bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒05‒09
thirteen papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. High penetrance of myeloid neoplasia with diverse clinical and cytogenetic features in three siblings with a familial GATA2 deficiency.
  2. Germline Structural Variations in Cancer Predisposition Genes.
  3. Genetic Variants in Patients With a Family History of Pancreatic Cancer: Impact of Multigene Panel Testing.
  4. Germline Genetics of Prostate Cancer: Prevalence of Risk Variants and Clinical Implications for Disease Management.
  5. Application of targeted nanopore sequencing for the screening and determination of structural variants in patients with Lynch syndrome.
  6. Functional consequences of a rare missense BARD1 c.403G>A germline mutation identified in a triple-negative breast cancer patient.
  7. A novel stop codon mutation in exon 5 (c.639G>A) of the cadherin-1 gene in a Vietnamese man with hereditary diffuse gastric cancer: a case report.
  8. CDKN2A genetic testing in melanoma-prone families in Sweden in the years 2015-2020: implications for novel national recommendations.
  9. Cost-Effectiveness Analysis of Olaparib Maintenance Treatment for Germline BRCA-Mutated Metastatic Pancreatic Cancer.
  10. Germline and somatic mutations in the pathology of pineal cyst: A whole-exome sequencing study of 93 individuals.
  11. Pediatric Cushing syndrome: An early sign of an underling cancer predisposition syndrome.
  12. Unique Combination of Diamond-Blackfan Anemia and Lynch Syndrome in Adult Female: A Case Report.
  13. Thyroid paraganglioma in a patient with a history of carotid and vagal paraganglioma: metastatic or primary tumor?
  1. Cancer Genet. 2021 Apr 23. pii: S2210-7762(21)00102-2. [Epub ahead of print]256-257 77-80
    High penetrance of myeloid neoplasia with diverse clinical and cytogenetic features in three siblings with a familial GATA2 deficiency.
    Ellingford JM, Telford N, Urquhart J, Will AM, Bonney D, Adams B, Dixon R, Kerr B, Black GC, Wynn RF, Meyer S.
      Pathogenic germ-line variants in GATA2 (GATA2-deficiency) can cause childhood myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and can be associated with distinct clinical syndromic features. However, penetrance and genotype-phenotype correlations are incompletely understood. Here we report on the clinically diverse features of three siblings affected by GATA2c.1021_1031del over an 18-year period, all initially presenting in childhood and adolescence with MDS and AML with monosomy 7 (-7), and one also with trisomy 8 (+8). The siblings inherited a GATA2c.1021_1031del from their father who remains asymptomatic in his sixth decade. The two younger sisters are well after unrelated haematopoietic stem cell transplantation (HSCT), while the first boy died of severe chronic lung disease after sibling HSCT from his youngest sister, who subsequently also developed GATA2-deficiency associated MDS. This family illustrates high penetrance with variable genotype/phenotype correlation within one generation with GATA2-deficiency. We surmise that the lung disease post sibling HSCT was also caused by the GATA2-deficiency. The experience with this family underlines the necessity for GATA2 analysis in all apparently sporadic childhood and teenage MDS and AML with -7 also in the absence of a family history or other clinical features, and rigorous genetic testing in siblings. Moreover, our findings support the arguments for pre-emptive HSCT in variant-carrying siblings.
    DOI:  https://doi.org/10.1016/j.cancergen.2021.04.002
  2. Front Genet. 2021 ;12 634217
    Germline Structural Variations in Cancer Predisposition Genes.
    Pócza T, Grolmusz VK, Papp J, Butz H, Patócs A, Bozsik A.
      In addition to single nucleotide variations and small-scale indels, structural variations (SVs) also contribute to the genetic diversity of the genome. SVs, such as deletions, duplications, amplifications, or inversions may also affect coding regions of cancer-predisposing genes. These rearrangements may abrogate the open reading frame of these genes or adversely affect their expression and may thus act as germline mutations in hereditary cancer syndromes. With the capacity of disrupting the function of tumor suppressors, structural variations confer an increased risk of cancer and account for a remarkable fraction of heritability. The development of sequencing techniques enables the discovery of a constantly growing number of SVs of various types in cancer predisposition genes (CPGs). Here, we provide a comprehensive review of the landscape of germline SV types, detection methods, pathomechanisms, and frequency in CPGs, focusing on the two most common cancer syndromes: hereditary breast- and ovarian cancer and gastrointestinal cancers. Current knowledge about the possible molecular mechanisms driving to SVs is also summarized.
    Keywords:  cancer–predisposing genes; copy number variation; germline mutation; large genomic rearrangement; structural variation; structural variations
    DOI:  https://doi.org/10.3389/fgene.2021.634217
  3. Pancreas. 2021 Apr 01. 50(4): 602-606
    Genetic Variants in Patients With a Family History of Pancreatic Cancer: Impact of Multigene Panel Testing.
    Zhu H, Welinsky S, Soper ER, Brown KL, Abul-Husn NS, Lucas AL.
      OBJECTIVES: Up to 15% of pancreatic cancer is hereditary. We aim to study the prevalence of pathogenic germline variants (PGVs) in patients referred for genetic counseling with a family history (FH) of pancreatic cancer.METHODS: We performed a retrospective single institution cohort study of individuals who underwent cancer genetic counseling with a FH of pancreatic cancer.
    RESULTS: We identified 314 patients. Genetic testing was performed in 291 (92.7%) and 187 (59.6%) underwent expanded multigene panel testing. Fifty-four PGVs were found in 53 (16.9%) individuals; PGVs in BRCA1/2 (37%) were most common. Seventy-two variants of uncertain significance (VUS) were found in 58 (18.5%) individuals; VUS in ATM (16.7%) were the most common. Of the 112 (35.4%) with a first-degree family member with pancreatic cancer, 14 PGVs were identified in 14 (12.5%) individuals and 28 VUS were identified in 21 (18.8%) individuals. After genetic testing, 47 (15.0%) individuals met International Cancer of the Pancreas Screening criteria and 67 (21.3%) met American College of Gastroenterology criteria for pancreatic surveillance.
    CONCLUSIONS: Genetic testing of individuals with a FH of pancreatic cancer represents an opportunity to identify individuals who may be candidates for pancreatic surveillance.
    DOI:  https://doi.org/10.1097/MPA.0000000000001804
  4. Cancers (Basel). 2021 Apr 29. pii: 2154. [Epub ahead of print]13(9):
    Germline Genetics of Prostate Cancer: Prevalence of Risk Variants and Clinical Implications for Disease Management.
    Doan DK, Schmidt KT, Chau CH, Figg WD.
      Prostate cancer has entered into the era of precision medicine with the recent approvals of targeted therapeutics (olaparib and rucaparib). The presence of germline mutations has important hereditary cancer implications for patients with prostate cancer, and germline testing is increasingly important in cancer screening, risk assessment, and the overall treatment and management of the disease. In this review, we discuss germline variants associated with inherited predisposition, prostate cancer risk and outcomes. We review recommendations for germline testing, available testing platforms, genetic counseling as well as discuss the therapeutic implications of germline variants relevant to prostate cancer treatments. Understanding the role of germline (heritable) mutations that affect prostate cancer biology and risk as well as the subsequent effect of these alterations on potential therapies is critical as the treatment paradigm shifts towards precision medicine. Furthermore, enhancing patient education tactics and healthcare system infrastructure is essential for the utilization of relevant predictive biomarkers and the improvement of clinical outcomes of patients with prostate cancer or at high risk of developing the disease.
    Keywords:  genetics; germline testing; prostate cancer
    DOI:  https://doi.org/10.3390/cancers13092154
  5. J Hum Genet. 2021 May 06.
    Application of targeted nanopore sequencing for the screening and determination of structural variants in patients with Lynch syndrome.
    Yamaguchi K, Kasajima R, Takane K, Hatakeyama S, Shimizu E, Yamaguchi R, Katayama K, Arai M, Ishioka C, Iwama T, Kaneko S, Matsubara N, Moriya Y, Nomizu T, Sugano K, Tamura K, Tomita N, Yoshida T, Sugihara K, Nakamura Y, Miyano S, Imoto S, Furukawa Y, Ikenoue T.
      Lynch syndrome is a hereditary disease characterized by an increased risk of colorectal and other cancers. Germline variants in the mismatch repair (MMR) genes are responsible for this disease. Previously, we screened the MMR genes in colorectal cancer patients who fulfilled modified Amsterdam II criteria, and multiplex ligation-dependent probe amplification (MPLA) identified 11 structural variants (SVs) of MLH1 and MSH2 in 17 patients. In this study, we have tested the efficacy of long read-sequencing coupled with target enrichment for the determination of SVs and their breakpoints. DNA was captured by array probes designed to hybridize with target regions including four MMR genes and then sequenced using MinION, a nanopore sequencing platform. Approximately, 1000-fold coverage was obtained in the target regions compared with other regions. Application of this system to four test cases among the 17 patients correctly mapped the breakpoints. In addition, we newly found a deletion across an 84 kb region of MSH2 in a case without the pathogenic single nucleotide variants. These data suggest that long read-sequencing combined with hybridization-based enrichment is an efficient method to identify both SVs and their breakpoints. This strategy might replace MLPA for the screening of SVs in hereditary diseases.
    DOI:  https://doi.org/10.1038/s10038-021-00927-9
  6. Breast Cancer Res. 2021 May 01. 23(1): 53
    Functional consequences of a rare missense BARD1 c.403G>A germline mutation identified in a triple-negative breast cancer patient.
    Zheng Y, Li B, Pan D, Cao J, Zhang J, Wang X, Li X, Hou W, Bao D, Ren L, Yang J, Wang S, Qiu Y, Zhou F, Liu Z, Zhu S, Zhang L, Qing T, Wang Y, Yu Y, Wu J, Hu X, Shi L.
      We identified a rare missense germline mutation in BARD1 (c.403G>A or p.Asp135Asn) as pathogenic using integrated genomics and transcriptomics profiling of germline and tumor samples from an early-onset triple-negative breast cancer patient who later was administrated with a PARP inhibitor for 2 months. We demonstrated in cell and mouse models that, compared to the wild-type, (1) c.403G>A mutant cell lines were more sensitive to irradiation, a DNA damage agent, and a PARP inhibitor; (2) c.403G>A mutation inhibited interaction between BARD1 and RAD51 (but not BRCA1); and (3) c.403G>A mutant mice were hypersensitive to ionizing radiation. Our study shed lights on the clinical interpretation of rare germline mutations of BARD1.
    Keywords:  BARD1; DNA damage; Functional assay; Integrated genomics profiling; Irradiation; PARP inhibitor; Rare mutation; Triple-negative breast cancer; c.403G>A; p.Asp135Asn
    DOI:  https://doi.org/10.1186/s13058-021-01428-5
  7. J Med Case Rep. 2021 May 04. 15(1): 263
    A novel stop codon mutation in exon 5 (c.639G>A) of the cadherin-1 gene in a Vietnamese man with hereditary diffuse gastric cancer: a case report.
    Dang DNT, Nguyen HTT, Ngo HD, Tran BM, Vu AD, Dang HQ, Ta VT.
      BACKGROUND: Germline pathogenic variants in the cadherin-1 (CDH1) gene cause a predisposition to hereditary diffuse gastric cancer (HDGC). We report an HDGC case in Vietnam and identify a novel mutation in the CDH1 gene.CASE PRESENTATION: A 28-year-old Vietnamese man was diagnosed with HDGC and a novel mutation at c.639G>A. All exons of CDH1 were sequenced in his pedigree, which revealed the c.639G>A mutation in the proband, his father, and uncle. The patient refused treatment and died 4 months after diagnosis. Endoscopic surveillance of the father and the uncle showed structural abnormalities in the father.
    CONCLUSION: In cases of HDGC, identification of the CDH1 gene mutation is very important for better counseling and more effective strategies to prevent the development of diseases, such as prophylactic gastrectomy for family members with genetic mutations.
    Keywords:  C.639G>A; Cadherin-1; Case report; Hereditary diffuse gastric cancer
    DOI:  https://doi.org/10.1186/s13256-021-02837-y
  8. Acta Oncol. 2021 May 04. 1-9
    CDKN2A genetic testing in melanoma-prone families in Sweden in the years 2015-2020: implications for novel national recommendations.
    Pissa M, Helkkula T, Appelqvist F, Silander G, Borg Å, Pettersson J, Lapins J, Nielsen K, Höiom V, Helgadottir H.
      Background: Inherited pathogenic variants (PVs) in the CDKN2A gene are among the strongest known risk factors for cutaneous melanoma. Carriers are at high risks to develop multiple primary melanomas and other cancers, in particular pancreatic cancer. In this study, the CDKN2A testing, carried out in Sweden in the years 2015-2020, was evaluated.Materials and methods: Included families had (1) three or more cases of melanoma and/or pancreatic cancer, (2) two melanomas in first-degree relatives, the youngest case <55 years or (3) individuals with three or more multiple primary melanomas, the first before the age of 55 years, and no other affected family members. The included families had at least one affected member that had been tested for CDKN2A PVs.Results: In total, 403 families were included, whereof 913 family members had been diagnosed with cutaneous melanoma and 129 with pancreatic cancer, 33 (8.2%) were found to have PVs in CDKN2A. Frequencies ranged from 0.9% in families with only two melanomas to 43.2% in families with three or more melanoma cases and pancreatic cancer (p < 0.001). The frequency of PVs ranged from 2.1% to 16.5% in families where the youngest case was ≥55 years or <35 years (p = 0.040). In families with or without CDKN2A PVs, 37.6% and 10.0% had melanoma cases that had died from melanoma, respectively (p < 0.001).Discussion: Significant differences were seen in the frequencies of CDKN2A PVs, dependent on numbers or age at diagnosis of melanomas and diagnoses of pancreatic cancers in the family. Further, melanoma cases belonging to families that tested positive for CDKN2A PVs had a significantly higher mortality. To summarize, the current evaluation shows that, with adequately selected criteria to guide genetic testing, CDKN2A PVs are identified at significant frequencies. Identification of carrier families is of importance to ensure that members are enrolled in a preventive surveillance program.
    Keywords:  CDKN2A; Familial melanoma; genetic testing; multiple primary melanoma; mutations; pancreatic cancer
    DOI:  https://doi.org/10.1080/0284186X.2021.1914346
  9. Front Pharmacol. 2021 ;12 632818
    Cost-Effectiveness Analysis of Olaparib Maintenance Treatment for Germline BRCA-Mutated Metastatic Pancreatic Cancer.
    Li N, Zheng H, Huang Y, Zheng B, Cai H, Liu M.
      Background: The PARP inhibitor olaparib has been shown to have clinical efficacy in patients with a germline BRCA mutation and ovarian or breast cancer. However, the high treatment cost associated with this drug limits its viability as a clinical treatment option. This work aims to evaluate the cost-effectiveness of olaparib as a maintenance treatment for metastatic pancreatic cancer from the perspective of the United States and China healthcare systems and provides valuable suggestions for clinical decision making. Method: A three-state Markov model (progression-free, progressed disease, death) was constructed using TreeAge Pro 2020 software to evaluate the economic value of olaparib vs. placebo maintenance treatment for metastatic pancreatic cancer based on the clinical data derived from phase III randomized controlled trial (POLO, ClinicalTrials.gov number, NCT02184195). Total costs, quality-adjusted life years and incremental cost-effectiveness ratio were used as economic indicators for this analysis. A 5-years horizon and 5%/year discount rates were used. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) were performed to assess the model uncertainty. Results: The incremental cost-effectiveness ratios (ICERs) of the use of olaparib vs. placebo in China and the United States were $6,694/QALY and $13327/QALY, respectively. All ICERs were far below the thresholds of $30829 in China and $50000 in the United States. Sensitivity analysis confirmed a stable economic advantage in the use of olaparib vs. placebo as maintenance therapy in China and the United States. Conclusion: Olaparib was estimated to be more cost effective than placebo for the maintenance therapy of patients with a germline BRCA mutation and pancreatic cancer in China and the United States at thresholds of $30829 and $50000 per QALY, respectively.
    Keywords:  cost-effectiveness; germline BRCA-mutated; metastatic; olaparib; pancreatic cancer
    DOI:  https://doi.org/10.3389/fphar.2021.632818
  10. Mol Genet Genomic Med. 2021 May 04. e1691
    Germline and somatic mutations in the pathology of pineal cyst: A whole-exome sequencing study of 93 individuals.
    Yan Y, Martinez R, Rasheed MN, Cahal J, Xu Z, Rui Y, Qualmann KJ, Hagan JP, Kim DH.
      BACKGROUND: Pineal cyst is a benign lesion commonly occurring in people of any age. Until now, the underlying molecular alterations have not been explored.METHODS: We performed whole exome sequencing of 93 germline samples and 21 pineal cyst tissue samples to illustrate its genetic architecture and somatic mutations. The dominant and recessive inheritance modes were considered, and a probability was calculated to evaluate the significance of variant overrepresentation.
    RESULTS: By analyzing pineal cyst as a Mendelian disease with a dominant inheritance pattern, we identified 42,325 rare germline variants, and NM_001004711.1:c.476A>G was highly enriched (FDR<0.2). By analyzing it as a recessive disorder, we identified 753 homozygous rare variants detected in at least one pineal cyst sample each. One STIM2 rare variant, NM_001169117.1:c.1652C>T, was overrepresented (FDR<0.05). Analyzing at a gene-based level, we identified a list of the most commonlymutated germline genes, including POP4, GNGT2 and TMEM254. A somatic mutation analysis of 21 samples identified 16 variants in 15 genes, which mainly participated in the biological processes of gene expression and epigenetic regulation, immune response modulation, and transferase activity.
    CONCLUSION: These molecular profiles are novel for this condition and provide data for investigators interested in pineal cysts.
    Keywords:  germline mutation; pineal cyst; somatic mutation; whole exome sequencing
    DOI:  https://doi.org/10.1002/mgg3.1691
  11. Am J Med Genet A. 2021 May 07.
    Pediatric Cushing syndrome: An early sign of an underling cancer predisposition syndrome.
    Schweiger BM, Esakhan CL, Frishberg D, Grand K, Garg R, Sanchez-Lara PA.
      Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth and cancer predisposition syndrome that can be associated with a spectrum of clinical features including isolated lateralized overgrowth, macrosomia, macroglossia, organomegaly, omphalocele/umbilical hernia, and distinct facial features. Because of a range of clinical presentations and molecular defects involving Chromosome 11p15, many cases will fall within what is now being defined as the Beckwith-Wiedemann spectrum (BWSp). Cushing syndrome (CS) in infants is a rare neuroendocrinological disease associated with hypercortisolism that has rarely been reported in patients with BWS. Here, we describe the first case of a 5-month-old male with CS secondary to paternal uniparental disomy of Chromosome 11p without additional clinical signs or symptoms of BWS. This case continues to expand the phenotypic spectrum of BWSp.
    Keywords:  Beckwith-Wiedemann syndrome; Cushing syndrome; adrenocortical carcinoma; cancer predisposition syndrome; chromosome microarray; uniparental disomy
    DOI:  https://doi.org/10.1002/ajmg.a.62255
  12. Front Oncol. 2021 ;11 652696
    Unique Combination of Diamond-Blackfan Anemia and Lynch Syndrome in Adult Female: A Case Report.
    Tsukanov AS, Pikunov DY, Shubin VP, Barinov AA, Kashnikov VN, Shelygin YA, Kaprin AD, Filonenko EV, Sidorov DV, Maschan AA, Novichkova GA, Yasko LA, Raykina EV, Rumyantsev AG.
      We present an extremely rare clinical case of a 38-year-old Russian patient with multiple malignant neoplasms of the uterus and colon caused by genetically confirmed two hereditary diseases: Diamond-Blackfan anemia and Lynch syndrome. Molecular genetic research carried out by various methods (NGS, Sanger sequencing, aCGH, and MLPA) revealed a pathogenic nonsense variant in the MSH6 gene: NM_000179.2: c.742C>T, p.(Arg248Ter), as well as a new deletion of the chromosome 15's locus with the capture of 82,662,932-84,816,747 bp interval, including the complete sequence of the RPS17 gene. The lack of expediency of studying microsatellite instability in endometrial tumors using standard mononucleotide markers NR21, NR24, NR27, BAT25, BAT26 was demonstrated. The estimated prevalence of patients with combination of Diamond-Blackfan anemia and Lynch syndrome in the world is one per 480 million people.
    Keywords:  Diamond–Blackfan anemia; Lynch syndrome; NGS; aCGH; colorectal cancer; endometrial cancer; microsatellite instability
    DOI:  https://doi.org/10.3389/fonc.2021.652696
  13. J Surg Case Rep. 2021 Apr;2021(4): rjab102
    Thyroid paraganglioma in a patient with a history of carotid and vagal paraganglioma: metastatic or primary tumor?
    Yepuri N, Vanga GR, Naous R, Kinthala S.
      Paragangliomas (PGs) are extremely rare multicentric neoplasms. Hereditary or familial PGs are associated with germline mutations in succinate dehydrogenase genes, seen in one-third of cases. Primary PGs of the thyroid are uncommon neuroendocrine neoplasms that account for 0.012% of all head and neck lesions. Although majority of these tumors are solitary, familial PGs are associated with synchronous tumors (carotid/vagal). We report an interesting case of primary thyroid PG in a patient with a previous history of a right carotid body, right vagal PGs and positive familial history, confining the differential diagnosis to recurrent lesions, which is the most common occurrence or new primary or a metastatic lesion. However, long interval and surgical anatomy suggests the diagnosis to be a primary lesion. In conclusion, although these lesions present multicentrically present at varying intervals, their occurrence at anatomically distinct sites should raise the concern for a new primary PG.
    Keywords:  Familial; Metastatic; Paraganglioma; Primary; Succinate dehydrogenase (SDH) genes; Thyroid
    DOI:  https://doi.org/10.1093/jscr/rjab102
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