bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒06‒21
twenty-one papers selected by
Joanna Zawacka-Pankau
  1. Germline pathogenic variants in transcription factors predisposing to pediatric acute myeloid leukemia: results from the French ELAM02 trial.
  2. Cancer surveillance and distress among adult pathogenic TP53 germline variant carriers in Germany: A multicenter feasibility and acceptance survey.
  3. Report of 2 Pediatric Cases With Li-Fraumeni Syndrome Related Malignancy in a Family.
  4. Comparison of suspected Lynch syndrome patients carrying BRCA and BRCA-like variants with Lynch syndrome probands: Phenotypic characteristics and pedigree analyses.
  5. Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants.
  6. A Germline PALB2 Pathogenic Variant identified in a Pediatric High Grade Glioma.
  7. Novel Morphological and Genetic Features of Fumarate Hydratase Deficient Renal Cell Carcinoma in HLRCC Syndrome Patients with a Tailored Therapeutic Approach.
  8. Genetic counselors' perspectives on population-based screening for BRCA-related hereditary breast and ovarian cancer and Lynch syndrome.
  9. Clinical Characteristics and Mutation Analysis of Ovarian Sertoli-Leydig Cell Tumors.
  10. Feasibility of Gynaecologist Led Lynch Syndrome Testing in Women with Endometrial Cancer.
  11. Hereditary Gastric and Breast Cancer Syndromes Related to CDH1 Germline Mutation: A Multidisciplinary Clinical Review.
  12. Feasibility of tumor testing for BRCA status in high-grade serous ovarian cancer using fresh-frozen tissue based approach.
  13. Sequencing of RNA in single cells reveals a distinct transcriptome signature of hematopoiesis in GATA2 deficiency.
  14. Clinical characteristics and exploratory genomic analyses of germline BRCA1 or BRCA2 mutations in breast cancer.
  15. Synchronous detection of SDHA-related gallbladder paraganglioma and pancreatic neuroendocrine tumor.
  16. Inherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma: A Comprehensive Review.
  17. Two subsequent metachroneus solid tumors: Oncocytic variant adrenocortical carcinoma and rhabdomyosarcoma of childhood: Case report and Literature Review.
  18. Germline control of anti-tumour immunity.
  19. Hereditary pancreatitis model by blastocyst complementation in mouse.
  20. Clinical Applications of Molecular Biomarkers in Prostate Cancer.
  21. Association Between Genotype and Phenotype in Consecutive Unrelated Individuals With Retinoblastoma.
  1. Haematologica. 2020 Jun 18. pii: haematol.2020.248872. [Epub ahead of print]
    Germline pathogenic variants in transcription factors predisposing to pediatric acute myeloid leukemia: results from the French ELAM02 trial.
    Fenwarth L, Duployez N, Marceau-Renaut A, Abou Chahla W, Ducassou S, Gandemer V, Pasquet M, Leblanc T, Schneider P, Domenech C, Saultier P, Leverger G, Lapillonne H, Preudhomme C, Petit A.
      
    Keywords:  Acute Myeloid Leukemia; Cytogenetics and Molecular Genetics; Predisposition syndrome
    DOI:  https://doi.org/10.3324/haematol.2020.248872
  2. Cancer. 2020 Jun 18.
    Cancer surveillance and distress among adult pathogenic TP53 germline variant carriers in Germany: A multicenter feasibility and acceptance survey.
    Rippinger N, Fischer C, Haun MW, Rhiem K, Grill S, Kiechle M, Cremer FW, Kast K, Nguyen HP, Ditsch N, Kratz CP, Vogel J, Speiser D, Hettmer S, Glimm H, Fröhling S, Jäger D, Seitz S, Hahne A, Maatouk I, Sutter C, Schmutzler RK, Dikow N, Schott S.
      BACKGROUND: Li-Fraumeni syndrome (LFS) is a high-risk cancer predisposition syndrome caused by pathogenic germline variants of TP53. Cancer surveillance has noted a significant survival advantage in individuals with LFS; however, little is known about the feasibility, acceptance, and psychosocial effects of such a program.METHODS: Pathogenic TP53 germline variant carriers completed a 7-part questionnaire evaluating sociodemographics, cancer history, surveillance participation, reasons for nonadherence, worries, and distress adapted from the Cancer Worry Scale. Counselees' common concerns and suggestions were assessed in MAXQDA Analytics Pro 12.
    RESULTS: Forty-nine participants (46 females and 3 males), aged 40.0 ± 12.6 years, formed the study population; 43 (88%) had a personal cancer history (including multiple cancers in 10 [20%]). Forty-three individuals participated (88%) in surveillance during the study or formerly. Willingness to undergo surveillance was influenced by satisfaction with genetic testing and counseling (P = .019 [Fisher-Yates test]) but not by sociodemographics, cancer history, or distress level. Almost one-third of the participants reported logistical difficulties in implementing surveillance because of the high frequency of medical visits, scheduling difficulties, and the travel distance to their surveillance providers. Self-reported distress and perceived emotional burden for family members and partners were moderate (median for self-reported distress, 3.3; median for perceived emotional burden, 3.0). For both, the interquartile range was moderate to very high (2.7-3.7 and 3.0-3.7, respectively).
    CONCLUSIONS: Individuals with LFS require efficient counseling as well as an accessible, well-organized, interdisciplinary, standardized surveillance program to increase adherence and psychological coping.
    Keywords:  Li-Fraumeni syndrome; adherence; hereditary breast cancer; pathogenic TP53 germline variant; surveillance
    DOI:  https://doi.org/10.1002/cncr.33004
  3. J Pediatr Hematol Oncol. 2020 Jun 16.
    Report of 2 Pediatric Cases With Li-Fraumeni Syndrome Related Malignancy in a Family.
    Takeoka M, Toyoda H, Hirayama J, Suzuki N, Hanaki R, Amano K, Iwamoto S, Hirayama M.
      Li-Fraumeni syndrome (LFS) is a rare inherited disease characterized by a high and early-onset cancer risk. A cancer surveillance program is important to reduce cancer-related morbidity and mortality in individuals with LFS. We report 2 pediatric cases with LFS-related malignancy in a family. Eight-year-old elder brother was diagnosed with adrenocortical carcinoma and was found to have a heterozygous missense germline mutation c.736A>G: p.Met246Val in the TP53 gene. Cancer screening led to the diagnosis of rhabdomyosarcoma at a curable stage in his 2-year-old younger brother. Comprehensive surveillance resulted in early tumor detection and improved survival.
    DOI:  https://doi.org/10.1097/MPH.0000000000001862
  4. Mol Genet Genomic Med. 2020 Jun 16. e1359
    Comparison of suspected Lynch syndrome patients carrying BRCA and BRCA-like variants with Lynch syndrome probands: Phenotypic characteristics and pedigree analyses.
    Xu Y, Li C, Wang Z, Liu F, Xu Y.
      BACKGROUND: Colorectal cancer (CRC) patients diagnosed with Lynch syndrome (LS) are recommended genetic testing. Increasing numbers of germline variants involved in homologous recombination have been identified in suspected LS patients. This study compared phenotypic the characteristics of suspected LS patients carrying BRCA and BRCA-like variants with those of LS patients.METHODS: Forty-two patients carrying pathogenic variants of DNA mismatch repair (MMR) genes (MMR group), 9 carrying BRCA variants, and 11 carrying BRCA-like variants (BRCA/BRCA-like group) who met LS clinical criteria were enrolled in this study. Clinical characteristics, pedigrees, and survival rates were compared and BRCA variants were analyzed.
    RESULTS: The earliest CRC-onset age and tumor differentiation were higher in the BRCA/BRCA-like group than in the MMR group. Metachronous CRCs were more numerous in the MMR group, resulting in a higher progression-free survival rate in the BRCA/BRCA-like group. Extra-colorectal cancers were more frequently observed in the BRCA/BRCA-like group. BRCA2 and BRCA1 variants were clustered in exons 11 and 4/7, respectively.
    CONCLUSION: BRCA and BRCA-like variants in CRC patients with LS showed moderate penetrance. BRCA/BRCA-like variant carriers had a higher risk for extra-colorectal cancers. Surveillance of susceptible organs other than the intestine should be performed for probands and affected family members.
    Keywords:  BRCA; BRCA-like; Lynch syndrome; colorectal cancer; mismatch repair
    DOI:  https://doi.org/10.1002/mgg3.1359
  5. Front Oncol. 2020 ;10 666
    Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants.
    Nikitin AG, Chudakova DA, Enikeev RF, Sakaeva D, Druzhkov M, Shigapova LH, Brovkina OI, Shagimardanova EI, Gusev OA, Gordiev MG.
      Genome instability-the increased tendency of acquiring mutations in the genome and ability of a cell to tolerate high mutation burden-is one of the drivers of cancer. Genome instability results from many causes including defects in DNA repair systems. Previously, it has been shown that germline pathogenic mutations in DNA Mismatch Repair (MMR) pathway cause cancer-predisposing Lynch Syndrome. We proposed that Lynch Syndrome-related germline mutations (LS-mutations) are associated with breast cancer (BC). In this study, we performed Targeted Next-Generation Sequencing of MMR pathway genes MLH1, MSH2, MSH6, EPCAM, and PMS2 in a cohort of 711 patients with hereditary BC, 60 patients with sporadic BC, and 492 healthy donors. Sixty-nine patients (9.7%) with hereditary BC harbored at least one germline mutation in the MMR pathway genes, of them 32 patients (4.5%) harbored mutations in MMR pathway genes which we define as pathogenic or likely pathogenic, and of them 26 patients (3.6%) did not have any pathogenic mutations in DDR pathway genes, compared to two mutations in MMR pathway genes (0.4%) detected in a group of 492 healthy donors [p = 0.00013, OR = 8.9 (CI 95% 2.2-78.4)]. Our study demonstrates that LS-mutations are present in patients with hereditary BC more frequently than in healthy donors, and that there is an association of hereditary BC and mutations c.1321G>A in MLH1, c.260C>G and c.2178G>C in MSH2, c.3217C>T in MSH6, c.1268C>G and c.86G>C in PMS2 genes. This finding provides a rationale for including pathogenic LS-mutations into genetic counseling tests for patients with hereditary BC.
    Keywords:  EPCAM; Lynch syndrome; MLH1; MSH2; MSH6; PMS2; Targeted Next-Generation Sequencing; breast cancer
    DOI:  https://doi.org/10.3389/fonc.2020.00666
  6. Cold Spring Harb Mol Case Stud. 2020 Jun 18. pii: mcs.a005397. [Epub ahead of print]
    A Germline PALB2 Pathogenic Variant identified in a Pediatric High Grade Glioma.
    Zhong Y, Schubert J, Wu J, Xu F, Lin F, Cao K, Zelley K, Luo M, Foster J, Cole KA, Macfarland S, Resnick AC, Storm PB, Li MM.
      PALB2 (partner and localizer of BRCA2) gene encodes a protein that co-localizes with BRCA2 in nuclear foci and likely permits the stable intra-nuclear localization and accumulation of BRCA2. PALB2 plays a critical role in maintaining genome integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. It has a known loss of function disease mechanism. Biallelic PALB2 pathogenic variants have been described in autosomal recessive Fanconi Anemia. Heterozygous pathogenic variants in PALB2 are associated with increased risk for female and male breast cancer and pancreatic cancer (1-3). Heterozygous germline PALB2 mutations have also been observed in patients with medulloblastoma (4). However, PALB2-related cancer predisposition to high grade gliomas has not been reported. Here we report a germline PALB2 pathogenic variant (c.509_510delGA, p.Arg170Ilefs*14, NM_024675.3) found in a pediatric patient with high grade glioma. This variant was first identified by tumor sequencing using the Children's Hospital of Philadelphia (CHOP) Comprehensive Solid Tumor Panel then confirmed to be a germline change using the CHOP Comprehensive Hereditary Cancer Panel on DNA from a blood sample of this patient. Parental studies showed that this variant was paternally inherited. Further studies are needed to illustrate if pathogenic variants in PALB2 convey increased risk to developing brain tumor. This case also highlights the potential of identifying germline mutation through tumor sequencing.
    Keywords:  Glioma
    DOI:  https://doi.org/10.1101/mcs.a005397
  7. Genes Chromosomes Cancer. 2020 Jun 14.
    Novel Morphological and Genetic Features of Fumarate Hydratase Deficient Renal Cell Carcinoma in HLRCC Syndrome Patients with a Tailored Therapeutic Approach.
    Wyvekens N, Valtcheva N, Mischo A, Helmchen B, Hermanns T, Choschzick M, Hötker AM, Rauch A, Mühleisen B, Akhoundova D, Weber A, Moch H, Rupp NJ.
      The hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is defined by germline mutations in the fumarate hydratase (FH) gene and associated with leiomyomas and aggressive renal cell carcinomas with FH deficiency. Here, we comprehensively characterize two new patients with HLRCC syndrome on a morphological, immunohistochemical and genetic level. The patients developed aggressive HLRCC syndrome-associated RCC, uterine leiomyomas and dermal leiomyomas. One HLRCC syndrome-associated RCC exhibited an unusual morphology with accumulation of "colloid-like" cytoplasmic inclusions, which might serve as a novel sentinel feature to trigger further testing. This case showed partially retained FH expression, initially hampering correct diagnosis. Comprehensive next-generation sequencing analyses of HLRCC syndrome-associated RCC and leiomyomas in our patients revealed divergent genetic changes in the FH gene in different tumors from the same patient. While all leiomyomas (uterine and cutaneous) showed a FH loss of heterozygosity (LOH) as a wildtype allele inactivating event, one HLRCC-RCC showed a second, undescribed NM_000143.3; c.947C > T; p.Ala316Val FH mutation accompanying the preexisting splice site mutation c.378 + 2 T > C. In the other HLRCC syndrome-associated RCC, the FH mutation (NM_000143.3; c.462 T > G; p.Asn154Lys with a somatic LOH) represents another variant of unknown significance that we link to HLRCC - and thus classify as likely pathogenic. Due to the specific diagnosis of metastatic HLRCC syndrome-associated RCC, both cases were treated in first line with bevacizumab / erlotinib and showed remarkable and long lasting responses. These findings allow new morphological and molecular insights into the biology of the HLRCC syndrome, corroborate the "second hit" hypothesis of tumor formation in HLRCC patients and may promote a distinct therapeutic approach. This article is protected by copyright. All rights reserved.
    Keywords:  HLRCC; fumarase deficient; fumarate hydratase deficient; hereditary; leiomyoma; renal cell carcinoma
    DOI:  https://doi.org/10.1002/gcc.22878
  8. J Genet Couns. 2020 Jun 20.
    Genetic counselors' perspectives on population-based screening for BRCA-related hereditary breast and ovarian cancer and Lynch syndrome.
    De Simone LM, Arjunan A, Vogel Postula KJ, Maga T, Bucheit LA.
      Early identification of those with BRCA-related Hereditary Breast and Ovarian Cancer Syndrome (HBOC) and Lynch syndrome has the potential for early cancer detection and/or prevention; as such, these conditions are considered Tier 1 genetic conditions by the U.S. Center for Disease Control and Prevention. Given the decreasing cost of genetic testing, population-based screening (PBS) for such conditions may be the next step toward cancer prevention. This study aimed to understand genetic counselors' perspectives toward offering PBS for the Tier 1 conditions BRCA-related HBOC and Lynch syndrome. An online survey was distributed to 3,609 members of the National Society of Genetic Counselors. A total of 367 individuals participated in the study. Fifty percent of respondents felt that PBS for inherited cancer should not be offered; 93.3% felt that the current healthcare system is unprepared for implementation of PBS. However, most respondents agreed that PBS should be implemented within the next 10 years. Attitudes toward offering PBS were associated with respondents' work setting, cancer specialization, and perceived preparedness (p's < 0.05). The most commonly reported barriers to the implementation of PBS were shortage of genetic professionals and lack of infrastructure. Data in this study provide evidence that infrastructural barriers and educational gaps of non-genetic professionals would need to be addressed before successful integration of PBS into the healthcare system.
    Keywords:   BRCA1 ; BRCA2 ; Lynch syndrome; genetic counseling; genetic testing; hereditary breast and ovarian cancer; population screening; population-based screening; predictive genetic testing; public health
    DOI:  https://doi.org/10.1002/jgc4.1305
  9. Oncologist. 2020 Jun 17.
    Clinical Characteristics and Mutation Analysis of Ovarian Sertoli-Leydig Cell Tumors.
    Yuan Z, Huo X, Jiang D, Yu M, Cao D, Wu H, Shen K, Yang J, Zhang Y, Zhou H, Wang Y.
      BACKGROUND: There are not many studies on Sertoli-Leydig cell tumors (SLCTs) and no data in the population of Chinese patients with SLCTs from the genetic level. In addition, most studies have explored only the DICER1 gene in SLCT; no clear idea exists of the genetic landscape of SLCT.METHODS: Patients who underwent surgical resection between January 2012 and October 2018 in our institution were recruited. Whole exome sequencing was performed on formalin-fixed, paraffin-embedded tumor tissue and peripheral blood or normal tissue samples.
    RESULTS: Seventeen patients were recruited with 19 tumor samples. The rate of tumor-associated germline mutations was 6 of 17 (35.3%), and that of DICER1 germline mutations was 4 of 17 (23.5%). Regarding clinical relapse, patients with germline tumor-associated mutations had significantly poorer prognosis than those without (p = .007), and those with germline DICER1 mutations were relatively more likely to exhibit clinical relapse, although not to a significant degree (p = .069). Regarding somatic mutations, firstly, the subclone evolution analysis demonstrated that the two tumor samples on the contralateral ovary were primary tumors. Secondly, somatic mutations were most commonly found in CDC27 (10/19, 52.6%), DICER1 (4/19, 21.1%), and MUC22 (4/19, 21.1%). And the analysis of cancer cell fractions showed that DICER1 mutations were correlated with tumorigenesis of SLCTs. The rates of germline and somatic DICER1 mutations were higher in patients who were younger than 18 years than in older patients (p = .022 and p = .001, respectively).
    CONCLUSION: Our study indicates that genetic testing may have important clinical significance for patients with SLCTs, particularly for younger patients.
    IMPLICATIONS FOR PRACTICE: Bilateral ovarian Sertoli-Leydig cell tumors were verified to be primary tumors from the genetic perspective. The rates of germline and somatic DICER1 mutations were 4 in 17 (23.5%) and 4 in 19 (21.1%), respectively. The rates of germline and somatic DICER1 mutations were higher in patients who were younger than 18 years than in older patients (p = .022 and p = .001, respectively).
    Keywords:  DICER1; Germline mutation; Sertoli-Leydig cell tumors; Somatic mutation; Whole exome sequencing
    DOI:  https://doi.org/10.1634/theoncologist.2020-0110
  10. J Clin Med. 2020 Jun 12. pii: E1842. [Epub ahead of print]9(6):
    Feasibility of Gynaecologist Led Lynch Syndrome Testing in Women with Endometrial Cancer.
    Ryan NA, Donnelly L, Stocking K, Evans DG, Crosbie EJ.
      A barrier to Lynch syndrome testing is the need for prior genetic counselling, a resource demanding process for both patients and healthcare services. We explored the impact of gynaecologist led Lynch syndrome testing in women with endometrial cancer. Women were approached before surgery, on the day of surgery or during routine follow up. Lynch syndrome testing was offered irrespective of age, family history or tumour characteristics. Women's reasons for being tested were explored using the Motivations and Concerns for GeNEtic Testing (MACGNET) instrument. The short form State-Trait Anxiety Inventory (STAI-6) was used to measure anxiety levels. Only 3/305 women declined Lynch syndrome testing. In total, 175/220 completed MACGNET and STAI-6 psychological instruments. The consent process took an average of 7min 36sec (SD 5min 16sec) to complete. The point of care at which consent was taken (before, day of surgery, during follow up) did not influence motivation for Lynch syndrome testing. Anxiety levels were significantly lower when women were consented during follow up (mean reversed STAI-6 score 32 vs 42, p = 0.001). Anxiety levels were not affected by familial cancer history (p = 0.41). Gynaecologist led Lynch syndrome testing is feasible and may even be desirable in endometrial cancer, especially when offered during routine follow up.
    Keywords:  Lynch syndrome; anxiety; consent; endometrial cancer; germline testing
    DOI:  https://doi.org/10.3390/jcm9061842
  11. Cancers (Basel). 2020 Jun 17. pii: E1598. [Epub ahead of print]12(6):
    Hereditary Gastric and Breast Cancer Syndromes Related to CDH1 Germline Mutation: A Multidisciplinary Clinical Review.
    Corso G, Montagna G, Figueiredo J, La Vecchia C, Fumagalli Romario U, Fernandes MS, Seixas S, Roviello F, Trovato C, Guerini-Rocco E, Fusco N, Pravettoni G, Petrocchi S, Rotili A, Massari G, Magnoni F, De Lorenzi F, Bottoni M, Galimberti V, Sanches JM, Calvello M, Seruca R, Bonanni B.
      E-cadherin (CDH1 gene) germline mutations are associated with the development of diffuse gastric cancer in the context of the so-called hereditary diffuse gastric syndrome, and with an inherited predisposition of lobular breast carcinoma. In 2019, the international gastric cancer linkage consortium revised the clinical criteria and established guidelines for the genetic screening of CDH1 germline syndromes. Nevertheless, the introduction of multigene panel testing in clinical practice has led to an increased identification of E-cadherin mutations in individuals without a positive family history of gastric or breast cancers. This observation motivated us to review and present a novel multidisciplinary clinical approach (nutritional, surgical, and image screening) for single subjects who present germline CDH1 mutations but do not fulfil the classic clinical criteria, namely those identified as-(1) incidental finding and (2) individuals with lobular breast cancer without family history of gastric cancer (GC).
    Keywords:  CDH1 gene; E-cadherin; breast cancer; gastric cancer; germline mutations; hereditary syndrome; prophylactic surgery
    DOI:  https://doi.org/10.3390/cancers12061598
  12. Gynecol Oncol. 2020 Jun 15. pii: S0090-8258(20)32294-0. [Epub ahead of print]
    Feasibility of tumor testing for BRCA status in high-grade serous ovarian cancer using fresh-frozen tissue based approach.
    Marchetti C, Minucci A, D'Indinosante M, Ergasti R, Arcieri M, Capoluongo ED, Pietragalla A, Caricato C, Scambia G, Fagotti A.
      OBJECTIVE: For many years, BRCA mutational status has only been considered as a predictor of ovarian cancer susceptibility and as a prognostic factor. Nonetheless, in the era of precision medicine, it has also become a predictive biomarker of response to platinum-based-chemotherapy and, more recently, to PARP-inhibitors, also in the frontline setting. We assessed the feasibility of a fresh frozen tissue-based-BRCA-screening workflow in a tertiary referral center.METHODS: We consecutively enrolled a series of 456 newly diagnosed FIGO-Stage IIIC-IV, high grade serous-ovarian cancer patients. All patients receiving tumor-biopsy underwent tBRCA-testing.
    RESULTS: Clinically relevant tissue-BRCA (tBRCA) variants were observed in 145 women (31.8%), particularly we recognized 89 (61.4%) patients with BRCA1-pathogenetic variants (PVs) and 56 women (38.6%) with BRCA2-PVs. Among 292 tBRCA wild-type (wt) patients, 88 cases were germline BRCA tested (gBRCA) and 86 (97.8%) were confirmed as gBRCAwt, while 1 (1.1%) had gBRCA variant of uncertain significance and 1 had gBRCA mutation (1.1%). The concordance of tumor test versus germline BRCA test was 86.3% (209/242). Large genomic rearrangements (LGRs) were suspected in 13/292 tBRCAwt patients (4.5%) by using bioinformatic algorithm and multiplex ligation-dependent probe amplification (MLPA) was performed, with evidence of PVs in only 1 case.
    CONCLUSIONS: Fresh-frozen tissue-based BRCA screening workflow is feasible and reliable. It allows to enlarge the BRCA mutated population that might receive PARPi with the greatest benefit, without missing cascade testing for family members and therefore, maintaining its preventive role.
    Keywords:  BRCA gene; Epithelial ovarian cancer; Molecular profile; NGS; Personalized medicine
    DOI:  https://doi.org/10.1016/j.ygyno.2020.06.479
  13. Blood Adv. 2020 Jun 23. 4(12): 2656-2670
    Sequencing of RNA in single cells reveals a distinct transcriptome signature of hematopoiesis in GATA2 deficiency.
    Wu Z, Gao S, Diamond C, Kajigaya S, Chen J, Shi R, Palmer C, Hsu AP, Calvo KR, Hickstein DD, Holland SM, Young NS.
      Constitutional GATA2 deficiency caused by heterozygous germline GATA2 mutations has a broad spectrum of clinical phenotypes, including systemic infections, lymphedema, cytopenias, and myeloid neoplasms. Genotype-phenotype correlation is not well understood mechanistically in GATA2 deficiency. We performed whole transcriptome sequencing of single hematopoietic stem and progenitor cells from 8 patients, who had pathogenic GATA2 mutations and myelodysplasia. Mapping patients' cells onto normal hematopoiesis, we observed deficiency in lymphoid/myeloid progenitors, also evident from highly constrained gene correlations. HSPCs of patients exhibited distinct patterns of gene expression and coexpression compared with counterparts from healthy donors. Distinct lineages showed differently altered transcriptional profiles. Stem cells in patients had dysregulated gene expression related to apoptosis, cell cycle, and quiescence; increased expression of erythroid/megakaryocytic priming genes; and decreased lymphoid priming genes. The prominent deficiency in lympho-myeloid lineages in GATA2 deficiency appeared at least partly due to the expression of aberrant gene programs in stem cells prior to lineage commitment. We computationally imputed cells with chromosomal abnormalities and determined their gene expression; DNA repair genes were downregulated in trisomy 8 cells, potentially rendering these cells vulnerable to second-hit somatic mutations and additional chromosomal abnormalities. Cells with complex cytogenetic abnormalities showed defects in genes related to multilineage differentiation and cell cycle. Single-cell RNA sequencing is powerful in resolving transcriptomes of cell subpopulations despite a paucity of cells in marrow failure. Our study discloses previously uncharacterized transcriptome signatures of stem cells and progenitors in GATA2 deficiency, providing a broad perspective of potential mechanisms by which germline mutations modulate early hematopoiesis in a human disease. This trial was registered at www.clinicaltrials.gov as NCT01905826, NCT01861106, and NCT00001620.
    DOI:  https://doi.org/10.1182/bloodadvances.2019001352
  14. Mol Cancer Res. 2020 Jun 17. pii: molcanres.1108.2019. [Epub ahead of print]
    Clinical characteristics and exploratory genomic analyses of germline BRCA1 or BRCA2 mutations in breast cancer.
    Park S, Lee E, Park S, Lee S, Nam SJ, Kim SW, Lee JE, Yu JH, Kim JY, Ahn JS, Im YH, Park WY, Park K, Park YH.
      gBRCA1/2 mutations increase the incidence of breast cancer (BC) by interrupting the homologous recombination repair (HRR) pathway. Although gBRCA1 and gBRCA2 BC have similar clinical profiles, different molecular characteristics have been observed. In this study, we conducted comprehensive genomic analyses and compared gBRCA1/2 BC. Sanger sequencing to identify gBRCA1/2 mutations was conducted in 2,720 patients, and gBRCA1 (n=128) and gBRCA2 (n=126) mutations were analyzed. Within that population, deep target sequencing (TS) and matched whole transcriptome sequencing (WTS) results were available for 46 and 34 patients, respectively. An internal database of breast-cancer patients with wild-type gBRCA was used to compile a TS (n=195) and WTS (n=137) reference dataset. Three specific mutation sites, p.Y130X (n=14) and p.1210Afs (n=13) in gBRCA1 and p.R294X (n=22) in gBRCA2, were comparably frequent. Immunohistochemistry subtyping determined that the incidence of triple negative BC was higher among those with a gBRCA1 mutation (71.9%), and estrogen receptor (ER)-positive BC was dominant in those with a gBRCA2 mutation (76.2%). gBRCA1/2 mutations were mutually exclusive with PIK3CA somatic mutations (P<0.05), and gBRCA1 frequently co-occurred with TP53 somatic mutations (P<0.05). The median tumor mutation burden was 6.53 per megabase (MB) in gBRCA1 and 6.44 per MB in gBRCA2. The expression of AR, ESR1, and PGR was significantly upregulated with gBRCA2 mutation compared with gBRCA1 mutation. gBRCA1 and gBRCA2 BC have similar clinical characteristics, but they have different molecular subtypes, co-altered somatic mutations, and gene expression patterns. Implications: Even though gBRCA1 and gBRCA2 mutations both alter HRR pathways, our results suggest that they generate different molecular characteristics and different mechanisms of carcinogenesis.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-19-1108
  15. Pathol Res Pract. 2020 Jul;pii: S0344-0338(20)30620-8. [Epub ahead of print]216(7): 153006
    Synchronous detection of SDHA-related gallbladder paraganglioma and pancreatic neuroendocrine tumor.
    Aaquist T, Medhus JB, Thomassen A, Detlefsen S.
      Primary gallbladder paragangliomas (PGLs) are exceedingly rare. PGLs are extraadrenal neuroendocrine tumors that are morphologically inseparable from intraadrenal pheochromocytomas. PGLs and pheochromocytomas are some of the most heritable tumor types in the body and are often associated with other tumors or part of a genetic syndrome. We report a case of gallbladder PGL presenting synchronously with pancreatic neuroendocrine tumor (NET) and pulmonary IgG4-related disease in a 74-year old male patient with disseminated prostate adenocarcinoma. Due to the high rate of germline mutations and the possible syndromal manifestation of PGLs as well as pancreatic NETs, this patient was offered genetic testing, and a pathogenic SDHA germline mutation was found. Immunohistochemically, there was loss of SDHA and SDHB in the PGL but neither in the NET nor in the prostate adenocarcinoma. To our knowledge, this case is the first report of gallbladder PGL associated with pancreatic NET. It is likely that the identified SDHA germline mutation played a role in the development of gallbladder PGL in this patient.
    Keywords:  Endocrine neoplasia; Gallbladder; Multiple tumors; Neuroendocrine tumor; Pancreas; Paraganglioma
    DOI:  https://doi.org/10.1016/j.prp.2020.153006
  16. Int J Mol Sci. 2020 Jun 17. pii: E4327. [Epub ahead of print]21(12):
    Inherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma: A Comprehensive Review.
    Panou V, Røe OD.
      Malignant mesothelioma (MM) is mainly caused by air-born asbestos but genetic susceptibility is also suspected to be a risk factor. Recent studies suggest an increasing number of candidate genes that may predispose to MM besides the well-characterized BRCA1-associated protein-1 gene. The aim of this review is to summarize the most important studies on germline mutations for MM. A total of 860 publications were retrieved from Scopus, PubMed and Web of Science, of which 81 met the inclusion criteria and were consider for this review. More than 50% of the genes that are reported to predispose to MM are involved in DNA repair mechanisms, and the majority of them have a role in the homologous recombination pathway. Genetic alterations in tumor suppressor genes involved in chromatin, transcription and hypoxia regulation have also been described. Furthermore, we identified several single nucleotide polymorphisms (SNPs) that may promote MM tumorigenesis as a result of an asbestos-gene interaction, including SNPs in DNA repair, carcinogen detoxification and other genes previously associated with other malignancies. The identification of inherited mutations for MM and an understanding of the underlying pathways may allow early detection and prevention of malignancies in high-risk individuals and pave the way for targeted therapies.
    Keywords:  genetic cancer susceptibility; inherited genetic mutations; malignant mesothelioma; single nucleotide polymorphisms
    DOI:  https://doi.org/10.3390/ijms21124327
  17. J Clin Res Pediatr Endocrinol. 2020 Jun 16.
    Two subsequent metachroneus solid tumors: Oncocytic variant adrenocortical carcinoma and rhabdomyosarcoma of childhood: Case report and Literature Review.
    Akin O, Atas E, Atasoy İA, Durmaz N, Kartal Ö.
      Most cases of malignancies appear to be sporadic, but some syndromes are associated with malignancies with germline variants. Herein, a child with an unusual association of oncocytic variant adrenocortical carcinoma (ACC) and rhabdomyosarcoma was presented. An 18-month-old-boy was admitted with virilization of the genital area, penis enlargement, and erection which had begun six months ago. Serum total testosterone: 457 ng/dl (<10), androstenedione: 3.35ng/ml (<0.5) and DHEA-SO4: 206 mcg/dl (<35) were measured higher than normal ranges. Right adrenal mass was detected. After adrenalectomy, histopathological examination revealed oncocytic variant ACC. Three-month later from surgery, the child then presented with 6x8 cm sized swelling of the left leg. Histopathological examination revealed embryonal RMS. Testing for tumour protein (TP53) variant by DNA sequence analysis was positive; however; FISH analysis was negative. After chemotherapy and local radiotherapy, the patient is in good condition without tumour recurrence. Only about one-third of these tumours have a variant of TP53. This status also applies to other genetic variants related to cancer. However, a significant association of malignancies strongly suggests a problem in tumour suppressor genes or new variants. Another suppressor gene that is yet unidentified can also be present and effective in this locus. The occurrence of ACC as a part of a syndrome and positive family history of malignancies in patients are clinically important. These patients and their families should be scanned for genetic abnormalities. The patient with ACC should be followed-up carefully for other tumours to detect malignancy early.
    Keywords:  Child; TP53; adrenocortical carcinoma; oncocytic variant; rhabdomyosarcoma
    DOI:  https://doi.org/10.4274/jcrpe.galenos.2020.2020.0060
  18. Nat Rev Cancer. 2020 Jun 17.
    Germline control of anti-tumour immunity.
    Harjes U.
      
    DOI:  https://doi.org/10.1038/s41568-020-0282-x
  19. Oncotarget. 2020 Jun 02. 11(22): 2061-2073
    Hereditary pancreatitis model by blastocyst complementation in mouse.
    Asai A, Konno M, Kawamoto K, Isotani A, Mori M, Eguchi H, Doki Y, Arai T, Ishii H.
      The application of pluripotent stem cells is expected to contribute to the elucidation of unknown mechanism of human diseases. However, in vitro induction of organ-specific cells, such as pancreas and liver, is still difficult and the reproduction of their disorders in a model has been unfeasible. To study the mechanism of human hereditary pancreatitis (HP), we here performed the blastocyst complementation (BC) method. In the BC method, mouse embryonic stem (ES) cells harboring CRISPR/CAS9-mediated mutations in the Prss1 gene were injected into blastocysts with deficient Pdx1 gene, which is a critical transcription factor in the development of pancreas. The results showed that trypsin was activated extremely in Prss1-mutant mice. This implied that the mouse phenotype mimics that of human HP and that the BC method was useful for the reproduction and study of pancreatic disorders. The present study opens the possibility of investigating uncharacterized human diseases by utilizing the BC method.
    Keywords:  PRSS1; blastocyst complementation; disease-specific pluripotent stem cells; hereditary pancreatitis
    DOI:  https://doi.org/10.18632/oncotarget.27595
  20. Cancers (Basel). 2020 Jun 12. pii: E1550. [Epub ahead of print]12(6):
    Clinical Applications of Molecular Biomarkers in Prostate Cancer.
    Couñago F, López-Campos F, Díaz-Gavela AA, Almagro E, Fenández-Pascual E, Henríquez I, Lozano R, Linares Espinós E, Gómez-Iturriaga A, de Velasco G, Quintana Franco LM, Rodríguez-Melcón I, López-Torrecilla J, Spratt DE, Guerrero LL, Martínez-Salamanca JI, Del Cerro E.
      There is clinically relevant molecular heterogeneity in prostate cancer (PCa), but this biological diversity has had only a minimal impact on clinical practice. Treatment outcomes in patients with localised PCa are often highly variable, even among patients stratified to the same risk group or disease state based on standard clinical and pathological parameters. In recent years, the development of gene panels has provided valuable data on the differential expression of genes in patients with PCa. Nevertheless, there is an urgent need to identify and validate prognostic and predictive biomarkers that can be applied across clinical scenarios, ranging from localised disease to metastatic castration-resistant PCa. The availability of such tools would allow for precision medicine to finally reach PCa patients. In this review, we evaluate current data on molecular biomarkers for PCa, with an emphasis on the biomarkers and gene panels with the most robust evidence to support their application in routine clinical practice.
    Keywords:  DNA repair; biomarkers; gene panels; genetic testing; germline mutation; precision medicine; prostate cancer; prostate genomics
    DOI:  https://doi.org/10.3390/cancers12061550
  21. JAMA Ophthalmol. 2020 Jun 18.
    Association Between Genotype and Phenotype in Consecutive Unrelated Individuals With Retinoblastoma.
    Salviat F, Gauthier-Villars M, Carton M, Cassoux N, Lumbroso-Le Rouic L, Dehainault C, Levy C, Golmard L, Aerts I, Doz F, Bonnet-Serrano F, Hayek S, Savignoni A, Stoppa-Lyonnet D, Houdayer C.
      Importance: Retinoblastoma (RB) is the most common pediatric intraocular neoplasm. RB is a complex model in which atypical pathogenic variants, modifier genes, imprinting, and mosaicism are known to be associated with the phenotype. In-depth understanding of RB therefore requires large genotype-phenotype studies.Objective: To assess the association between genotype and phenotype in patients with RB.
    Design, Setting, and Participants: This single-center, retrospective cohort study, conducted from January 1, 2000, to September 30, 2017, enrolled 1404 consecutive ascertained patients with RB who consulted an oncogeneticist. All patients had their genotype and phenotype recorded. Statistical analysis was performed from July 1, 2018, to December 31, 2018.
    Main Outcomes and Measures: RB1 germline and somatic pathogenic variant types, family history, and disease presentation characteristics (ie, age at diagnosis, sex, laterality, and International Intraocular Retinoblastoma Classification group).
    Results: Among 1404 patients with RB (734 [52.3%] female; mean [SD] age, 20.2 [21.2] months), 866 cases (61.7%) were unilateral and 538 cases (38.3%) were bilateral. Loss of function variants were found throughout the coding sequence, with 259 of 272 (95.2%) somatic pathogenic variants and 537 of 606 (88.6%) germline pathogenic variants (difference, 6.6%; 95% CI, 4.0%-9.2%; P < .001) after excluding tumor-specific pathogenic variants (ie, promoter methylation and loss of heterozygosity); a novel low-penetrance region was identified in exon 24. Compared with germline pathogenic variants estimated to retain RB protein expression, germline pathogenic variants estimated to abrogate RB protein expression were associated with an earlier mean (SD) age at diagnosis (12.3 [11.3] months among 457 patients vs 16.3 [13.2] months among 55 patients; difference, 4 months; 95% CI, 1.9-6.1 months; P = .01), more frequent bilateral involvement (84.2% among 452 patients vs 65.2% among 45 patients; difference, 18.9%; 95% CI, 14.5%-23.3%; P < .001), and more advanced International Intraocular Retinoblastoma Classification group (85.3% among 339 patients vs 73.9% among 34 patients; difference: 11.4%; 95% CI, 6.5%-16.3%; P = .047). Among the 765 nongermline carriers of an RB1 pathogenic variant, most were female (419 females [54.8%] vs 346 males [45.2%]; P = .008), and males were more likely to have bilateral RB (23 males [71.4%] vs 12 females [34.3%]; P = .01).
    Conclusions and Relevance: These results suggest that RB risk is associated with the germline pathogenic variant and with maintenance of RB protein and that there is a sex-linked mechanism for nongermline carriers.
    DOI:  https://doi.org/10.1001/jamaophthalmol.2020.2100
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