bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021–09–26
fiveteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Case Report: Identification of a Novel Pathogenic Germline TP53 Variant in a Family With Li-Fraumeni Syndrome.
  2. CDH1 germline mutations in a Chinese cohort with hereditary diffuse gastric cancer.
  3. MCM9 is associated with germline predisposition to early-onset cancer-clinical evidence.
  4. Germline mutations in a DNA repair pathway are associated with familial colorectal cancer.
  5. Biological Role and Clinical Implications of microRNAs in BRCA Mutation Carriers.
  6. RNF43 Pathogenic Germline Variant in a Family with Colorectal Cancer.
  7. Oncology clinic-based germline genetic testing for exocrine pancreatic cancer enables timely return of results and unveils low uptake of cascade testing.
  8. A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer.
  9. SDHC phaeochromocytoma and paraganglioma: A UK-wide case series.
  10. Germline mutation analyses of malignant ground glass opacity nodules in non-smoking lung adenocarcinoma patients.
  11. A BRCA1 coiled-coil domain variant disrupting PALB2 interaction promotes the development of mammary tumors and confers a targetable defect in homologous recombination repair.
  12. Two cases of non-small cell lung cancer patients with somatic or germline EGFR R776H mutation.
  13. Soma-to-germline RNA communication.
  14. Ovarian germ cell tumor/mastocytosis with KIT mutation: a unique clinicopathological entity.
  15. Papillary thyroid cancer in a patient with germline CHEK2 mutation: a case report.
  1. Front Genet. 2021 ;12 734809
    Case Report: Identification of a Novel Pathogenic Germline TP53 Variant in a Family With Li-Fraumeni Syndrome.
    Francesco Paduano, Fernanda Fabiani, Emma Colao, Francesco Trapasso, Nicola Perrotti, Vito Barbieri, Francesco Baudi, Rodolfo Iuliano.
      Li-Fraumeni syndrome (LFS) is an inherited autosomal dominant disease characterized by a predisposition to many cancers. Germline pathogenic variants in TP53 are primarily responsible for LFS. By performing a targeted sequencing panel in a proband with liver carcinoma having a deceased son affected by osteosarcoma, we found the novel heterozygous frameshift variant c.645del (p.Ser215Argfs*32) in the TP53 gene. This variant co-segregated with typical LFS cancers in the family pedigree, consistent with the pathogenicity of this novel and previously undescribed TP53 variant.
    Keywords:  LFS cancers; Li-Fraumeni; TP53; germline TP53 variant; targeted sequencing
    DOI:  https://doi.org/10.3389/fgene.2021.734809
  2. J Cancer Res Clin Oncol. 2021 Sep 18.
    CDH1 germline mutations in a Chinese cohort with hereditary diffuse gastric cancer.
    Zhiwen Pan, Zhixuan Fu, Cong Luo, Yejiang Bao, Mingli Wang, Wenming Cao, Xiaohong Xu.
       PURPOSE: Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer (HDGC) and have been identified in multiple ethnicities. However, CDH1 germline mutations have seldom been documented in Chinese patients with HDGC, and their frequency remains unclear. Here, we aimed to examine the frequency of CDH1 germline mutations in Chinese patients with HDGC. In total, 285 patients who met the International Gastric Cancer Linkage Consortium 2015 testing criteria of HDGC for CDH1 germline mutations were recruited.
    METHODS: All 16 CDH1 exons, including neighboring intronic sequences, were amplified using polymerase chain reaction and screened using Sanger sequencing. Variants were analyzed using Mutation Surveyor V4.0, SIFT, and PolyPhen-2 software.
    RESULTS: Three nonsense and nine missense CDH1 germline mutations were identified in 21 of 285 index cases (7.4%). Two CDH1 germline mutations, N405Y (Asn405Tyr) and W409X (Trp409Ter), were identified as new variants. In addition, up to 28.6% of CDH1 mutations in the 21 indicated patients were identified as c.1775G>C (E551Q). The frequency of CDH1 mutations was 6.5% (7/108) in HDGC and 7.9% (14/177) in early onset diffuse gastric cancer (EODGC). The mutation detection rates of CDH1 in males and females were 6.7% (4/60) and 8.5% (10/117) in EODGC and 4.6% (3/65) and 9.3% (4/43) in HDGC, respectively.
    CONCLUSION: These data reveal, for the first time, the type and frequency of CDH1 germline mutations in Chinese HDGC and demonstrate that germline CDH1 mutations are a noteworthy contributor to the high frequency of HDGC in Chinese.
    Keywords:  CDH1; E-cadherin; Germline mutation; Hereditary diffuse gastric cancer; Mutation screening
    DOI:  https://doi.org/10.1007/s00432-021-03775-4
  3. NPJ Genom Med. 2021 Sep 23. 6(1): 78
    MCM9 is associated with germline predisposition to early-onset cancer-clinical evidence.
    Yael Goldberg, Ola Aleme, Lilach Peled-Perets, Sergi Castellvi-Bel, Maartje Nielsen, Stavit A Shalev.
      Mutated MCM9 has been associated with primary ovarian insufficiency. Although MCM9 plays a role in genome maintenance and has been reported as a candidate gene in a few patients with inherited colorectal cancer (CRC), it has not been clearly established as a cancer predisposition gene. We re-evaluated family members with MCM9-associated fertility problems. The heterozygote parents had a few colonic polys. Three siblings had early-onset cancer: one had metastatic cervical cancer and two had early-onset CRC. Moreover, a review of the literature on MCM9 carriers revealed that of nine bi-allelic carriers reported, eight had early-onset cancer. We provide clinical evidence for MCM9 as a cancer germline predisposition gene associated with early-onset cancer and polyposis, mainly in a recessive inheritance pattern. These observations, coupled with the phenotype in knockout mice, suggest that diagnostic testing for polyposis, CRC, and infertility should include MCM9 analysis. Early screening protocols may be beneficial for carriers.
    DOI:  https://doi.org/10.1038/s41525-021-00242-4
  4. JCI Insight. 2021 Sep 22. pii: e148931. [Epub ahead of print]6(18):
    Germline mutations in a DNA repair pathway are associated with familial colorectal cancer.
    Pingping Xu, Danfeng Sun, Yaqi Gao, Yi Jiang, Ming Zhong, Gang Zhao, Jinxian Chen, Zheng Wang, Qiang Liu, Jie Hong, Haoyan Chen, Ying-Xuan Chen, Jing-Yuan Fang.
      Aiming to identify rare high-penetrance mutations in new genes for the underlying predisposition in familial colorectal cancer (CRC), we performed whole-exome sequencing in 24 familial CRCs. Mutations in genes that regulate DNA repair (RMI1, PALB2, FANCI) were identified that were related to the Fanconi anemia DNA repair pathway. In one pedigree, we found a nonsense mutation in CHEK2. CHEK2 played an essential role in cell cycle and DNA damage repair. Somatic mutation analysis in CHEK2 variant carriers showed mutations in TP53, APC, and FBXW7. Loss of heterozygosity was found in carcinoma of CHEK2 variant carrier, and IHC showed loss of Chk2 expression in cancer tissue. We identified a second variant in CHEK2 in 126 sporadic CRCs. A KO cellular model for CHEK2 (CHEK2KO) was generated by CRISPR/Cas9. Functional experiments demonstrated that CHEK2KO cells showed defective cell cycle arrest and apoptosis, as well as reduced p53 phosphorylation, upon DNA damage. We associated germline mutations in genes that regulate the DNA repair pathway with the development of CRC. We identified CHEK2 as a regulator of DNA damage response and perhaps as a gene involved in CRC germline predisposition. These findings link CRC predisposition to the DNA repair pathway, supporting the connection between genome integrity and cancer risk.
    Keywords:  Cancer; Cell cycle; DNA repair; Gastroenterology; Genetics
    DOI:  https://doi.org/10.1172/jci.insight.148931
  5. Front Oncol. 2021 ;11 700853
    Biological Role and Clinical Implications of microRNAs in BRCA Mutation Carriers.
    Chiara Tommasi, Benedetta Pellegrino, Daniela Boggiani, Angelica Sikokis, Maria Michiara, Vera Uliana, Beatrice Bortesi, Francesco Bonatti, Paola Mozzoni, Silvana Pinelli, Anna Squadrilli, Maria Vittoria Viani, Diana Cassi, Giuseppe Maglietta, Marco Meleti, Antonino Musolino.
      Women with pathogenic germline mutations in BRCA1 and BRCA2 genes have an increased risk to develop breast and ovarian cancer. There is, however, a high interpersonal variability in the modality and timing of tumor onset in those subjects, thus suggesting a potential role of other individual's genetic, epigenetic, and environmental risk factors in modulating the penetrance of BRCA mutations. MicroRNAs (miRNAs) are small noncoding RNAs that can modulate the expression of several genes involved in cancer initiation and progression. MiRNAs are dysregulated at all stages of breast cancer and although they are accessible and evaluable, a standardized method for miRNA assessment is needed to ensure comparable data analysis and accuracy of results. The aim of this review was to highlight the role of miRNAs as potential biological markers for BRCA mutation carriers. In particular, biological and clinical implications of a link between lifestyle and nutritional modifiable factors, miRNA expression and germline BRCA1 and BRCA2 mutations are discussed with the knowledge of the best available scientific evidence.
    Keywords:  BRCA1/2 mutations; breast cancer; breast cancer risk; miRNAs; nutriepigenomics
    DOI:  https://doi.org/10.3389/fonc.2021.700853
  6. Clin Genet. 2021 Sep 19.
    RNF43 Pathogenic Germline Variant in a Family with Colorectal Cancer.
    Reger R Mikaeel, Joanne P Young, Yun Li, Nicola K Poplawski, Eric Smith, Mehgan Horsnell, Wendy Uylaki, Yoko Tomita, Amanda R Townsend, Jinghua Feng, Arne Zibat, Silke Kaulfuß, Christian Müller, Gökhan Yigit, Bernd Wollnik, Hamish Scott, Lesley Rawlings, Henry Denae, Cassandra Vakulin, Andrew Dubowsky, Timothy J Price.
      The role of RNF43 as a cause of an inherited predisposition to colorectal cancer (CRC) is yet to be fully explored. This report presents our findings of two individuals with CRC from a single family carrying a likely-pathogenic inherited germline variant in RNF43. The proband (III:1) and the proband's mother (II:2) were diagnosed with mismatch repair proficient CRCs at the age of 50 years and 65 years, respectively. Both patients had BRAFV600E mutated colon tumours, indicating that the CRCs arose in sessile serrated lesions. The germline variant RNF43:c.375+1G>A was identified in both patients. RNA studies showed that this variant resulted in an aberrantly spliced transcript which was predicted to encode RNF43:p.Ala126Ilefs*50 resulting in premature termination of protein synthesis and was classified as a likely-pathogenic variant. Our report adds further evidence to the hereditary role of RNF43 as a tumour suppressor gene in colorectal tumorigenesis and supports the inclusion of RNF43 as a gene of interest in the investigation of CRC predispositions outside the setting of serrated polyposis.
    Keywords:  Colorectal cancer; Germline variant; RNA Splicing; RNF43; Serrated polyposis
    DOI:  https://doi.org/10.1111/cge.14064
  7. J Med Genet. 2021 Sep 23. pii: jmedgenet-2021-108054. [Epub ahead of print]
    Oncology clinic-based germline genetic testing for exocrine pancreatic cancer enables timely return of results and unveils low uptake of cascade testing.
    Yifan Wang, Bryn Golesworthy, Adeline Cuggia, Celine Domecq, Prosanto Chaudhury, Jeffrey Barkun, Peter Metrakos, Jamil Asselah, Nathaniel Bouganim, Zu-Hua Gao, George Chong, William D Foulkes, George Zogopoulos.
       BACKGROUND: Traditional medical genetics models are unable to meet the growing demand for germline genetic testing (GT) in patients with exocrine pancreatic cancer (PC). This study investigates the impact of an ambulatory oncology clinic-based GT model.
    METHODS: From 2012 to 2021, patients with PC were prospectively enrolled and considered for GT. Two chronological cohorts were compared: (1) the preuniversal genetic testing (pre-UGT) cohort, which received GT based on clinical criteria or family history; and (2) the post-UGT cohort, where an 86-gene panel was offered to all patients with PC.
    RESULTS: Of 847 eligible patients, 735 (86.8%) were enrolled (pre-UGT, n=579; post-UGT, n=156). A higher proportion of the post-UGT cohort received prospective GT (97.4% vs 58.5%, p<0.001). The rate of pathogenic germline alterations (PGA) across both cohorts was 9.9%, with 8.0% of PGAs in PC susceptibility genes. The post-UGT cohort had a higher prevalence of overall PGAs (17.2% vs 6.6%, p<0.001) and PGAs in PC susceptibility genes (11.9% vs 6.3%, p<0.001). The median turnaround time from enrolment to GT report was shorter in the post-UGT cohort (13 days vs 42 days, p<0.001). Probands with a PGA disclosed their GT results to 84% of their first-degree relatives (FDRs). However, only 31% of informed FDRs underwent GT, and the number of new cases per index case was 0.52.
    CONCLUSION: A point-of-care GT model is feasible and expedites access to GT for patients with PC. Strategies to increase the uptake of cascade testing are needed to maximise the clinical impact of an oncology clinic-based GT model.
    Keywords:  genetic carrier screening; genetic predisposition to disease; genetic testing; germ-line mutation; pancreatic diseases
    DOI:  https://doi.org/10.1136/jmedgenet-2021-108054
  8. Am J Hum Genet. 2021 Sep 18. pii: S0002-9297(21)00338-4. [Epub ahead of print]
    A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer.
    PanScan Consortium
      Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10-17, OR = 1.36, 95% CI = 1.31-1.40) and identified colocalization (PP = 0.87) with aberrant exon 5-7 CTRB2 splicing in pancreatic tissues (pGTEx = 1.40 × 10-69, βGTEx = 1.99; pLTG = 1.02 × 10-30, βLTG = 1.99). Imputation of a 584 bp structural variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (p = 2.83 × 10-16, OR = 1.36, 95% CI = 1.31-1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsinogen B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). We propose that intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein leads to ER stress and pancreatic inflammation, which may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles.
    Keywords:  genetics; pancreatic cancer; pancreatic enzymes; polymorphic variation; splicing QTL
    DOI:  https://doi.org/10.1016/j.ajhg.2021.09.002
  9. Clin Endocrinol (Oxf). 2021 Sep 24.
    SDHC phaeochromocytoma and paraganglioma: A UK-wide case series.
    Sophie T Williams, Prodromos Chatzikyriakou, Paul V Carroll, Barbara M McGowan, Anand Velusamy, Gemma White, Rupert Obholzer, Scott Akker, Nicola Tufton, Ruth T Casey, Eamonn R Maher, Soo-Mi Park, Mary Porteous, Rebecca Dyer, Tricia Tan, Florian Wernig, Angela F Brady, Monika Kosicka-Slawinska, Benjamin C Whitelaw, Huw Dorkins, Fiona Lalloo, Paul Brennan, Joseph Carlow, Richard Martin, Anna L Mitchell, Rachel Harrison, Lara Hawkes, John Newell-Price, Alan Kelsall, Rebecca Igbokwe, Julian Adlard, Schaida Schirwani, Rosemarie Davidson, Patrick J Morrison, Teng-Teng Chung, Christopher Bowles, Louise Izatt.
       OBJECTIVE: Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported.
    DESIGN: This retrospective case series collated data from 18 UK Genetics and Endocrinology departments.
    PATIENTS: Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included.
    MEASUREMENTS: Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation.
    RESULTS: We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively.
    CONCLUSIONS: This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.
    Keywords:  gastrointestinal tumour; paraganglioma; phaeochromocytoma; rare diseases; succinate dehydrogenase
    DOI:  https://doi.org/10.1111/cen.14594
  10. PeerJ. 2021 ;9 e12048
    Germline mutation analyses of malignant ground glass opacity nodules in non-smoking lung adenocarcinoma patients.
    Wenjun Mao, Ruo Chen, Rongguo Lu, Shengfei Wang, Huizhu Song, Dan You, Feng Liu, Yijun He, Mingfeng Zheng.
       Background: Germline mutations play an important role in the pathogenesis of lung cancer. Nonetheless, research on malignant ground glass opacity (GGO) nodules is limited.
    Methods: A total of 13 participants with malignant GGO nodules were recruited in this study. Peripheral blood was used for exome sequencing, and germline mutations were analyzed using InterVar. The whole exome sequencing dataset was analyzed using a filtering strategy. KOBAS 3.0 was used to analyze KEGG pathway to further identify possible deleterious mutations.
    Results: There were seven potentially deleterious germline mutations. NM_001184790:exon8: c.C1070T in PARD3, NM_001170721:exon4:c.C392T in BCAR1 and NM_001127221:exon46: c.G6587A in CACNA1A were present in three cases each; rs756875895 frameshift in MAX, NM_005732: exon13:c.2165_2166insT in RAD50 and NM_001142316:exon2:c.G203C in LMO2, were present in two cases each; one variant was present in NOTCH3.
    Conclusions: Our results expand the germline mutation spectrum in malignant GGO nodules. Importantly, these findings will potentially help screen the high-risk population, guide their health management, and contribute to their clinical treatment and determination of prognosis.
    Keywords:  Germline mutation; Ground glass opacity; Lung adenocarcinoma; Non-smoking
    DOI:  https://doi.org/10.7717/peerj.12048
  11. Cancer Res. 2021 Sep 21. pii: canres.1415.2021. [Epub ahead of print]
    A BRCA1 coiled-coil domain variant disrupting PALB2 interaction promotes the development of mammary tumors and confers a targetable defect in homologous recombination repair.
    Emilia M Pulver, Chirantani Mukherjee, Gerarda van de Kamp, Stefan J Roobol, Magdalena B Rother, Hanneke van der Gulden, Roebi de Bruijn, Maria Valeria Lattanzio, Eline van der Burg, Anne Paulien Drenth, Nicole S Verkaik, Kerstin Hahn, Sjoerd Klarenbeek, Renske de Korte-Grimmerink, Marieke van de Ven, Colin E J Pritchard, Ivo J Huijbers, Bing Xia, Dik C van Gent, Jeroen Essers, Haico van Attikum, Arnab Ray Chaudhuri, Peter Bouwman, Jos Jonkers.
      The BRCA1 tumor suppressor gene encodes a multi-domain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks (DSB), which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathological features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR-incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1415
  12. Lung Cancer. 2021 May 31. pii: S0169-5002(21)00427-X. [Epub ahead of print]161 94-97
    Two cases of non-small cell lung cancer patients with somatic or germline EGFR R776H mutation.
    Tianxing Guo, Lihuan Zhu, Wujin Li, Rongjia Lin, Yun Ding, Qiaolin Kang, Lin Shao, Chanhe Li, Xiaojie Pan.
      The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has revolutionized the treatment for non-small cell lung cancer (NSCLC). Comprehensive genomic profiling for NSCLC enables clinicians to identify more uncommon genetic alterations in EGFR. It remains unclear whether patients with certain rare EGFR mutations can benefit from EGFR inhibitors. On the other hand, emerging evidence has also showed the involvement of inherited factors in lung cancer development. However, only few germline EGFR mutations have been reported, and their association with NSCLC familial risk remains ambiguous. Here, we report two cases of NSCLCs with uncommon EGFR mutation R776H. One patient carrying somatic EGFR R776H and L861Q was treated with afatinib and achieved a durable response. The other patient harbored a germline EGFR R776H and her son inherited the same germline R776H mutation whose CT examination showed multiple ground-glass nodules in both lungs requiring further follow-up and diagnosis. Our study demonstrated the responsiveness of compound R776H-L861Q mutations to afatinib. We also revealed the transmission of EGFR R776H and suggested it may confer the high susceptibility to lung cancer.
    Keywords:  Afatinib; EGFR R776H; Non-small cell lung cancer
    DOI:  https://doi.org/10.1016/j.lungcan.2021.05.036
  13. Nat Rev Genet. 2021 Sep 20.
    Soma-to-germline RNA communication.
    Colin C Conine, Oliver J Rando.
      More than a century ago, August Weissman defined a distinction between the germline (responsible for propagating heritable information from generation to generation) and the perishable soma. A central motivation for this distinction was to argue against the inheritance of acquired characters, as the germline was partly defined by its protection from external conditions. However, recent decades have seen an explosion of studies documenting the intergenerational and transgenerational effects of environmental conditions, forcing a re-evaluation of how external signals are sensed by, or communicated to, the germline epigenome. Here, motivated by the centrality of small RNAs in paradigms of epigenetic inheritance, we review across species the myriad examples of intercellular RNA trafficking from nurse cells or somatic tissues to developing gametes.
    DOI:  https://doi.org/10.1038/s41576-021-00412-1
  14. Genes Chromosomes Cancer. 2021 Sep 23.
    Ovarian germ cell tumor/mastocytosis with KIT mutation: a unique clinicopathological entity.
    Peifang Xiao, Ping Chen, Xingping Lang, Qi An, Chunxiao Yang, Si Chen, Kai Wang, Nan Chen, Yang Hao, Jingwen Ding, Zhiheng Li, Shaoyan Hu, Sheng Xiao.
      Most tumors are sporadic and originated from somatic mutations. Some rare germline mutations cause familial tumors, often involving multiple tissues or organs. Tumors from somatic mosaicism during embryonic development are extremely rare. We describe here a pediatric patient who developed both an ovarian germ cell tumor and systemic mastocytosis. Targeted DNA NGS analysis revealed similar genomic changes including the same KIT D816V mutation in both tissues, suggesting a common progenitor cancer cell. The KIT mutated cells are likely from early embryonic development during germ cell migration. A literature search found additional 8 similar cases. These diseases are characterized by pediatric-onset, all-female, neoplastic proliferation in both gonad and bone marrow, and a common oncogenic cause, i.e., KIT mutation, constituting a clinically and genetically homogenous disease entity. Importantly, the association of germ cell tumors with hematopoietic neoplasms suggests that the primordial germ cells are the primitive hematopoietic stem cells, a much-debated and unsettled question. This article is protected by copyright. All rights reserved.
    Keywords:  KIT; germ cell tumors; mastocytosis
    DOI:  https://doi.org/10.1002/gcc.23000
  15. Ann Endocrinol (Paris). 2021 Sep 20. pii: S0003-4266(21)01069-6. [Epub ahead of print]
    Papillary thyroid cancer in a patient with germline CHEK2 mutation: a case report.
    Tiago da Silva Santos, Nataliya Tkachenko, André Couto de Carvalho.
      
    DOI:  https://doi.org/10.1016/j.ando.2021.08.886
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