bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022‒01‒02
eleven papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. Case Report : Li-Fraumeni Syndrome with Central Nervous System Tumors in Two Siblings.
  2. Germline TP53 c.566C>T mutation incidentally diagnosed during treatment for acute myeloid leukemia: A case report.
  3. Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor.
  4. Should all patients undergoing genetic testing for hereditary breast cancer syndromes be offered a multigene panel?
  5. Optimization of an mHealth lifestyle intervention for families with hereditary cancer syndromes: Study protocol for a multiphase optimization strategy feasibility study.
  6. Cancer Predisposition Genetic Analysis in Children with Brain Tumors Treated at a Single Institution in Japan.
  7. The first comprehensive database of germline pathogenic variants in East Asian cancer patients.
  8. Identification of Genetic Risk Factors for Familial Urinary Bladder Cancer: An Exome Sequencing Study.
  9. Pathogenic 'germline' variants associated with myeloproliferative disorders in apparently normal individuals: inherited or acquired genetic alterations?
  10. Clonal Hematopoiesis-Associated Gene Mutations in a Clinical Cohort of 448 Patients with Ovarian Cancer.
  11. Long-term survival of a patient with metastatiс choroid plexus carcinoma, de novo germline TP53 mutated, after craniospinal proton irradiation.
  1. BMC Pediatr. 2021 Dec 27. 21(1): 588
    Case Report : Li-Fraumeni Syndrome with Central Nervous System Tumors in Two Siblings.
    Zishi Fang, Yan Su, Hailang Sun, Ming Ge, Zhan Qi, Chanjuan Hao, Suyun Qian, Xiaoli Ma.
      BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline TP53 gene mutations. It is characterized by high risk of early-onset cancer, and has been confirmed as associated with multiple tumors clinically. So pediatricians should be more alert to LFS in children with tumors. Choroid plexus carcinoma (CPC) is a rare, malignant tumor which account for less than 1% of all central nervous system (CNS) tumors. However, when such tumorigenesis occurs, it is important to be vigilant for the presence of LFS.CASE PRESENTATION: The first patient is a 32-month-old boy admitted for convulsions and then was found intracranial space-occupying lesion. Underwent operation, he was diagnosis as choroid plexus carcinoma (WHO Grade III). After 5 months, his elder sister, a 13-year-old girl, was brought to emergency department for confusion and intermittent convulsions. Surgery was performed immediately after head CT examination found the lesion. The pathology result indicated glioblastoma. Because the siblings of the same family have successively suffered from malignant tumors, we performed genetic testing on this family. TP53 gene mutation occurred in both children of these two cases from their father, and their other brother was not spared either. So the two siblings both met the diagnostic criteria of LFS. Then they all received systematic anti-tumor therapy, and follow-up hitherto.
    CONCLUSION: Here we reported a rare LFS case that two siblings were inherited the same TP53 germline mutations from their father. They suffered from choroid plexus carcinoma and glioblastoma and were finally diagnosed with LFS. In this LFS family, the primary tumors of the two children were both central nervous system tumors, which were not reported in the previous literature. It is suggested that clinicians should be alert to LFS related tumors, which is helpful for early diagnosis. Timely detection of TP53 gene is an important way for early diagnosis of LFS, especially in children with tumor. The incidence of secondary tumor in LFS patients is significantly higher, and other family members of the LFS patient also have an increased risk of suffering from the tumors. Therefore, early diagnosis and timely tumor surveillance can obtain better therapeutic effect and prognosis for both proband and their family.
    Keywords:  Choroid plexus carcinoma; Glioblastoma; Li-Fraumeni Syndrome; Pediatric Oncology; TP53 Gene Mutation
    DOI:  https://doi.org/10.1186/s12887-021-03070-8
  2. Clin Case Rep. 2021 Dec;9(12): e05221
    Germline TP53 c.566C>T mutation incidentally diagnosed during treatment for acute myeloid leukemia: A case report.
    Hiroshi Sato, Seiki Matsuo, Yukiko Ando, Yuko Imamura, Masaya Hirose.
      TP53 mutations in acute myeloid leukemia (AML) are associated with poor outcomes. The number of somatic and/or germline genetic tests for therapy is increasing. Patients with such incidental findings should undergo adequate genetic counseling.
    Keywords:  TP53; acute myeloid leukemia; genetic counseling; variant of uncertain significance
    DOI:  https://doi.org/10.1002/ccr3.5221
  3. JCO Precis Oncol. 2021 ;pii: PO.21.00281. [Epub ahead of print]5
    Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor.
    Jaclyn Schienda, Alanna J Church, Laura B Corson, Brennan Decker, Catherine M Clinton, Danielle K Manning, Alma Imamovic-Tuco, Deirdre Reidy, Gianna R Strand, Mark A Applebaum, Rochelle Bagatell, Steven G DuBois, Julia L Glade-Bender, Wenjun Kang, AeRang Kim, Theodore W Laetsch, Margaret E Macy, Luke Maese, Navin Pinto, Amit J Sabnis, Joshua D Schiffman, Susan I Colace, Samuel L Volchenboum, Daniel A Weiser, Jonathan A Nowak, Neal I Lindeman, Katherine A Janeway, Brian D Crompton, Junne Kamihara.
      PURPOSE: Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks.MATERIALS AND METHODS: Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation.
    RESULTS: One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events.
    CONCLUSION: A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition.
    DOI:  https://doi.org/10.1200/PO.21.00281
  4. Curr Opin Obstet Gynecol. 2022 Feb 01. 34(1): 36-40
    Should all patients undergoing genetic testing for hereditary breast cancer syndromes be offered a multigene panel?
    Erica L Silver, Mariana Niell-Swiller.
      PURPOSE OF REVIEW: We aim to demonstrate why multigene panel testing (MGPT) is the superior testing option for individuals undergoing hereditary cancer genetic testing. We will outline the clinical benefits and possible limitations of MGPT for individuals at risk for a hereditary cancer syndrome.RECENT FINDINGS: The use of MGPT increases the identification of individuals with hereditary cancer syndromes. Recent studies continue to prove that MGPT is a superior option to single gene/or syndrome testing. MGPT is a cost-effective testing approach for those meeting criteria for genetic testing. Individuals interested in MGPT should understand the benefits and limitations of this approach, including an increase in variant identification and possible incidental findings. MGPT also increases the number of individuals who would benefit from cascade testing.
    SUMMARY: MGPT should be considered as the standard approach to hereditary cancer genetic testing as opposed to single gene or single syndrome testing. MGPT identifies a larger proportion of individuals with a hereditary cancer syndrome and leads to better management and improved uptake of cascade testing.
    DOI:  https://doi.org/10.1097/GCO.0000000000000764
  5. Contemp Clin Trials. 2021 Dec 28. pii: S1551-7144(21)00398-0. [Epub ahead of print] 106662
    Optimization of an mHealth lifestyle intervention for families with hereditary cancer syndromes: Study protocol for a multiphase optimization strategy feasibility study.
    Karen Basen-Engquist, Margaret Raber, Larkin L Strong, Susan Schembre, Liang Li, Banu Arun, Karen Lu, Nancy You, Eduardo Vilar, Patrick Lynch, Sara Fares, Susan K Peterson.
      BACKGROUND: Individuals at increased hereditary risk of cancer are an important target for health promotion and cancer prevention interventions. Health-4-Families uses the Multiphase Optimization STrategy (MOST) framework and is designed to pilot digital delivery strategies for a distance-based, 16-week intervention to promote weight management, healthy diet, and increased physical activity among individuals with BRCA1/BRCA2 or DNA mismatch repair (MMR) pathogenic germline variants. This communication describes participant recruitment and the design of the Health-4-Families pilot study.METHODS: Health-4-Families is a full-factorial (16 condition) randomized pilot study of four lifestyle intervention components: social networking, telephone or email coaching, text messaging, and self-monitoring. The primary outcome was feasibility and satisfaction with these study components. Participants with pathogenic germline variants were identified via clinic surveillance lists and advocacy organizations and were invited to participate with family members. All participants had to report meeting at least one of the following criteria: (1) having a BMI ≥ 25 kg/m2, (2) consuming <5 servings of fruit and vegetables per day, or (3) getting <150 min of moderate-to-vigorous intensity activity per week.
    RESULTS: The majority of screened potential participants with pathogenic variants (83%) were eligible; 86% of those eligible provided informed consent and 79% (n = 104) completed baseline. A total of 206 family members were nominated by study participants and 49% (n = 102) completed baseline.
    DISCUSSION: Recruitment data suggest that individuals with pathogenic germline variants, who are at increased risk for hereditary cancers, are motivated to participate in digital lifestyle interventions. This recruitment success highlights the importance of identifying and prioritizing effective and efficient intervention components for hereditary cancer families. We intend to use the outcomes of our pilot study to inform a fully-powered factorial study for this community.
    Keywords:  Behavior modification; Hereditary breast cancer; Hereditary ovarian cancer; Lynch syndrome; Multiphase optimization strategy; Telemedicine
    DOI:  https://doi.org/10.1016/j.cct.2021.106662
  6. Oncology. 2021 Dec 27.
    Cancer Predisposition Genetic Analysis in Children with Brain Tumors Treated at a Single Institution in Japan.
    Hiroko Fukushima, Ryoko Suzuki, Yuni Yamaki, Sho Hosaka, Masako Inaba, Ai Muroi, Takao Tsurubuchi, Wataru Morii, Emiko Noguchi, Hidetoshi Takada.
      Brain tumors affect one-third of all children with cancer. Approximately 10% of children with cancer carry variants in cancer predisposition genes. However, germline analyses in large cohorts of Asian children have not been reported. Thirty-eight Japanese patients with pediatric brain tumors were included in this study (19 boys, 19 girls). DNA was extracted from the patients' peripheral blood, and cancer-associated genes were analyzed using targeted resequencing. Rare variants with allele frequencies <0.1% in the general population and variants suspected to be pathogenic were extracted and analyzed. Pathogenic variants were found in 7 patients (18%): 2 nonsense variants of CHEK2 and FANCI; 2 frameshift deletions in SMARCB1 and PTCH1; and 3 missense variants of TSC1, WRN, and MLH1. The median age at diagnosis was 9.1 years, and three of the 7 patients had a family history of cancer. One patient diagnosed with basal cell nevus syndrome, also called Gorlin syndrome, developed a second neoplasm, and another with an SMARCB1 variant and an atypical teratoid/rhabdoid tumor developed a thyroid adenomatous nodule. This is the first cancer-related germline analysis with detailed clinical information reported in Japanese children with brain tumors. The prevalence was almost equivalent to that in white children.
    DOI:  https://doi.org/10.1159/000521621
  7. Database (Oxford). 2021 Dec 29. pii: baab075. [Epub ahead of print]2021(2021):
    The first comprehensive database of germline pathogenic variants in East Asian cancer patients.
    Xiaoshun Shi, Ruidong Li, Jianxue Zhai, Allen Menglin Chen, Kailing Huang, Zhouxia Zheng, Zhuona Chen, Xiaoyin Dong, Xiguang Liu, Di Lu, Siyang Feng, Dingwei Diao, Pengfei Ren, Zhaoguo Liu, Grant Morahan, Kaican Cai.
      Pathogenic germline variants in cancer-associated genes are risk factors for cancer predisposition. However, systematic mining and summarizing of cancer pathogenic or likely pathogenic variants has not been performed for people of East Asian descent. This study aimed to investigate publicly available data to identify germline variants in East Asian cancer cohorts and compare them to variants in Caucasian cancer cohorts. Based on the data we retrieved, we built a comprehensive database, named COGVIC (Catalog of Germline Variants in Cancer). A total of 233 variants in the East Asian population were identified. The majority (87%) of genes with cancer-associated variants were not shared between the East Asian and Caucasian cohorts. This included pathogenic variants in BRCA2. Our study summarized the prevalence of germline variants in East Asian cancer cohorts and provides an easy-to-use online tool to explore germline mutations related to cancer susceptibility.DATABASE URL: http://www.cogvic.vip/.
    DOI:  https://doi.org/10.1093/database/baab075
  8. JCO Precis Oncol. 2021 ;pii: PO.21.00115. [Epub ahead of print]5
    Identification of Genetic Risk Factors for Familial Urinary Bladder Cancer: An Exome Sequencing Study.
    Alexander Pemov, Talia Wegman-Ostrosky, Jung Kim, Stella Koutros, Brenna Douthitt, Kristine Jones, Bin Zhu, Dalsu Baris, Molly Schwenn, Alison Johnson, Margaret R Karagas, Brian D Carter, Marjorie L McCullough, Maria Teresa Landi, Neal D Freedman, Demetrius Albanes, Debra T Silverman, Nathaniel Rothman, Neil E Caporaso, Mark H Greene, Joseph F Fraumeni, Douglas R Stewart.
      PURPOSE: Previous studies have shown an approximately two-fold elevation in the relative risk of urinary bladder cancer (UBC) among people with a family history that could not be entirely explained by shared environmental exposures, thus suggesting a genetic component in its predisposition. Multiple genome-wide association studies and recent gene panel sequencing studies identified several genetic loci that are associated with UBC risk; however, the list of UBC-associated variants and genes is incomplete.MATERIALS AND METHODS: We exome sequenced eight patients from three multiplex UBC pedigrees and a group of 77 unrelated familial UBC cases matched to 241 cancer-free controls. In addition, we examined pathogenic germline variation in 444 candidate genes in 392 The Cancer Genome Atlas UBC cases.
    RESULTS: In the pedigrees, segregating variants were family-specific although the identified genes clustered in common pathways, most notably DNA repair (MLH1 and MSH2) and cellular metabolism (IDH1 and ME1). In the familial UBC group, the proportion of pathogenic and likely pathogenic variants was significantly higher in cases compared with controls (P = .003). Pathogenic and likely pathogenic variant load was also significantly increased in genes involved in cilia biogenesis (P = .001). In addition, a pathogenic variant in CHEK2 (NM_007194.4:c.1100del; p.T367Mfs*15) was over-represented in cases (variant frequency = 2.6%; 95% CI, 0.71 to 6.52) compared with controls (variant frequency = 0.21%; 95% CI, 0.01 to 1.15), but was not statistically significant.
    CONCLUSION: These results point to a complex polygenic predisposition to UBC. Despite heterogeneity, the genes cluster in several biologically relevant pathways and processes, for example, DNA repair, cilia biogenesis, and cellular metabolism. Larger studies are required to determine the importance of CHEK2 in UBC etiology.
    DOI:  https://doi.org/10.1200/PO.21.00115
  9. Clin Genet. 2021 Dec 27.
    Pathogenic 'germline' variants associated with myeloproliferative disorders in apparently normal individuals: inherited or acquired genetic alterations?
    Reiner Veitia, Hideki Innan.
      Myeloproliferative syndromes (MPS) are hematologic malignancies due to the expansion of an abnormal hematopoietic stem cell. They include chronic myeloid leukemia (CML) and non-CML MPS such as polycythemia vera, essential thrombocythemia and primary myelofibrosis. The latter are distinguished by somatic pathogenic variants affecting JAK2, CALR or MPL genes. Apparent germline pathogenic variants have been reported in the general population. Here, we found that two gnomAD data-sets report more homozygotes than expected for the JAK2 c.1849G > T(Val617Phe) variant. We propose that somatic gene conversion underlies the presence of those unexpected homozygotes in normal populations. Consistently, homozygous individuals are older than 65 years. We also found a lower-than-expected frequency of the JAK2 variant in younger individuals suggesting that somatic mutation can underlie its presence in (at least some) heterozygotes. Regarding pathogenic variants in MPL and CALR, they are also present in the gnomAD data-sets explored. However, we cannot conclude that such seemingly germline variants are in fact somatic alterations. These results suggest that apparently normal individuals bearing MPS-related variants can be subclinical/undiagnosed MPS cases of somatic origin. It would be interesting to assess the hematologic phenotype of such individuals and the presence of the relevant variants in other tissues.
    Keywords:  CALR; JAK2; MPL; Myeloproliferative disorder; essential thrombocythemia and primary myelofibrosis; polycythemia vera
    DOI:  https://doi.org/10.1111/cge.14104
  10. J Natl Cancer Inst. 2021 Dec 28. pii: djab231. [Epub ahead of print]
    Clonal Hematopoiesis-Associated Gene Mutations in a Clinical Cohort of 448 Patients with Ovarian Cancer.
    Konstantin Weber-Lassalle, Corinna Ernst, Alexander Reuss, Kathrin Möllenhoff, Klaus Baumann, Christian Jackisch, Jan Hauke, Dimo Dietrich, Julika Borde, Tjoung-Won Park-Simon, Lars Hanker, Katharina Prieske, Sandra Schmidt, Nana Weber-Lassalle, Esther Pohl-Rescigno, Stefan Kommoss, Frederik Marmé, Florian Heitz, Julia C Stingl, Rita K Schmutzler, Philipp Harter, Eric Hahnen.
      BACKGROUND: Cancer patients are at risk of secondary therapy-related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)-associated genes are t-MN risk factors and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH-associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity.METHODS: We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH-associated genes (ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53). Results were analyzed according to the BRCA1/2 germline (gBRCA1/2) mutation status. All statistical tests were 2-sided.
    RESULTS: Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH-associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for gBRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D: odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P = .007; TP53: odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P = .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs noncarriers (PPM1D: mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P < .001; TP53: mean [SD] =2.83 [1.33] vs 1.07 [1.01], P < .001). No interaction between platinum-based chemotherapy and gBRCA1/2 mutation status with the occurrence of CH-associated gene mutations was observed.
    CONCLUSION: A positive gBRCA1/2 mutation status is not a risk factor to acquire CH-associated gene mutations. OC patients may benefit from monitoring CH-associated gene mutations, especially following carboplatin exposure. Future clinical studies are required to assess whether treatment regimen should be adapted according to individual t-MN risks.
    DOI:  https://doi.org/10.1093/jnci/djab231
  11. Pediatr Blood Cancer. 2021 Dec 26. e29486
    Long-term survival of a patient with metastatiс choroid plexus carcinoma, de novo germline TP53 mutated, after craniospinal proton irradiation.
    Andge Valiakhmetova, Ludmila Yasko, Ludmila Papusha, Margarita Zaytseva, Alexander Druy, Ludmila Shishkina, Galina Novichkova, Sergey Gorelyshev, Alexander Karachunsky.
      
    DOI:  https://doi.org/10.1002/pbc.29486
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