bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒12‒13
seventeen papers selected by
Joanna Zawacka-Pankau
University of Warsaw
  1. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants.
  2. SVA retrotransposon insertion in exon of MMR genes results in aberrant RNA splicing and causes Lynch syndrome.
  3. Exome sequencing identifies a recurrent variant in SERPINA3 associating with hereditary susceptibility to breast cancer.
  4. Molecular screening and clinicopathologic characteristics of Lynch-like syndrome in a Chinese colorectal cancer cohort.
  5. A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients.
  6. Simultaneous diagnosis of liver PEComa in a family with known Li-Fraumeni syndrome: a case report.
  7. Metachronous cutaneous squamous cell carcinoma in a young patient as the only presenting symptom to uncover Lynch syndrome with MLH1 Germline mutation.
  8. Somatic and germline analysis of a familial Rothmund-Thomson syndrome in two siblings with osteosarcoma.
  9. Novel Pathogenic Germline Variant of the Adenomatous Polyposis Coli (APC) Gene, p.S2627Gfs*12 Identified in a Mild Phenotype of APC-Associated Polyposis: A Case Report.
  10. Heritability of Low ER Staining/HER2-Breast Tumors: Are We Missing an Opportunity for Germline Testing?
  11. Germline variation networks in the PI3K/AKT pathway corresponding to familial high-incidence lung cancer pedigrees.
  12. Functional significance of germline EPAS1 variants.
  13. Acute Myeloid Leukemia Case Harboring Unusual FLT3 Variant: Somatic vs Germline?
  14. Functional characterisation guides classification of novel BAP1 germline variants.
  15. Five Italian Families with Two Mutations in BRCA Genes.
  16. Cancer Predisposition Syndromes Associated With Pediatric High-Grade Gliomas.
  17. Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy.
  1. Hum Mutat. 2020 Dec 10.
    Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants.
    Fortuno C, Lee K, Olivier M, Pesaran T, Mai PL, de Andrade KC, Attardi LD, Crowley S, Gareth Evans D, Feng BJ, Foreman AKM, Frone MN, Huether R, James PA, McGoldrick K, Mester J, Seifert BA, Slavin TP, Witkowski L, Zhang L, Plon SE, Spurdle AB, Savage SA, .
      Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome (LFS), a cancer predisposition disorder inherited in an autosomal dominant pattern associated with high risk of malignancy, including early onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for twenty ACMG/AMP criteria while nine were deemed not applicable. The original strength level for ten criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data amongst experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification. This article is protected by copyright. All rights reserved.
    Keywords:  TP53; cancer; pathogenic variant; variant curation
    DOI:  https://doi.org/10.1002/humu.24152
  2. Eur J Hum Genet. 2020 Dec 08.
    SVA retrotransposon insertion in exon of MMR genes results in aberrant RNA splicing and causes Lynch syndrome.
    Yamamoto G, Miyabe I, Tanaka K, Kakuta M, Watanabe M, Kawakami S, Ishida H, Akagi K.
      Lynch syndrome is an autosomal dominant hereditary cancer syndrome in which many cancers develop, the main one being colorectal cancer. Germline pathogenic variants in one of four mismatch repair (MMR) genes are known to be causative of this disease. Accurate diagnosis using genetic testing can greatly benefit the health of those affected. Recently, owing to the improvement of sequence techniques, complicated variants affecting the functions of MMR genes were discovered. In this study, we analyzed insertions of a retrotransposon-like sequence in exon 5 of the MSH6 gene and exon 3 of the MSH2 gene found in Japanese families suspected of having Lynch syndrome. Both of these insertions induced aberrant splicing, and these variants were successfully identified by mRNA sequencing or visual observation of mapping results, although a standard DNA-seq analysis pipeline failed to detect them. The insertion sequences were ~2.5 kbp in length and were found to have the structure of an SVA retrotransposon (SVA). One SVA sequence was not present in the hg19 or hg38 reference genome, but was in a Japanese-specific reference sequence (JRGv2). Our study illustrates the difficulties of identifying SVA insertions in disease genes, and that the possibility of polymorphic insertions should be considered when analyzing mobile elements.
    DOI:  https://doi.org/10.1038/s41431-020-00779-5
  3. Eur J Cancer. 2020 Dec 03. pii: S0959-8049(20)31319-8. [Epub ahead of print]143 46-51
    Exome sequencing identifies a recurrent variant in SERPINA3 associating with hereditary susceptibility to breast cancer.
    Koivuluoma S, Tervasmäki A, Kauppila S, Winqvist R, Kumpula T, Kuismin O, Moilanen J, Pylkäs K.
      BACKGROUND: Breast cancer is strongly influenced by hereditary risk factors. Yet, the known susceptibility genes and genomic loci explain only about half of the familial component of the disease. To identify novel breast cancer predisposing gene defects, here we have performed massive parallel sequencing for Northern Finnish breast cancer cases.METHODS: Ninety-eight breast cancer cases with indication of hereditary disease susceptibility were exome sequenced. Data filtering strategy focused on predictably deleterious rare variants that were still enriched in the sequenced cohort. Findings were confirmed with additional, geographically matched breast cancer cohorts.
    RESULTS: A recurrent heterozygous splice acceptor variant, c.918-1G>C, in SERPINA3, was identified, and it was significantly enriched both in the hereditary (6/201, 3.0%, p = 0.006, OR 5.1, 95% CI 1.7-14.8) and unselected breast cancer cohort (26/1569, 1.7%, p = 0.009, OR 2.8, 95% CI 1.3-6.2). SERPINA3 c.918-1G>C carriers were also significantly more likely to have a rare tumor subtype, medullary breast cancer, than the non-carriers (4/26, 15.4%, p = 0.000014, OR 42.9, 95% CI 11.7-157.1).
    CONCLUSION: These findings demonstrate that c.918-1G>C germline variant in SERPINA3 gene, encoding a member of the serine protease inhibitor class, is a novel breast cancer predisposing allele.
    Keywords:  Breast cancer; Exome sequencing; Founder variant; Hereditary predisposition; SERPINA3
    DOI:  https://doi.org/10.1016/j.ejca.2020.10.033
  4. Am J Cancer Res. 2020 ;10(11): 3920-3934
    Molecular screening and clinicopathologic characteristics of Lynch-like syndrome in a Chinese colorectal cancer cohort.
    Xu HX, Zhu P, Zheng YY, Zhang X, Chen YQ, Qiao LC, Zhang YF, Jiang F, Li YR, Chen HJ, Chen YG, Gu YF, Yang BL.
      Colorectal cancers (CRC) with microsatellite instability (MSI) or mismatch repair-deficiency (dMMR), but without detectable MMR germline mutations are termed Lynch-like syndrome (LLS). We assess the clinicopathologic and molecular characteristics of LLS tumors and the proportion in LLS, which remain poorly investigated in China. We enrolled 404 CRC patients with surgery in our institution from 2014 to 2018. LLS tumors were detected by a molecular stratification based on MMR protein expression, MLH1 methylation and MMR gene mutation. LLS tumors were profiled for germline mutations in 425 cancer-relevant genes. Among 42 MMR-deficient tumors, 7 (16.7%) were attributable to MLH1 methylation and 7 (16.7%) to germline mutations, leaving 28 LLS cases (66.6%). LLS tumors were diagnosed at a mean age of 60.7 years, had an almost equivalent ratio among rectum, left colon and right colon, and had high rates of lymph node metastases (50%, 4/28 N2). Most MMR gene mutations (88.2%, 15/17) in LLS tumors were variants of unknown significance (VUS). Two novel frameshift mutations were detected in ATM and ARID1A, which are emerging as candidate responsible genes for LLS. In this study, 28 (66.6%) MMRd tumors were classified as LLS, which were significantly higher than reports of western countries. LLS tumors were more likely to carry lymph node metastases. However, it's hard to differentiated LLS tumors from LS through family history, tumor location, histological type of tumors, immunohistochemistry (IHC) for MMR proteins and MSI analysis.
    Keywords:  Chinese; Colorectal cancer; Lynch-like syndrome (LLS); microsatellite instability; molecular screening
  5. Clin Chem. 2020 Dec 06. pii: hvaa250. [Epub ahead of print]
    A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients.
    Feliubadaló L, Moles-Fernández A, Santamariña-Pena M, Sánchez AT, López-Novo A, Porras LM, Blanco A, Capellá G, de la Hoya M, Molina IJ, Osorio A, Pineda M, Rueda D, de la Cruz X, Diez O, Ruiz-Ponte C, Gutiérrez-Enríquez S, Vega A, Lázaro C.
      BACKGROUND: Gene panel testing by massive parallel sequencing has increased the diagnostic yield but also the number of variants of uncertain significance. Clinical interpretation of genomic data requires expertise for each gene and disease. Heterozygous ATM pathogenic variants increase the risk of cancer, particularly breast cancer. For this reason, ATM is included in most hereditary cancer panels. It is a large gene, showing a high number of variants, most of them of uncertain significance. Hence, we initiated a collaborative effort to improve and standardize variant classification for the ATM gene.METHODS: Six independent laboratories collected information from 766 ATM variant carriers harboring 283 different variants. Data were submitted in a consensus template form, variant nomenclature and clinical information were curated, and monthly team conferences were established to review and adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria to ATM, which were used to classify 50 representative variants.
    RESULTS: Amid 283 different variants, 99 appeared more than once, 35 had differences in classification among laboratories. Refinement of ACMG/AMP criteria to ATM involved specification for twenty-one criteria and adjustment of strength for fourteen others. Afterwards, 50 variants carried by 254 index cases were classified with the established framework resulting in a consensus classification for all of them and a reduction in the number of variants of uncertain significance from 58% to 42%.
    CONCLUSIONS: Our results highlight the relevance of data sharing and data curation by multidisciplinary experts to achieve improved variant classification that will eventually improve clinical management.
    Keywords:  (5): ATM; ACMG/AMP guidelines; Spanish database; hereditary cancer; variant classification
    DOI:  https://doi.org/10.1093/clinchem/hvaa250
  6. Clin Sarcoma Res. 2020 Nov 24. 10(1): 24
    Simultaneous diagnosis of liver PEComa in a family with known Li-Fraumeni syndrome: a case report.
    Galera López MDM, Márquez Rodas I, Agra Pujol C, García Pérez Á, Velasco Sánchez E, Álvarez Álvarez R.
      BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary disease. It is associated with the loss of function of the p53 protein and an increased risk of malignant tumor development at early age. The most frequently detected tumors include breast cancer, sarcomas, leukemia, brain tumors, and adrenocortical carcinomas. While sarcomas account for only 1% of solid tumors, they are more frequently detected in these families.CASE PRESENTATION: We report a simultaneous diagnosis of hepatic perivascular epithelioid cell tumor (PEComa), a very rare subtype of sarcoma, in two siblings with a LFS.
    CONCLUSIONS: The simultaneous diagnosis of PEComa in two siblings presented in this case allowed us to review the frequency of PEComa in this genetic syndrome previously reported, which was very little. Despite its rarity, PEComa must be considered in the differential diagnosis of new-onset liver lesions in patients who were previously diagnosed with LFS.
    Keywords:  Hepatic lesion; Li–Fraumeni syndrome; Perivascular epithelioid cell tumor; Sarcoma; p53
    DOI:  https://doi.org/10.1186/s13569-020-00143-7
  7. Hered Cancer Clin Pract. 2020 Nov 16. 18(1): 23
    Metachronous cutaneous squamous cell carcinoma in a young patient as the only presenting symptom to uncover Lynch syndrome with MLH1 Germline mutation.
    Khaddour K, Fields RC, Ansstas M, Rosman IS, Ansstas G.
      BACKGROUND: Cutaneous malignancies are rare complications of Lynch syndrome and can include Muir-Torre and Turcot syndromes that are associated with sebaceous gland tumors and keratoacanthomas. The incidence and clinical course of cutaneous squamous cell carcinoma have not been well documented in Lynch syndrome due to its rarity.CASE PRESENTATION: A 49-year male presented with an enlarging groin skin lesion that was biopsed and demonstrated cutaneous squamous cell carcinoma for which he underwent a surgical resection. The patient experienced later a recurrence of cutaneous squamous cell carcinoma around the resected margins. Next generation sequencing of tumor tissue revealed mutations in MSH6 and MLH1, in addition to high microsatellite instability. The patient underwent pembrolizumab treatment with complete resolution of the cutaneous lesion in the groin, but subsequently developed a new mass in the right antecubital fossa shortly after discontinuation of pembrolizumab. Repeat biopsy of the antecubital fossa lesion revealed a recurrence of cutaneous squamous cell carcinoma. Germline mutation testing revealed MLH1 mutation, compatible with Lynch syndrome, and the patient restarted pembrolizumab which was associated with a complete response. The patient was referred for genetic counseling and cancer screening.
    CONCLUSIONS: Cutaneous squamous cell carcinoma, although rare, can be the initial presenting symptom in patients with Lynch syndrome. This association has been described in patients with germline mutations in MLH1. Lynch syndrome should be considered when evaluating young patients presenting with recurrent cutaneous squamous cell carcinoma with positive family history of malignancy and/ or without any identifiable risk factors for skin cancers, including those with a durable and rapid response to immunotherapy.
    Keywords:  Cutaneous squamous cell carcinoma; Germline mutation; Lynch syndrome; MLH1; Microsatellite instability; Pembrolizumab
    DOI:  https://doi.org/10.1186/s13053-020-00155-w
  8. NPJ Genom Med. 2020 ;5 51
    Somatic and germline analysis of a familial Rothmund-Thomson syndrome in two siblings with osteosarcoma.
    Gutiérrez-Jimeno M, Panizo-Morgado E, Tamayo I, San Julián M, Catalán-Lambán A, Alonso MM, Patiño-García A.
      Rothmund-Thomson syndrome (RTS) is characterized by a rash that begins in the first few months of life and eventually develops into poikiloderma. Associated symptoms are alterations in the teeth, sparse hair, thin eyebrows, lack of eyelashes, low stature, bone abnormalities, hematological illnesses, gastrointestinal disease, malnutrition, cataracts, and predisposition to cancer, principally to bone tumors and skin cancer. Diagnostic certitude is provided by a genetic study involving detection of pathogenic variants of the RECQL4 gene. We hereby present a familiar case of RTS in two siblings from a Portuguese family, both diagnosed with osteosarcoma. Genomic analysis (203 genes) of both tumors as well as germline analysis of the RECQL4 gene, thus confirming the syndrome in the family, have been performed. The relevance of clinical recognition of the hallmarks of the disease and thus early diagnosis with early intervention is highlighted.
    Keywords:  Bone cancer; Cancer genomics; Molecular medicine
    DOI:  https://doi.org/10.1038/s41525-020-00160-x
  9. Am J Case Rep. 2020 Dec 11. 21 e927293
    Novel Pathogenic Germline Variant of the Adenomatous Polyposis Coli (APC) Gene, p.S2627Gfs*12 Identified in a Mild Phenotype of APC-Associated Polyposis: A Case Report.
    Koeller DR, Schwartz A, Manning DK, Dong F, Lindeman NI, Garber JE, Ghazani AA.
      BACKGROUND The diagnoses of adenomatous polyposis coli (APC)-associated polyposis conditions are typically based on suggestive personal features and/or family history, and the identification of a pathogenic variant in the APC gene. However, with large-scale genome sequencing, it is now possible to identify pathogenic variants before or even without the presentation of the expected clinical features. This case describes a novel pathogenic APC variant. CASE REPORT We report the unexpected identification of a rare, pathogenic germline APC variant, p.S2627Gfs*12 in an 80-year-old man with a diagnosis of renal cell carcinoma, without any family history of APC-associated polyposis or personal history of colorectal cancer. After the identification of the APC variant, a review of the patient's medical records showed a personal history of 15 adenomatous polyps over a decade ago, with no follow-up genetic testing at the time. CONCLUSIONS This novel APC variant has not been characterized to date. The presence of the APC-p.S2627Gfs*12 variant in this patient led to the recommendation of additional cascade genetic testing and surveillance measures for any family members who tested positive for this variant. This report highlights the broad spectrum of the APC-associated polyposis features, and a mild phenotype associated with the pathogenic APC p.S2627Gfs*12 variant.
    DOI:  https://doi.org/10.12659/AJCR.927293
  10. Genes (Basel). 2020 Dec 08. pii: E1469. [Epub ahead of print]11(12):
    Heritability of Low ER Staining/HER2-Breast Tumors: Are We Missing an Opportunity for Germline Testing?
    Lovejoy LA, Turner CE, Wells JM, Shriver CD, Ellsworth RE.
      In 2010, the genetic testing criteria was changed to allow women diagnosed ≤ 60 years old with triple negative breast cancer (TNBC) to undergo germline testing. In the same year, estrogen receptor (ER) positivity was defined as having ≥1% ER staining cells. While tumors with 1-10% ER staining cells and HER2 negative (HER2-) status share characteristics with TNBC, the utility of germline testing in women with ER low positive/HER2- (ERLP/HER2-) tumors is not well-understood. To this end, all patients with hormone receptor positive staining cells ≤ 10% and negative HER2 status were identified. Clinical genetic test results were extracted for patients who underwent testing. Panel testing was performed for those women who had genomic DNA available for research purposes. ERLP/HER2-tumors constituted 2.7% of all tumors in the database. Patients did not differ significantly from those with TNBC by age at diagnosis, ethnicity, family history or tumor size, stage or grade (p > 0.05). Mutation frequency did not differ significantly (p = 0.757) between groups (ERLP/HER2- 16.1%; TNBC 16.7%). Hereditary forms of breast cancer were similar in both ERLP/HER2- and TNBC, thus current guidelines may result in the under testing of women with low ER tumors, resulting in missed opportunities to improve patient management.
    Keywords:  ASCO/CAP guidelines; ER low positive; breast cancer; genetic testing
    DOI:  https://doi.org/10.3390/genes11121469
  11. BMC Cancer. 2020 Dec 09. 20(1): 1209
    Germline variation networks in the PI3K/AKT pathway corresponding to familial high-incidence lung cancer pedigrees.
    Lin H, Zhang G, Zhang XC, Lian XL, Zhong WZ, Su J, Chen SL, Wu YL.
      BACKGROUND: There were scarcely germline variants of familial lung cancer (LC) identified. We conducted an study with whole-exome sequencing of pedigrees with familial lung cancer to analyze the potential genetic susceptibility.METHODS: Probands with the highest hereditary background were identified by our large-scale epidemiological study and five ones were enrolled as a learning set. The germline SNPs (single-nucleotide polymorphisms) of other five similar probands, four healthy individuals in the formerly pedigrees and three patients with sporadic LC were used as a validation set, controlled by three healthy individuals without family history of any cancer. The network of mutated genes was generated using STRING-DB and visualized using Cytoscape.
    RESULTS: Specific and shared somatic mutations and germline SNPs were not the shared cause of familial lung cancer. However, individual germline SNPs showed distinct protein-protein interaction network patterns in probands versus healthy individuals and patients with sporadic lung cancer. SNP-containing genes were enriched in the PI3K/AKT pathway. These results were validated in the validation set. Furthermore, patients with familial lung cancer were distinguished by many germline variations in the PI3K/AKT pathway by a simple SVM classification method. It is worth emphasizing that one person with many germline variations in the PI3K/AKT pathway developed lung cancer during follow-up.
    CONCLUSIONS: The phenomenon that the enrichments of germline SNPs in the PI3K/AKT pathway might be a major predictor of familial susceptibility to lung cancer.
    Keywords:  Familial lung cancer; Germline variation networks; PI3K/AKT pathway; Whole-exome sequencing
    DOI:  https://doi.org/10.1186/s12885-020-07528-3
  12. Endocr Relat Cancer. 2020 Dec 01. pii: ERC-20-0280.R1. [Epub ahead of print]
    Functional significance of germline EPAS1 variants.
    Dwight T, Kim E, Bastard K, Benn DE, Eisenhofer G, Richter S, Mannelli M, Rapizzi E, Prejbisz A, Peczkowska M, Pacak K, Clifton-Bligh R.
      Mosaic or somatic EPAS1 mutations are associated with a range of phenotypes including pheochromocytoma and/or paraganglioma (PPGL), polycythaemia and somatostatinoma. The pathogenic potential of germline EPAS1 variants however is not well understood. We report a number of germline EPAS1 variants occurring in patients with PPGL, including a novel variant c.739C>A (p.Arg247Ser); a previously described variant c.1121T>A (p.Phe374Tyr); several rare variants, c.581A>G (p.His194Arg), c.2353C>A (p.Pro785Thr) and c.2365A>G (p.Ile789Val); and a common variant c.2296A>C (p.Thr766Pro). We performed detailed functional studies to understand their pathogenic role in PPGL. In transient transfection studies, EPAS1/HIF-2α p.Arg247Ser, p.Phe374Tyr and p.Pro785Thr were all stable in normoxia. In co-immunoprecipitation assays, only the novel variant p.Arg247Ser showed diminished interaction with pVHL. A direct interaction between HIF-2α Arg247 and pVHL was confirmed in structural models. Transactivation was assessed by means of a HRE-containing reporter gene in transiently transfected cells, and significantly higher reporter activity was only observed with EPAS1/HIF-2α p.Phe374Tyr and p.Pro785Thr. In conclusion, three germline EPAS1 variants (c.739C>A (p.Arg247Ser), c.1121T>A (p.Phe374Tyr) and c.2353C>A (p.Pro785Thr)) all have some functional features in common with somatic activating mutations. Our findings suggest that these three germline variants are hypermorphic alleles that may act as modifiers to the expression of PPGLs.
    DOI:  https://doi.org/10.1530/ERC-20-0280
  13. Lab Med. 2020 Dec 07. pii: lmaa080. [Epub ahead of print]
    Acute Myeloid Leukemia Case Harboring Unusual FLT3 Variant: Somatic vs Germline?
    Singh N, Morlote D, Vnencak-Jones C, Papadantonakis N, Harada S.
      FLT3 mutations are considered a prognostic and predictive marker. Here we report on a patient with a rare FLT3 germline variant in the context of relapsed acute myeloid leukemia (AML). A female patient aged 57 years presented with AML with mutations in the IDH2, ASXL1, and DNMT3A genes. She underwent allogenic hematopoietic stem cell transplant but relapsed 2 years posttransplant. Targeted next generation sequencing identified a new missense variant in the FLT3 tyrosine kinase domain c.2440G > T (p.A814S). The treating team considered the possibility of patient eligibility for an FLT3 inhibitor. Because both somatic and germline mutations can be identified in tumor tissue with high-throughput sequencing, it becomes important to distinguish the origin of these alterations when possible-especially, in this challenging case, to define the treatment modality. Simultaneous tumor/germline sequencing allows for the identification of rare germline mutations and may help in determining their significance in the pathogenesis of disease.
    Keywords:   FLT3 ; Cytogenetically normal (CN)-AML; Hematopathology; Highthroughput sequencing; Molecular pathology; Somatic vs Germline alterations/mutations
    DOI:  https://doi.org/10.1093/labmed/lmaa080
  14. NPJ Genom Med. 2020 Nov 19. 5(1): 50
    Functional characterisation guides classification of novel BAP1 germline variants.
    Hong JH, Chong ST, Lee PH, Tan J, Heng HL, Ishak NDB, Chan SH, Teh BT, Ngeow J.
      We have identified six patients harbouring distinct germline BAP1 mutations. In this study, we functionally characterise known BAP1 pathogenic and likely benign germline variants out of these six patients to aid in the evaluation and classification of unknown BAP1 germline variants. We found that pathogenic germline variants tend to encode truncated proteins, show diminished expression of epithelial-mesenchymal transition (EMT) markers, are localised in the cytosol and have reduced deubiquitinase capabilities. We show that these functional assays are useful for BAP1 variant curation and may be added in the American College of Medical Genetics and Genomics (ACMG) criteria for BAP1 variant classification. This will allow clinicians to distinguish between BAP1 pathogenic and likely benign variants reliably and may aid to quickly benchmark newly identified BAP1 germline variants. Classification of novel BAP1 germline variants allows clinicians to inform predisposed patients and relevant family members regarding potential cancer risks, with appropriate clinical interventions implemented if required.
    DOI:  https://doi.org/10.1038/s41525-020-00157-6
  15. Genes (Basel). 2020 Dec 03. pii: E1451. [Epub ahead of print]11(12):
    Five Italian Families with Two Mutations in BRCA Genes.
    Vietri MT, Caliendo G, D'Elia G, Resse M, Casamassimi A, Minucci PB, Dello Ioio C, Cioffi M, Molinari AM.
      Double heterozygosity (DH) in BRCA1 and BRCA2 genes and double mutation (DM) in BRCA1 or BRCA2 are extremely rare events in the general population, and few cases have been reported worldwide so far. Here, we describe five probands, all women, with breast and/or ovarian cancer and their families. Particularly, we identified two probands with DH in the BRCA1/2 genes with a frequency of 0.3% and three probands with DM in the BRCA2 gene with a frequency of 0.5%. The DH BRCA1 c.547+2T>A (IVS8+2T>A)/BRCA2 c.2830A>T (p.Lys944Ter) and BRCA1 c.3752_3755GTCT (p.Ser1253fs)/BRCA2 c.425+2T>C (IVS4+2T>C) have not been described together so far. The DM in BRCA2, c.631G>A (p.Val211Ile) and c.7008-2A>T (IVS13-2A>T), found in three unrelated probands, was previously reported in further unrelated patients. Due to its peculiarity, it is likely that both pathogenic variants descend from a common ancestor and, therefore, are founder mutations. Interestingly, analyzing the tumor types occurring in DH and DM families, we observed ovarian cancer only in DH families, probably due to the presence in DH patients of BRCA1 pathogenic variants, which predispose one more to ovarian cancer onset. Furthermore, male breast cancer and pancreatic cancer ensued in families with DM but not with DH. These data confirm that BRCA2 pathogenic variants have greater penetrance to develop breast cancer in men and are associated with an increased risk of pancreatic cancer.
    Keywords:  BRCA1; BRCA2; double heterozygosity (DH); double mutations (DM); hereditary breast and ovarian cancer
    DOI:  https://doi.org/10.3390/genes11121451
  16. Front Pediatr. 2020 ;8 561487
    Cancer Predisposition Syndromes Associated With Pediatric High-Grade Gliomas.
    Ceglie G, Del Baldo G, Agolini E, Rinelli M, Cacchione A, Del Bufalo F, Vinci M, Carta R, Boccuto L, Miele E, Mastronuzzi A, Locatelli F, Carai A.
      Pediatric High-Grade Gliomas (pHGG) are among the deadliest childhood brain tumors and can be associated with an underlying cancer predisposing syndrome. The thorough understanding of these syndromes can aid the clinician in their prompt recognition, leading to an informed genetic counseling for families and to a wider understanding of a specific genetic landscape of the tumor for target therapies. In this review, we summarize the main pHGG-associated cancer predisposing conditions, providing a guide for suspecting these syndromes and referring for genetic counseling.
    Keywords:  brain tumors; cancer predisposition; genetics of cancer; high grade gliomas; pediatric neuro- oncology
    DOI:  https://doi.org/10.3389/fped.2020.561487
  17. Lung Cancer. 2020 Dec 03. pii: S0169-5002(20)30718-2. [Epub ahead of print]151 39-43
    Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy.
    Li X, Zhang D, Li B, Zou B, Wang S, Fan B, Li W, Yu J, Wang L.
      INTRODUCTION: B-cell lymphoma 2-like 11 (BCL-2-like 11, BCL2L11, also known as BIM) deletion polymorphism (BIM-del) has been associated with resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), and is a poor prognostic factor for EGFR-mutant non-small-cell lung cancer (NSCLC) patients. Nevertheless, the impact of BIM-del in advanced NSCLC patients treated with the third-generation EGFR-TKI osimertinib remains undetermined. This study aims to evaluate the relationship between BIM-del and therapeutic efficacy of osimertinib in pretreated NSCLC patients.METHODS: Patients subjected to EGFR T790 M detection and prior osimertinib treatment between December 2015 and December 2019 in our hospital were enrolled in this study. Peripheral blood samples from these patients were collected to detect BIM-del by polymerase chain reaction. Cox proportional hazards models were used to analyze the clinical outcomes of patients with and without BIM-del.
    RESULTS: In total, 152 Chinese Han NSCLC patients-including 143 T790M-positive and nine T790M-negative patients-were enrolled. BIM-del was detected in only 17.5 % of T790M-positive patients (25/143). The majority of patients were aged <65 years (81.8 %, 117/143), were female (58.7 %, 84/143), were non-smokers (82.5 %, 118/143), had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (88.8 %, 129/143), and exhibited metastases in the central nervous system (CNS) (54.5 %, 78/143). There were no associations between the BIM-del and clinical characteristics (including age, sex, histology, smoking status, stage, ECOG PS score, and CNS metastases). Patients with BIM-del had a poorer objective response rate than those without (28.0 % versus 52.5 %, p = 0.026). Besides, BIM-del was associated with a significantly shorter progression-free survival (PFS) and a moderately shorter overall survival (OS) (8.3 versus 10.5 months, p = 0.031 and 15.9 versus 25.2 months, p = 0.1, respectively). Multivariate analysis indicated that BIM-del was an independent prognostic factor for PFS but not for OS in EGFR T790 M NSCLC patients.
    CONCLUSIONS: BIM-del is associated with poor clinical responses and outcomes, and might be a negative predictive and prognostic biomarker in EGFR T790 M NSCLC patients with osimertinib treatment.
    Keywords:  BIM deletion polymorphism; Epidermal growth factor receptor mutation; Non-small-cell lung cancer; Osimertinib
    DOI:  https://doi.org/10.1016/j.lungcan.2020.12.002
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