTENT AND FINDINGS: Loss-of-function mutations in the CDH1 gene, which encodes the cell adhesion protein E-cadherin, have been identified as the primary cause of HDGC. The loss of E-cadherin expression disrupts cell-cell adhesion and activates oncogenic signaling pathways, ultimately promoting cancer cell growth and dissemination. Prophylactic total gastrectomy (PTG) is recommended for pathogenic CDH1 variant carriers with a family history of diffuse gastric cancer (DGC). However, recent studies of endoscopic surveillance utilizing specific biopsy protocols have demonstrated the potential for surveillance as an alternative to total gastrectomy in selected patients. Researchers are actively investigating the consequences of E-cadherin loss in gastric epithelium and have identified potential molecular drivers of HDGC development using animal models and organoids. These discoveries provide promise for chemoprevention strategies, biomarker discovery, and targeted therapies for diffuse-type gastric cancer.
    CONCLUSIONS: The understanding of HDGC has significantly advanced in recent years, with the loss of E-cadherin expression identified as a crucial factor in disease pathogenesis. The use of advanced in vitro models offers substantial promise for investigating the molecular mechanisms underlying HDGC and identifying novel therapeutic targets. By leveraging advanced models, continuing clinical trials, and improving clinical management of affected individuals, researchers can work towards the development of more effective treatment strategies for HDGC. The goal is to prevent cancers from developing in patients with CDH1 gene variants and minimize the burden of cancer.
    Keywords:  CDH1; E-cadherin; hereditary diffuse gastric cancer (HDGC)
    DOI:  https://doi.org/10.21037/cco-23-36
  7. Int J Surg Pathol. 2023 Jun 13. 10668969231180285
    Fumarate Hydratase-Deficient Leiomyoma of the Uterine Corpus: Comparative Morphologic Analysis of Protein-Deficient Tumors With and Without Pathogenic Germline Fumarate Hydratase Gene Mutations.
    Wangpan Shi, Yu Liu, Omonigho Aisagbonhi, Andres A Roma, Farnaz Hasteh, Somaye Y Zare, Oluwole Fadare.
      Deficiency of fumarate hydratase (FH) protein expression in uterine corpus leiomyomas may be attributable to either germline or somatic mutations of the FH gene, the former being definitional for the hereditary leiomyomatosis and renal cell cancer syndrome. The authors assess whether, using previously reported FH-associated morphologic features, FH protein-deficient uterine corpus leiomyomas associated with a pathogenic germline mutations of the FH gene (group 1) are distinguishable from FH protein-deficient uterine corpus leiomyomas without such mutations (and whose FH protein loss is presumed to be attributable to somatic/epigenetic inactivation or other unknown phenomena: group 2). Groups 1 and 2 were compared regarding a variety of clinicopathologic features, including 7 core "FH-associated" tumoral morphologic features: staghorn vasculature; alveolar-type edema; bizarre nuclei; chain-like tumor nuclei; hyaline cytoplasmic globules; prominent nucleoli, intranuclear inclusions, and perinucleolar halos; and prominent eosinophilic/fibrillary cytoplasm. Among 2418 patients diagnosed with uterine corpus leiomyoma during the study period, FH-associated morphologic features were reported in 1.5% (37 patients), and FH immunohistochemistry was performed in 29 (1.19%). Fourteen (48.27%) of the 29 patients showed FH protein deficiency by immunohistochemistry. Twelve patients underwent germline testing, of which 8 (66.7%) were classified as group 1 and 4 (33.3%) as group 2. FH protein-deficient tumors were larger (10.44 vs 4.08 cm, P  =  0.01) and associated with younger patients (42.05 vs 47.97, P  =  0.004) than 370 randomly selected uterine leiomyoma controls. Groups 1 and 2 showed no significant differences in patient age and tumor size. In group 1 tumors, the FH-associated morphologic features were generally present diffusely; all group 1 tumors displayed ≥5 FH-associated features, whereas all group 2 tumors displayed <5 FH-associated features (means 6.5  ±  0.53 vs 3.5  ±  1.00, P < 0.001). Notably, eosinophilic/fibrillary cytoplasm and alveolar-type edema were each significantly more prevalent in group 1 tumors than group 2 tumors (P  =  0.018 for both). No single morphologic feature was found to be completely sensitive and specific in making the distinction between group 1 and 2 tumors. Our findings suggest that groups 1 and 2 are unlikely to be morphologically distinguishable by individual morphologic features. Whether there is a combination of features that can reliably make this distinction is unclear and will require additional studies with larger cohorts.
    Keywords:  HLRCC; fumarate hydratase-deficient leiomyoma; germline mutation; hereditary leiomyomatosis and renal cell cancer syndrome; morphological study; uterus
    DOI:  https://doi.org/10.1177/10668969231180285
  8. BMC Med Genomics. 2023 Jun 09. 16(1): 126
    Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing.
    Ashish Kumar Singh, Bente Talseth-Palmer, Alexandre Xavier, Rodney J Scott, Finn Drabløs, Wenche Sjursen.
       BACKGROUND: Hereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch repair genes, causing one of several types of familial colorectal cancer (CRC) syndromes. Most of the mutations are low-penetrant variants, contributing to an increased risk of familial colorectal cancer, and they are often found in additional genes and pathways not previously associated with CRC. The aim of this study was to identify such variants, both high-penetrant and low-penetrant ones.
    METHODS: We performed whole exome sequencing on constitutional DNA extracted from blood of 48 patients suspected of familial colorectal cancer and used multiple in silico prediction tools and available literature-based evidence to detect and investigate genetic variants.
    RESULTS: We identified several causative and some potentially causative germline variants in genes known for their association with colorectal cancer. In addition, we identified several variants in genes not typically included in relevant gene panels for colorectal cancer, including CFTR, PABPC1 and TYRO3, which may be associated with an increased risk for cancer.
    CONCLUSIONS: Identification of variants in additional genes that potentially can be associated with familial colorectal cancer indicates a larger genetic spectrum of this disease, not limited only to mismatch repair genes. Usage of multiple in silico tools based on different methods and combined through a consensus approach increases the sensitivity of predictions and narrows down a large list of variants to the ones that are most likely to be significant.
    Keywords:  Colorectal cancer (CRC); Copy number variation (CNV); Familial colorectal cancer Type X (FCCTX); Lynch syndrome (LS); Mismatch repair (MMR); Variant annotation; Variant filtration; Whole exome sequencing (WES)
    DOI:  https://doi.org/10.1186/s12920-023-01562-3
  9. Acta Neuropathol Commun. 2023 06 12. 11(1): 94
    Molecular reclassification reveals low prevalence of germline predisposition in children with ependymoma.
    Jon Foss-Skiftesvik, René Mathiasen, Thomas van Overeem Hansen, Karin Wadt, Kjeld Schmiegelow, Ulrik Kristoffer Stoltze.
      
    Keywords:  Ependymoma; Genetic predisposition; Germline; Sequencing; Tumor methylation profiling
    DOI:  https://doi.org/10.1186/s40478-023-01594-x
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