bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒10‒17
fourteen papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. Medical guidelines for Li-Fraumeni syndrome 2019, version 1.1.
  2. Genetic features and clinical outcomes of patients with isolated and comutated DDX41-mutated myeloid neoplasms.
  3. Hereditary hemochromatosis and JAK2-positive polycythemia vera.
  4. Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing.
  5. Germline mutations among Polish patients with acute myeloid leukemia.
  6. Concurrent pathogenic variations in patients with hereditary cancer syndromes.
  7. Pathogenicity of VHL variants in families with non-syndromic von Hippel-Lindau phenotypes: An integrated evaluation of germline and somatic genomic results.
  8. Association Between Hereditary Lobular Breast Cancer Due to CDH1 Variants and Gastric Cancer Risk.
  9. Germline RAD51B variants confer susceptibility to breast and ovarian cancers deficient in homologous recombination.
  10. Uptake and timing of bilateral and contralateral risk-reducing mastectomy in women with Li-Fraumeni syndrome.
  11. Identification of novel RB1 genetic variants in Retinoblastoma patients and their impact on clinical outcome.
  12. Recurrent Germline Mutations of CHEK2 as a New Susceptibility Gene in Patients with Pheochromocytomas and Paragangliomas.
  13. Identification of a novel pathogenic variant in PALB2 and BARD1 genes by a multigene sequencing panel in triple negative breast cancer in Morocco.
  14. Preexisting TP53-Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients With High-grade Ovarian Cancer Treated With Rucaparib.
  1. Int J Clin Oncol. 2021 Oct 11.
    Medical guidelines for Li-Fraumeni syndrome 2019, version 1.1.
    Tadashi Kumamoto, Fumito Yamazaki, Yoshiko Nakano, Chieko Tamura, Shimon Tashiro, Hiroyoshi Hattori, Akira Nakagawara, Yukiko Tsunematsu.
      Li-Fraumeni syndrome (LFS) is a hereditary tumor that exhibits autosomal dominant inheritance. LFS develops in individuals with a pathogenic germline variant of the cancer-suppressor gene, TP53 (individuals with TP53 pathogenic variant). The number of individuals with TP53 pathogenic variant among the general population is said to be 1 in 500 to 20,000. Meanwhile, it is found in 1.6% (median value, range of 0-6.7%) of patients with pediatric cancer and 0.2% of adult patients with cancer. LFS is diagnosed by the presence of germline TP53 pathogenic variants. However, patients can still be diagnosed with LFS even in the absence of a TP53 pathogenic variant if the familial history of cancers fit the classic LFS diagnostic criteria. It is recommended that TP53 genetic testing be promptly performed if LFS is suspected. Chompret criteria are widely used for the TP53 genetic test. However, as there are a certain number of cases of LFS that do not fit the criteria, if LFS is suspected, TP53 genetic testing should be performed regardless of the criteria. The probability of individuals with TP53 pathogenic variant developing cancer in their lifetime (penetrance) is 75% for men and almost 100% for women. The LFS core tumors (breast cancer, osteosarcoma, soft tissue sarcoma, brain tumor, and adrenocortical cancer) constitute the majority of cases; however, various types of cancers, such as hematological malignancy, epithelial cancer, and pediatric cancers, such as neuroblastoma, can also develop. Furthermore, approximately half of the cases develop simultaneous or metachronous multiple cancers. The types of TP53 pathogenic variants and factors that modify the functions of TP53 have an impact on the clinical presentation, although there are currently no definitive findings. There is currently no cancer preventive agent for individuals with TP53 pathogenic variant. Surgical treatments, such as risk-reducing bilateral mastectomy warrant further investigation. Theoretically, exposure to radiation could induce the onset of secondary cancer; therefore, imaging and treatments that use radiation should be avoided as much as possible. As a method to follow-up LFS, routine cancer surveillance comprising whole-body MRI scan, brain MRI scan, breast MRI scan, and abdominal ultrasonography (US) should be performed immediately after the diagnosis. However, the effectiveness of this surveillance is unknown, and there are problems, such as adverse events associated with a high rate of false positives, overdiagnosis, and sedation used during imaging as well as negative psychological impact. The detection rate of cancer through cancer surveillance is extremely high. Many cases are detected at an early stage, and treatments are low intensity; thus, cancer surveillance could contribute to an improvement in QOL, or at least, a reduction in complications associated with treatment. With the widespread use of genomic medicine, the diagnosis of LFS is unavoidable, and a comprehensive medical care system for LFS is necessary. Therefore, clinical trials that verify the feasibility and effectiveness of the program, comprising LFS registry, genetic counseling, and cancer surveillance, need to be prepared.
    Keywords:  Chompret criteria; Guideline; Li-Fraumeni syndrome; Surveillance; TP53
    DOI:  https://doi.org/10.1007/s10147-021-02011-w
  2. Blood Adv. 2021 Oct 13. pii: bloodadvances.2021005738. [Epub ahead of print]
    Genetic features and clinical outcomes of patients with isolated and comutated DDX41-mutated myeloid neoplasms.
    Hassan B Alkhateeb, Ahmad Nanaa, David S Viswanatha, James M Foran, Talha Badar, Lisa Sproat, Rong He, Phuong Nguyen, Dragan Jevremovic, Mohamad E Salama, Patricia Theresa Greipp, Naseema Gangat, Ayalew Tefferi, Mark R Litzow, Abhishek A Mangaonkar, Mithun Vinod Shah, Mrinal M Patnaik, Aref Al-Kali.
      DDX41 mutations (germline and somatic) are associated with late onset myelodysplastic syndromes/acute myeloid leukemia (MDS/AML). Myeloid neoplasms (MN) with germline predisposition was identified as a distinct category in the 2016 WHO classification revision, including MN with germline DDX41 mutation. We retrospectively analyzed the molecular findings and clinical characteristics of thirty-three DDX41-mutated (mDDX41) patients at our institution. We identified 14 distinct pathogenic DDX41 variants in 32 patients and 8 DDX41 variants of unknown significance (VUS) in 9 patients. Five (16%) patients had a second DDX41 somatic mutation p.R525H and 13 (40%) had at least one additional oncogenic co-mutation in other genes. The median age at the time of diagnosis was 66 years, with male predominance (72%) and the majority of patients had normal cytogenetics (91%). Two-year overall survival (OS) was 86% and 6 (21%) MDS/AML patients with relatively preserved hematopoietic function were observed without further intervention. In comparison to AML patients with prognostically more favorable subtypes [t(8;21), n=27 and inv(16), n=40], mDDX41 patients in our cohort showed similarly favorable OS. Our study highlights that mDDX41-MN patients often have an indolent course and mDDX41-AML has comparable OS to favorable-risk AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005738
  3. Clin Case Rep. 2021 Oct;9(10): e04907
    Hereditary hemochromatosis and JAK2-positive polycythemia vera.
    Ahmed Radwan, Ibraheem Othman.
      A 59-year-old man was diagnosed with JAK2-positive polycythemia vera. Subsequently, further laboratory testing revealed elevated ferritin and iron saturation. Genetic testing for HFE gene mutation screen revealed that the patient was positive for heterozygous C282Y mutation. The patient was ultimately diagnosed with both polycythemia vera and hereditary hemochromatosis.
    DOI:  https://doi.org/10.1002/ccr3.4907
  4. Eur Urol Oncol. 2021 Oct 12. pii: S2588-9311(21)00180-2. [Epub ahead of print]
    Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing.
    Hong Truong, Rania Sheikh, Ritesh Kotecha, Yelena Kemel, Peter A Reisz, Andrew T Lenis, Nikita N Mehta, Aliya Khurram, Vijai Joseph, Diana Mandelker, Alicia Latham, Ozge Ceyhan-Birsoy, Marc Ladanyi, Neil J Shah, Michael F Walsh, Martin H Voss, Chung-Han Lee, Paul Russo, Jonathan A Coleman, A Ari Hakimi, Darren R Feldman, Zsofia K Stadler, Mark E Robson, Robert J Motzer, Kenneth Offit, Sujata Patil, Maria I Carlo.
      BACKGROUND: Despite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking.OBJECTIVE: To define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing.
    DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020.
    OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher's exact or χ2 test).
    RESULTS AND LIMITATIONS: Of 232 patients with early-onset RCC, 50% had non-clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non-RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non-clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non-RCC-associated genes was 0% and 9.9%, respectively.
    CONCLUSIONS: Patients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing.
    PATIENT SUMMARY: In this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.
    Keywords:  Early-onset renal cell carcinoma; Genetic counseling; Germline sequencing; Hereditary renal cell carcinoma syndromes; Kidney cancer
    DOI:  https://doi.org/10.1016/j.euo.2021.09.005
  5. Hered Cancer Clin Pract. 2021 Oct 12. 19(1): 42
    Germline mutations among Polish patients with acute myeloid leukemia.
    Aneta Bąk, Katarzyna Skonieczka, Anna Jaśkowiec, Anna Junkiert-Czarnecka, Marta Heise, Maria Pilarska-Deltow, Stanisław Potoczek, Maria Czyżewska, Olga Haus.
      BACKGROUND: A small but important proportion of patients (4-10 %) with AML have germline mutations. They can cause the development of AML at an earlier age, confer a higher risk of relapse or predispose to secondary leukemias, including therapy-related leukemias. The analysis of germline mutations in a patient and his/her family is also critical for the selection of suitable family donors if the patient is a candidate for hematopoietic stem cell transplantation (HSCT).METHODS: 103 unrelated consecutive patients with de novo AML were enrolled in the study. Control group consisted of 103 persons from the general population. We performed NGS sequencing of bone marrow cells and buccal swabs DNA of six genes: CEBPA, DDX41, ETV6, TERT, GATA2, and IDH2 to detect germline pathogenic mutations.
    RESULTS: In the investigated group, 49 variants were detected in six genes. 26 of them were somatic and 23 germline. Germline variants were detected in all six tested genes. Eight pathogenic germline mutations were detected in 7 AML patients, in three genes: CEBPA, ETV6, and IDH2. One patient had two pathogenic germinal mutations, one in ETV6 and one in CEBPA gene. We identified one novel pathogenic germline mutation in CEBPA gene. The difference in frequency of all pathogenic germline mutations between the tested (7.77 %) and control groups (0.97 %) was statistically significant (p = 0.046). In the tested group, the median age at AML diagnosis was 11 years lower in patients with pathogenic germline mutations than in patients without them (p = 0.028).
    CONCLUSIONS: We showed higher frequency of CEBPA, ETV6, and IDH2 germline mutations in AML patients than in control group, which confirms the role of these mutations in the development of AML. We also showed that the median age at the onset of AML in patients with pathogenic germline mutations is significantly lower than in patients without them.
    Keywords:  AML; Acute myeloid leukemia; CEBPA; DDX41; ETV6; GATA2; IDH2; TERT; germline mutations
    DOI:  https://doi.org/10.1186/s13053-021-00200-2
  6. Eur J Med Genet. 2021 Oct 09. pii: S1769-7212(21)00232-9. [Epub ahead of print]64(12): 104366
    Concurrent pathogenic variations in patients with hereditary cancer syndromes.
    Nihat Bugra Agaoglu, Levent Doganay.
      Cancer is a multifactorial disorder; however, 5-10% of all cancers show hereditary background. In recent years many targeted next generation sequencing panels comprising cancer predisposition genes have been developed and used for diagnostic purposes in patients with increased cancer risk. Screening multiple genes at a time allows multiple variants in different genes to be detected as well. This study aims to determine the cases with concurrent mutations in different hereditary cancer predisposition genes and how they are clinically affected. Here, we screened 1090 index cases by next generation sequencing based hereditary cancer panels and evaluated the reflection of multiple variations on the phenotype. We detected 11 (1%) cases with pathogenic variants in more than one gene. These concurrent variations occurred mostly in BRCA1/2 (7/11) accompanied with MUTYH, ATM, CHECK2, NBN, and RAD50. In addition, MUTYH&ATM, NBN&MSH6, MUTYH&CHEK2 double heterozygous cases were detected. Moreover, we identified a case with three heterozygous variations in CDH1, MUTYH, and CHEK2. These patients presented malignancies that were mostly related to pathogenic variations they carried. Although they are rare, defining double heterozygous cases is important for managing appropriate therapy and accurate genetic consulting for the patients and family members.
    Keywords:  Concurrent variations; Double heterozygous; Hereditary cancer; Next generation sequencing
    DOI:  https://doi.org/10.1016/j.ejmg.2021.104366
  7. Eur J Med Genet. 2021 Oct 07. pii: S1769-7212(21)00225-1. [Epub ahead of print] 104359
    Pathogenicity of VHL variants in families with non-syndromic von Hippel-Lindau phenotypes: An integrated evaluation of germline and somatic genomic results.
    Huma Q Rana, Diane R Koeller, Alison Schwartz, Danielle K Manning, Katherine A Schneider, Katherine M Krajewski, Toni K Choueiri, Neal I Lindeman, Judy E Garber, Arezou A Ghazani.
      Von Hippel-Lindau (VHL) syndrome is a hereditary tumor syndrome associated with germline loss-of-function pathogenic variants (PVs) in the VHL gene. VHL is classically associated with a high penetrance for many different tumor types. The same tumors may be sporadic in the setting of somatic VHL PVs. With more large-scale genome sequencing, variants with low penetrance or variable expressivity are identified. This has introduced challenges in patient management and the clinical interpretation of germline VHL variants identified in non-classic families. Herein, we report individuals from 3 non-classic families with VHL variants who presented with unexpected or non-syndromic phenotypes, but often with a VHL component tumor. In family 1, two siblings, age 61, with pathogenic VHL p.Leu188Val presented with clear cell renal cell carcinoma and lobular breast cancer. In family 2, the proband, age 82, was found to have pathogenic germline VHL p.Tyr98His on testing for metastatic bladder cancer. In family 3, four members carried germline VHL p.Pro81Ser (variant of uncertain significance), after the proband, age 40, presented with cerebellar hemangioblastoma. None of the individuals in the above three families met clinical criteria of classic VHL, suggesting germline VHL p.Leu188Val, p.Y98H, and p.Tyr98His may be low penetrant variants. Large studies are needed to evaluate penetrance and possible effect of genetic and non-genetic modifiers. Somatic sequencing performed on their respective tumors could help discern the etiology of the component tumors, highlighting the role of somatic evaluation in these cases. Paired examination of somatic and germline findings provided a more complete landscape of genome alterations in cancer development.
    Keywords:  Hemangioblastoma; Next generation sequencing (NGS); RCC; VHL; von Hippel-Lindau
    DOI:  https://doi.org/10.1016/j.ejmg.2021.104359
  8. JAMA Surg. 2021 Oct 13.
    Association Between Hereditary Lobular Breast Cancer Due to CDH1 Variants and Gastric Cancer Risk.
    Lauren A Gamble, Alexander Rossi, Grace-Ann Fasaye, Chimene Kesserwan, Jonathan M Hernandez, Andrew M Blakely, Jeremy L Davis.
      Importance: Hereditary cancer risk is informed by the presence of a germline gene variant more so than by family history of cancer.Objective: To assess gastric cancer risk among patients who received a diagnosis of hereditary lobular breast cancer (HLBC) owing to a germline loss-of-function variant in CDH1 by establishing prevalence of signet ring cell carcinomas among asymptomatic patients.
    Design, Setting, and Participants: A prospective cohort study of patients with germline CDH1 pathogenic or likely pathogenic (P/LP) variants at a quaternary medical center were enrolled between October 2017 and January 2021. Data analysis was performed in May 2021. Analyses for associations were performed for these 3 patient groups: (1) family history of breast cancer and no gastric cancer in the HLBC group; (2) family history of gastric cancer and no breast cancer in the hereditary diffuse gastric cancer (HDGC) group; and (3) family history of both breast and gastric cancers in the mixed group. Categorical variables were compared using the Pearson χ2 test.
    Main Outcomes and Measures: The primary end point of this study was the prevalence of occult signet ring cell carcinoma of the stomach in patients with HLBC. Personal and family medical history, genotype, and pathologic data from risk-reducing total gastrectomy and surveillance endoscopy were examined.
    Results: A total of 283 patients with CDH1 P/LP variants (199 [70.3%] were female, and 259 [91.5%] were White; median age, 48 years [range, 18-81 years]) were enrolled in a prospective study of HDGC. The cohort consisted of 151 families. Patients were categorized according to family history of breast and/or gastric cancer: HLBC 15.5% [44 of 283 patients]), HDGC (16.2% [46 of 283 patients]), and mixed (68.2% [193 of 283 patients]). The HLBC group included 31 distinct families with 19 CDH1 variants; 10 of those variants were also present in the HDGC and mixed groups (52.6% [10 of 19 variants]). Nearly all of the patients with HLBC (93.8% [15 of 16 variants]) who elected for risk-reducing total gastrectomy owing to their underlying CDH1 P/LP variant harbored occult signet ring cell gastric adenocarcinoma on final pathology (median age, 50 years [range, 21-67 years]). The prevalence of occult gastric cancer among asymptomatic patients in the HDGC group was similar (94.7% [18 of 19 of variants]; P = .98).
    Conclusions and Relevance: Carriers of CDH1 P/LP variants with no family history of gastric cancer exhibited high rates of occult signet ring cell gastric cancer. Germline CDH1 P/LP variants appear to have a highly penetrant gastric phenotype irrespective of family history. These data may prove useful for counseling families with CDH1 variants presumed to have HLBC.
    DOI:  https://doi.org/10.1001/jamasurg.2021.5118
  9. NPJ Breast Cancer. 2021 Oct 11. 7(1): 135
    Germline RAD51B variants confer susceptibility to breast and ovarian cancers deficient in homologous recombination.
    Jeremy Setton, Pier Selenica, Semanti Mukherjee, Rachna Shah, Isabella Pecorari, Biko McMillan, Isaac X Pei, Yelena Kemel, Ozge Ceyhan-Birsoy, Margaret Sheehan, Kaitlyn Tkachuk, David N Brown, Liying Zhang, Karen Cadoo, Simon Powell, Britta Weigelt, Mark Robson, Nadeem Riaz, Kenneth Offit, Jorge S Reis-Filho, Diana Mandelker.
      Pathogenic germline mutations in the RAD51 paralog genes RAD51C and RAD51D, are known to confer susceptibility to ovarian and triple-negative breast cancer. Here, we investigated whether germline loss-of-function variants affecting another RAD51 paralog gene, RAD51B, are also associated with breast and ovarian cancer. Among 3422 consecutively accrued breast and ovarian cancer patients consented to tumor/germline sequencing, the observed carrier frequency of loss-of-function germline RAD51B variants was significantly higher than control cases from the gnomAD population database (0.26% vs 0.09%), with an odds ratio of 2.69 (95% CI: 1.4-5.3). Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.
    DOI:  https://doi.org/10.1038/s41523-021-00339-0
  10. Breast Cancer Res Treat. 2021 Oct 15.
    Uptake and timing of bilateral and contralateral risk-reducing mastectomy in women with Li-Fraumeni syndrome.
    Atara Siegel, Renee C Bremer, William M P Klein, Sharon A Savage, Jennifer T Loud, Payal P Khincha.
      PURPOSE: Women with Li-Fraumeni Syndrome (LFS) often consider risk-reducing mastectomy (RRM) due to extremely high risk of breast cancer at early ages. Data on uptake of RRM in LFS are scarce, and are inferred from experience in women with pathogenic variants (PVs) in BRCA1/2, despite differences in cancer risks. This study evaluated RRM uptake in a cohort of women with LFS.METHODS: Women (n = 205) with LFS enrolled in NCI's LFS study reported lifetime cancer diagnoses and mastectomies and completed questionnaires regarding reproductive history, cancer worry and risk perceptions. A subset of women participating in an annual cancer screening study received counseling regarding RRM.
    RESULTS: 65% (n = 71) of women diagnosed with presumed unilateral breast cancer (n = 109) underwent contralateral RRM over their lifetime. Nearly half (49%, n = 25) of the women who did not complete contralateral RRM within one year of their breast cancer diagnosis (n = 51) developed contralateral breast cancer (median interval = 6 years). Only 18.5% (n = 15) of women without breast cancer history (n = 81) underwent bilateral RRM. Median age at bilateral RRM of 39 years was sub-optimal for breast cancer risk reduction. Contralateral RRM was associated with early genetic diagnosis, participation in the screening study, and fewer prior cancers. Bilateral RRM uptake was associated with having had children, having breastfed, and high cancer worry.
    CONCLUSION: Uptake of contralateral RRM is high in women with LFS. The frequency of contralateral breast cancer necessitates active discussion of benefits of contralateral RRM and counseling regarding bilateral RRM should be tailored to the early age at risk of breast cancer onset in LFS. There is a need for research into the survival and long-term benefits of RRM in LFS.
    Keywords:  Breast cancer; Li–Fraumeni syndrome; Risk-reducing mastectomy; TP53
    DOI:  https://doi.org/10.1007/s10549-021-06410-5
  11. Ophthalmic Genet. 2021 Oct 13. 1-9
    Identification of novel RB1 genetic variants in Retinoblastoma patients and their impact on clinical outcome.
    Radhika Manukonda, Akhilesh Pujar, George Ramappa, Geeta K Vemuganti, Swathi Kaliki.
      BACKGROUND: Retinoblastoma (RB) is an intraocular childhood cancer develops due to inactivation of RB1 gene. Identification of RB1 genetic variants, correlating and confirming genetic test results with clinical outcomes are crucial for effective RB management.METHODS: Retrospective study of 62 RB patients and 14 family members who underwent genetic testing either by next generation sequencing (NGS) or multiplex ligation-dependent probe amplification (MLPA) or by both for screening RB1 germline mutations present in peripheral blood. Mutational outcomes were correlated with clinical outcomes evaluated over a follow-up period of 12 months.
    RESULTS: Of the 62 patients, 35 (56%) had bilateral RB and 27 (44%) had unilateral RB. Out of 24 (52%) variants detected by NGS, 9 (37.5%) were novel and 15 (62.5%) were known in 46 probands. Six (18%) gross deletions were detected by MLPA in 34 probands. The mutation detection rate by NGS and MLPA in unilateral cases was 15% (n = 4) and 74% (n = 26) in bilateral cases. In patients with RB1 genetic mutations versus those without, the rate of primary enucleation (7 (12%) vs 18 (44%) eyes; p = .0008) was inversely proportional to tumor recurrence (25 (45%) vs 6 (15%) eyes; p = .002). There was no difference in the rate of globe salvage and metastasis, over a mean follow-up period of 12 months.
    CONCLUSION: The mutations screening is important for risk assessment in future siblings and offspring of RB patients and most important in unilateral RB for determining if hereditary or not hereditary RB. Its role in predicting clinical outcomes is yet to be determined.
    Keywords:  RB1 gene; Retinoblastoma; clinical outcome; genetic testing; genetic variants; germline mutation; tumor recurrence
    DOI:  https://doi.org/10.1080/13816810.2021.1989602
  12. Int J Endocrinol. 2021 ;2021 1392386
    Recurrent Germline Mutations of CHEK2 as a New Susceptibility Gene in Patients with Pheochromocytomas and Paragangliomas.
    Yinjie Gao, Chao Ling, Xiaosen Ma, Huiping Wang, Yunying Cui, Min Nie, Anli Tong.
      Purpose: Recently, pheochromocytomas and paragangliomas (PPGLs) have been strongly suspected as hereditary tumors, as approximately 40% of patients carry germline mutations. In the cancers where defects occur to corrupt DNA repair and facilitate tumorigenesis, a CHEK2 strong association has been observed. Therefore, the purpose of this study was to investigate the effect of CHEK2 mutations for its possible pathogenicity in PPGLs.Methods: Four patients with CHEK2 mutations were recruited, as previously detected by the whole exome sequencing. Sanger sequencing was used to verify the germline mutations as well as the loss of heterozygosities (LOHs) in their somatic DNAs. Immunohistochemistry was used to analyze the expression of CHEK2 and its downstream target p53 Ser20 (phosphorylated p53).
    Results: The average age of studied patients was 44.25 ± 11.18 years, at the time diagnosis. One patient had multiple tumors which recurred quickly, while two patients had distant metastasis. None of the patient had any relevant family history. Four germline CHEK2 mutations were identified (c.246_260del; c.715G > A; c.1008+3A > T; and c.1111C > T). All the patients were predicted to have either pathogenic or suspected pathogenic mutations. There was no LOH of CHEK2 gene in somatic DNAs found. Additionally, neither CHEK2 proteins nor its downstream target p53 Ser20 were expressed in the tumor tissues. The inactivation of CHEK2 leads to the decrease in the p53 phosphorylation, which might promote tumorigenesis.
    Conclusions: For the first time, CHEK2 was identified as a susceptibility gene for PPGLs. However, the penetrance of CHEK2 gene with genotype-phenotype correlation needs to be investigated.
    DOI:  https://doi.org/10.1155/2021/1392386
  13. J Genomics. 2021 ;9 43-54
    Identification of a novel pathogenic variant in PALB2 and BARD1 genes by a multigene sequencing panel in triple negative breast cancer in Morocco.
    Abdelilah Laraqui, Mathias Cavaillé, Nancy Uhrhammer, Oubaida ElBiad, Yannick Bidet, Hicham El Rhaffouli, Hicham El Anaz, Driss Moussaoui Rahali, Jaouad Kouach, Khaled Guelzim, Bouabid Badaoui, Abderrahman AlBouzidi, Mohammed Oukabli, Rachid Tanz, Yasser Sbitti, Mohammed Ichou, Khaled Ennibi, Yassine Sekhsokh, Yves-Jean Bignon.
      Pathogenic variants (PVs) in BRCA genes have been mainly associated with an increasing risk of triple negative breast cancer (TNBC). The contribution of PVs in non-BRCA genes to TNBC seems likely since the processing of homologous recombination repair of double-strand DNA breaks involves several genes. Here, we investigate the susceptibility of genetic variation of the BRCA and non-BRCA genes in 30 early-onset Moroccan women with TNBC. Methods: Targeted capture-based next generation sequencing (NGS) method was performed with a multigene panel testing (MGPT) for variant screening. Panel sequencing was performed with genes involved in hereditary predisposition to cancer and candidate genes whose involvement remains unclear using Illumina MiSeq platform. Interpretation was conducted by following the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) criteria. Results: PVs were identified in 20% (6/30) of patients with TNBC. Of these, 16.7% (5/30) carried a BRCA PV [10% (3/30) in BRCA1, 6.7% (2/30) in BRCA2] and 6.6% (2/30) carried a non-BRCA PV. The identified PVs in BRCA genes (BRCA1 c.798_799delTT, BRCA1 c.3279delC, BRCA2 c.1310_1313del, and BRCA2 c.1658T>G) have been reported before and were classified as pathogenic. The identified founder PVs BRCA1 c.798_799del and BRCA2 c.1310_1313delAAGA represented 10% (3/30). Our MGPT allowed identification of several sequence variations in most investigated genes, among which we found novel truncating variations in PALB2 and BARD1 genes. The PALB2 c.3290dup and BARD1 c.1333G>T variants are classified as pathogenic. We also identified 42 variants of unknown/uncertain significance (VUS) in 70% (21/30) of patients with TNBC, including 50% (21/42) missense variants. The highest VUS rate was observed in ATM (13%, 4/30). Additionally, 35.7% (15/42) variants initially well-known as benign, likely benign or conflicting interpretations of pathogenicity have been reclassified as VUS according to ACMG-AMP. Conclusions: PALB2 and BARD1 along with BRCA genetic screening could be helpful for a larger proportion of early-onset TNBC in Morocco.
    Keywords:  ACMG-AMP guidelines; Moroccan Population; Multigene panel testing; Next Generation Sequencing; Triple negative breast cancer
    DOI:  https://doi.org/10.7150/jgen.61713
  14. JAMA Oncol. 2021 Oct 14.
    Preexisting TP53-Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients With High-grade Ovarian Cancer Treated With Rucaparib.
    Tanya T Kwan, Amit M Oza, Anna V Tinker, Isabelle Ray-Coquard, Ana Oaknin, Carol Aghajanian, Domenica Lorusso, Nicoletta Colombo, Andrew Dean, Johanne Weberpals, Eric Severson, Lan-Thanh Vo, Sandra Goble, Lara Maloney, Thomas Harding, Scott H Kaufmann, Jonathan A Ledermann, Robert L Coleman, Iain A McNeish, Kevin K Lin, Elizabeth M Swisher.
      Importance: A total of 1% to 3% of patients treated with a poly(adenosine diphosphate-ribose) polymerase inhibitor for high-grade ovarian cancer (HGOC) develop therapy-related myeloid neoplasms (t-MNs), which are rare but often fatal conditions. Although the cause of these t-MNs is unknown, clonal hematopoiesis of indeterminate potential (CHIP) variants can increase the risk of primary myeloid malignant neoplasms and are more frequent among patients with solid tumors.Objectives: To examine whether preexisting CHIP variants are associated with the development of t-MNs after rucaparib treatment and how these CHIP variants are affected by treatment.
    Design, Setting, and Participants: This retrospective genetic association study used peripheral blood cell (PBC) samples collected before rucaparib treatment from patients in the multicenter, single-arm ARIEL2 (Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer) (n = 491; between October 30, 2013, and August 9, 2016) and the multicenter, placebo-controlled, double-blind ARIEL3 (Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer) (n = 561; between April 7, 2014, and July 19, 2016), which tested rucaparib as HGOC therapy in the treatment and maintenance settings, respectively. The follow-up data cutoff date was September 1, 2019. Of 1052 patients in ARIEL2 and ARIEL3, PBC samples from 20 patients who developed t-MNs (cases) and 44 randomly selected patients who did not (controls) were analyzed for the presence of CHIP variants using targeted next-generation sequencing. Additional longitudinal analysis was performed on available ARIEL2 samples collected during treatment and at the end of treatment.
    Main Outcomes and Measures: Enrichment analysis of preexisting variants in 10 predefined CHIP-associated genes in cases relative to controls; association with clinical correlates.
    Results: Among 1052 patients (mean [SE] age, 61.7 [0.3] years) enrolled and dosed in ARIEL2 and ARIEL3, 22 (2.1%) developed t-MNs. The t-MNs were associated with longer overall exposure to prior platinum therapies (13.2 vs 9.0 months in ARIEL2, P = .04; 12.4 vs 9.6 months in ARIEL3, P = .003). The presence of homologous recombination repair gene variants in the tumor, either germline or somatic, was associated with increased prevalence of t-MNs (15 [4.1%] of 369 patients with HGOC associated with an HRR gene variant vs 7 [1.0%] of 683 patients with wild-type HGOC, P = .002). The prevalence of preexisting CHIP variants in TP53 but not other CHIP-associated genes at a variant allele frequency of 1% or greater was significantly higher in PBCs from cases vs controls (9 [45.0%] of 20 cases vs 6 [13.6%] of 44 controls, P = .009). TP53 CHIP was associated with longer prior exposure to platinum (mean 14.0 months of 15 TP53 CHIP cases vs 11.1 months of 49 non-TP53 CHIP cases; P = .02). Longitudinal analysis showed that preexisting TP53 CHIP variants expanded in patients who developed t-MNs.
    Conclusions and Relevance: The findings of this genetic association study suggest that preexisting TP53 CHIP variants may be associated with t-MNs after rucaparib treatment.
    DOI:  https://doi.org/10.1001/jamaoncol.2021.4664
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