bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023‒01‒29
seven papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family.
  2. Pathogenic Variants in Adult-Onset Cancer Predisposition Genes in Pediatric Cancer: Prevalence and Impact on Tumor Molecular Features and Clinical Management.
  3. FLCN-Driven Functional Adrenal Cortical Carcinoma with High Mitotic Tumor Grade: Extending the Endocrine Manifestations of Birt-Hogg-Dubé Syndrome.
  4. SDHB exon 1 deletion: A recurrent germline mutation in Colombian patients with pheochromocytomas and paragangliomas.
  5. A Focused Clinical Review of Lynch Syndrome.
  6. Identification of h-TERT Promoter Mutations in Germline DNA from North Indian Lung Carcinoma Patients.
  7. A Primary Lung and Breast Cancer Patient with Germline EGFR R776H Mutation: A Case Report and Literature Review.
  1. Mol Genet Genomic Med. 2023 Jan 24. e2104
    Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family.
    Ciyu Yang, Maksym Misyura, Sarah Kane, Vikas Rai, Alicia Latham, Liying Zhang.
      BACKGROUND: Germline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/LP) variants compared with that for MLH1 or MSH2 variants.METHODS: The proband was tested via a clinical testing, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). RT-PCR was performed using patient's blood DNA and cDNA was analyzed by DNA sequencing and a cloning approach.
    RESULTS: We report a 56-year-old female with endometrial cancer who carries a germline variant, MSH6 c.4001G > C, located at the last nucleotide of exon 9. While the pathogenicity of this variant was previously unknown, functional studies demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein.
    CONCLUSION: Our results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic.
    Keywords:  Lynch syndrome; MSH6; c.4001G > C; germline; splice site variant
    DOI:  https://doi.org/10.1002/mgg3.2104
  2. Clin Cancer Res. 2023 Jan 24. pii: CCR-22-2482. [Epub ahead of print]
    Pathogenic Variants in Adult-Onset Cancer Predisposition Genes in Pediatric Cancer: Prevalence and Impact on Tumor Molecular Features and Clinical Management.
    Rose B McGee, Ninad Oak, Lynn Harrison, Ke Xu, Regina Nuccio, Alise K Blake, Roya Mostafavi, Sara Lewis, Leslie M Taylor, Manish Kubal, Annastasia Ouma, Stacy J Hines-Dowell, Cheng Cheng, Larissa V Furtado, Kim E Nichols.
      PURPOSE: Clinical genomic sequencing of pediatric tumors is increasingly uncovering pathogenic variants in adult-onset cancer predisposition genes (aoCPGs). Nevertheless, it remains poorly understood how often aoCPG variants are of germline origin and whether they influence tumor molecular profiles and/or clinical care. In this study, we examined the prevalence, spectrum, and impacts of aoCPG variants on tumor genomic features and patient management at our institution.EXPERIMENTAL DESIGN: This is a retrospective study of 1,018 children with cancer who underwent clinical genomic sequencing of their tumors. Tumor genomic data were queried for pathogenic variants affecting 24 pre-selected aoCPGs. Available tumor whole genome sequencing (WGS) data were evaluated for second hit mutations, loss of heterozygosity (LOH), DNA mutational signatures, and homologous recombination deficiency (HRD). Patients whose tumors harbored one or more pathogenic aoCPG variants underwent subsequent germline testing based on hereditary cancer evaluation and family or provider preference.
    RESULTS: Thirty-three patients (3%) had tumors harboring pathogenic variants affecting one or more aoCPGs. Among 21 tumors with sufficient WGS sequencing data, six (29%) harbored a second hit or LOH affecting the remaining aoCPG allele with four of these six tumors (67%) also exhibited a DNA mutational signature consistent with the altered aoCPG. Two additional tumors demonstrated HRD, of uncertain relation to the identified aoCPG variant. Twenty-one of 26 patients (81%) completing germline testing were positive for the aoCPG variant in the germline. All germline positive patients were counseled regarding future cancer risks, surveillance, and risk reducing measures. No patients had immediate cancer therapy changed due to aoCPG data.
    CONCLUSIONS: AoCPG variants are rare in pediatric tumors; however, many originate in the germline. Almost one third of aoCPG variants exhibit a second hit and/or confer an abnormal DNA mutational profile suggesting a role in tumor formation. AoCPG information aids in cancer risk prediction but is not commonly used to alter the treatment of pediatric cancers.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-2482
  3. Endocr Pathol. 2023 Jan 26.
    FLCN-Driven Functional Adrenal Cortical Carcinoma with High Mitotic Tumor Grade: Extending the Endocrine Manifestations of Birt-Hogg-Dubé Syndrome.
    Renee Hofstedter, María Carolina Sanabria-Salas, Maria Di Jiang, Shereen Ezzat, Ozgur Mete, Raymond H Kim.
      Adrenal cortical carcinoma is an aggressive and rare malignancy of steroidogenic cells of the adrenal gland. Most adult adrenal cortical carcinomas are sporadic, but a small fraction may be associated with inherited tumor syndromes, such as Li-Fraumeni, multiple endocrine neoplasia 1, Lynch syndrome, and Beckwith-Wiedemann syndrome, as well as isolated case reports of non-syndromic manifestations occurring in the context of other pathogenic germline variants. Birt-Hogg-Dubé (BHD) is a rare autosomal dominant syndrome caused by germline pathogenic variants in the FLCN gene. BHD syndrome causes a constellation of symptoms, including cutaneous manifestations, pulmonary cysts and pneumothorax, and risk of renal tumors. With the exception of a single case of adrenal cortical carcinoma, very few reports on the occurrence of adrenal cortical neoplasia in patients with BHD syndrome have been described. However, information on variant allele fraction in the tumor was not available in the index case, which precludes any mechanism supporting loss of heterozygosity. Here we present a case of an adult-onset adrenal cortical carcinoma in a 50-year-old female, found to harbor a germline likely pathogenic variant in the FLCN gene, denoted as c.694C > T (p.Gln232Ter). Genetic testing on the tumor revealed the same FLCN variant at an allele fraction of 83%, suggesting a contributory role to the pathogenesis of the adrenal cortical carcinoma. This case further supports the expansion of the clinical presentation and tumor spectrum of BHD syndrome and the need to consider germline FLCN testing in the clinical genetic workup of patients with adrenal cortical carcinomas.
    Keywords:  Adrenal cortical carcinoma; Birt-Hogg-Dubé syndrome; FLCN; Functional adrenal cortical carcinoma; Germline variants
    DOI:  https://doi.org/10.1007/s12022-023-09748-2
  4. Front Genet. 2022 ;13 999329
    SDHB exon 1 deletion: A recurrent germline mutation in Colombian patients with pheochromocytomas and paragangliomas.
    María Carolina Manotas, Ana Lucía Rivera, Ana Milena Gómez, Patricia Abisambra, Gonzalo Guevara, Vilma Medina, Sandra Tapiero, Antonio Huertas, Julián Riaño-Moreno, Juan Carlos Mejía, Angélica María Gonzalez-Clavijo, Mireya Tapiero-García, Andrés Arturo Cuéllar-Cuéllar, Luis Felipe Fierro-Maya, María Carolina Sanabria-Salas.
      Pheochromocytomas (PCCs) and paragangliomas (PGLs) (known as PPGL in combination) are rare neuroendocrine tumors of the adrenal medulla and extra-adrenal ganglia. About 40% of the patients with PPGL have a hereditary predisposition. Here we present a case-series of 19 unrelated Colombian patients with a clinical diagnosis of PPGL tumors that underwent germline genetic testing as part of the Hereditary Cancer Program developed at the Instituto Nacional de Cancerología, Colombia (INC-C), the largest reference cancer center in the country. Ten of 19 patients (52.63%) were identified as carriers of a pathogenic/likely pathogenic (P/LP) germline variant in a known susceptibility gene. The majority of the P/LP variants were in the SDHB gene (9/10): one corresponded to a nonsense variant c.268C>T (p.Arg90*) and eight cases were found to be carriers of a recurrent CNV consisting of a large deletion of one copy of exon 1, explaining 42% (8/19) of all the affected cases. Only one additional case was found to be a carrier of a missense mutation in the VHL gene: c.355T>C (p.Phe119Leu). Our study highlights the major role of SDHB in Colombian patients with a clinical diagnosis of PGL/PCC tumors and supports the recommendation of including the analysis of large deletions/duplications of the SDHB gene as part of the genetic counselling to improve the detection rate of hereditary cases and their clinical care.
    Keywords:  germline mutation; hereditary; human; neoplastic syndromes; paragangliomas; pheochromocytomas; succinate dehydrogenase subunit B
    DOI:  https://doi.org/10.3389/fgene.2022.999329
  5. Cancer Manag Res. 2023 ;15 67-85
    A Focused Clinical Review of Lynch Syndrome.
    Demetra Georgiou, Laura Monje-Garcia, Tracie Miles, Kevin Monahan, Neil A J Ryan.
      Lynch syndrome (LS) is an autosomal dominant condition that increases an individual's risk of a constellation of cancers. LS is defined when an individual has inherited pathogenic variants in the mismatch repair genes. Currently, most people with LS are undiagnosed. Early detection of LS is vital as those with LS can be enrolled in cancer reduction strategies through chemoprophylaxis, risk reducing surgery and cancer surveillance. However, these interventions are often invasive and require refinement. Furthermore, not all LS associated cancers are currently amenable to surveillance. Historically only those with a strong family history suggestive of LS were offered testing; this has proved far too restrictive. New criteria for testing have recently been introduced including the universal screening for LS in associated cancers. This has increased the number of people being diagnosed with LS but has also brought about unique challenges such as when to consent for germline testing and questions over how and who should carry out the consent. The results of germline testing for LS can be complicated and the diagnostic pathway is not always clear. Furthermore, by testing only those with cancer for LS we fail to identify these individuals before they develop potentially fatal pathology. This review will outline these challenges and explore solutions. Furthermore, we consider the potential future of LS care and the related treatments and interventions which are the current focus of research.
    Keywords:  Lynch syndrome; genetic counselling; mainstreaming
    DOI:  https://doi.org/10.2147/CMAR.S283668
  6. Indian J Clin Biochem. 2023 Jan;38(1): 120-127
    Identification of h-TERT Promoter Mutations in Germline DNA from North Indian Lung Carcinoma Patients.
    Rajendra Prasad, Sonia Panchal, Isha Rani, Jai Kishan, Gaurav Parashar.
      Lung cancer is a severe and the leading cause of cancer related deaths worldwide. The recurrent h-TERT promoter mutations have been implicated in various cancer types. Thus, the present study is extended to analyze h-TERT promoter mutations from the North Indian lung carcinoma patients. Total 20 histopathologically and clinically confirmed cases of lung cancer were enrolled in this study. The genomic DNA was extracted from venous blood and subjected to amplification using appropriate h-TERT promoter primers. Amplified PCR products were subjected for DNA Sanger sequencing for the identification of novel h-TERT mutations. Further, these identified h-TERT promoter mutations were analysed for the prediction of pathophysiological consequences using bioinformatics tools such as Tfsitescan and CIIDER. The average age of patients was 45 ± 8 years which was categorized in early onset of lung cancer with predominance of male patients by 5.6 fold. Interestingly, h-TERT promoter mutations were observed highly frequent in lung cancer. Identified mutations include c. G272A, c. T122A, c. C150A, c. 123 del C, c. C123T, c. G105A, c. 107 Ins A, c. 276 del C corresponding to -168 G>A, -18 T>A, -46 C>A, -19 del C, -19 C>T, -1 G>A, -3 Ins A, -172 del C respectively from the translation start site in the promoter of the telomerase reverse transcriptase gene which are the first time reported in germline genome from lung cancer. Strikingly, c. -18 T>A [C.T122A] was found the most prevalent variant with 75% frequency. Notwithstanding, other mutations viz c. -G168A [c. G272A] and c. -1 G>A [c. G105A] were found to be at 35% and 15% frequency respectively whilst the rest of the mutations were present at 10% and 5% frequency. Additionally, bioinformatics analysis revealed that these mutations can lead to either loss or gain of various transcription factor binding sites in the h-TERT promoter region. Henceforth, these mutations may play a pivotal role in h-TERT gene expression. Taken together, these identified novel promoter mutations may alter the epigenetics and subsequently various transcription factor binding sites which are of great functional significance. Thereby, it is plausible that these germline mutations may involve either as predisposing factor or direct participation in the pathophysiology of lung cancer through entangled molecular mechanisms.
    Keywords:  Lung cancer; Novel mutations; Promoter region; Telomere; Transcription factor binding sites; h-TERT
    DOI:  https://doi.org/10.1007/s12291-022-01047-7
  7. Onco Targets Ther. 2023 ;16 17-22
    A Primary Lung and Breast Cancer Patient with Germline EGFR R776H Mutation: A Case Report and Literature Review.
    Dan Li, Xin Liu, SaiQiong Cui, DaFu Yang, Yue Zhu, Evenki Pan, Peng Yang, ZhaoXia Dai.
      For advanced non-small cell lung cancer (NSCLC) patients with common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or the exon 21 L858R mutation), tyrosine kinase inhibitors (TKIs) are the standard therapies. However, EGFR germline mutations are extremely rare in lung cancer, and the effective therapy is unclear. This study reports a patient with primary breast and lung cancer carried rare germline EGFR R776H and somatic L861Q mutation, who benefit from EGFR TKIs. Her family cancer history review demonstrated that her three out of four sisters with lung cancer were positive for EGFR R776H. Interestingly, only her healthy sister had type O blood, different from other sisters with type B blood. Our study provides a meaningful insight into the potential treatment option for patients with germline EGFR R776H and somatic L861Q mutation and highlights the importance of next-generation sequencing (NGS) in discovering rare genetic alterations to guide the prevention of genetic disease.
    Keywords:  EGFR R776H; Gefitinib; Osimertinib; germline mutation; non-small cell lung cancer
    DOI:  https://doi.org/10.2147/OTT.S391766
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