bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–08–14
seven papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Li-Fraumeni Syndrome: Mutation of TP53 Is a Biomarker of Hereditary Predisposition to Tumor: New Insights and Advances in the Treatment.
  2. Germline genetic biomarkers to stratify patients for personalized radiation treatment.
  3. Development and Validation of the PREMMplus Model for Multigene Hereditary Cancer Risk Assessment.
  4. HBOC syndrome with an uncharacterized variant in the BRCA1 gene in a patient diagnosed with endometrial cancer after surgery for bilateral breast cancer: A case report.
  5. Germline Variants Associated with Nasopharyngeal Carcinoma Predisposition Identified through Whole-Exome Sequencing.
  6. Hereditary Breast and Ovarian Cancer Genetic Risk: Screening and Treatment Among Transgender and Gender Diverse Patients.
  7. Germline GATA1 exon 2 mutation associated with chronic cytopenia and a non-down syndrome transient abnormal myelopoiesis with clonal trisomy 21.
  1. Cancers (Basel). 2022 Jul 27. pii: 3664. [Epub ahead of print]14(15):
    Li-Fraumeni Syndrome: Mutation of TP53 Is a Biomarker of Hereditary Predisposition to Tumor: New Insights and Advances in the Treatment.
    Valentina Rocca, Giovanni Blandino, Lucia D'Antona, Rodolfo Iuliano, Silvia Di Agostino.
      Li-Fraumeni syndrome (LFS) is a rare familial tumor predisposition syndrome with autosomal dominant inheritance, involving germline mutations of the TP53 tumor suppressor gene. The most frequent tumors that arise in patients under the age of 45 are osteosarcomas, soft-tissue sarcomas, breast tumors in young women, leukemias/lymphomas, brain tumors, and tumors of the adrenal cortex. To date, no other gene mutations have been associated with LFS. The diagnosis is usually confirmed by genetic testing for the identification of TP53 mutations; therefore, these mutations are considered the biomarkers associated with the tumor spectrum of LFS. Here, we aim to review novel molecular mechanisms involved in the oncogenic functions of mutant p53 in LFS and to discuss recent new diagnostic and therapeutic approaches exploiting TP53 mutations as biomarkers and druggable targets.
    Keywords:  Li–Fraumeni syndrome (LFS); TP53; biomarker; cancer predisposition; germline mutation
    DOI:  https://doi.org/10.3390/cancers14153664
  2. J Transl Med. 2022 Aug 12. 20(1): 360
    Germline genetic biomarkers to stratify patients for personalized radiation treatment.
    Ida Deichaite, Austin Hopper, Lena Krockenberger, Timothy J Sears, Leisa Sutton, Xenia Ray, Andrew Sharabi, Ami Navon, Parag Sanghvi, Hannah Carter, Vitali Moiseenko.
       BACKGROUND: Precision medicine incorporating genetic profiling is becoming a standard of care in medical oncology. However, in the field of radiation oncology there is limited use of genetic profiling and the impact of germline genetic biomarkers on radiosensitivity, radioresistance, or patient outcomes after radiation therapy is poorly understood. In HNSCC, the toxicity associated with treatment can cause delays or early cessation which has been associated with worse outcomes. Identifying potential biomarkers which can help predict toxicity, as well as response to treatment, is of significant interest.
    METHODS: Patients with HNSCC who received RT and underwent next generation sequencing of somatic tumor samples, transcriptome RNA-seq with matched normal tissue samples were included. Patients were then grouped by propensity towards increased late vs. early toxicity (Group A) and those without (Group B), assessed by CTCAE v5.0. The groups were then analyzed for association of specific germline variants with toxicity and clinical outcomes.
    RESULTS: In this study we analyzed 37 patients for correlation between germline variants and toxicity. We observed that TSC2, HLA-A, TET2, GEN1, NCOR2 and other germline variants were significantly associated with long term toxicities. 34 HNSCC patients treated with curative intent were evaluated for clinical outcomes. Group A had significantly improved overall survival as well as improved rates of locoregional recurrence and metastatic disease. Specific variants associated with improved clinical outcomes included TSC2, FANCD2, and PPP1R15A, while the HLA-A and GEN1 variants were not correlated with survival or recurrence. A group of five HLA-DMA/HLA-DMB variants was only found in Group B and was associated with a higher risk of locoregional recurrence.
    CONCLUSIONS: This study indicates that germline genetic biomarkers may have utility in predicting toxicity and outcomes after radiation therapy and deserve further investigation in precision radiation medicine approaches.
    Keywords:  GEN1; Germline variants; HLA-A; Head and neck squamous cell carcinoma; NCOR2; Predictive biomarkers of radiation toxicity; Radiogenomics; TET2; TSC2
    DOI:  https://doi.org/10.1186/s12967-022-03561-x
  3. J Clin Oncol. 2022 Aug 12. JCO2200120
    Development and Validation of the PREMMplus Model for Multigene Hereditary Cancer Risk Assessment.
    Matthew B Yurgelun, Hajime Uno, C Sloane Furniss, Chinedu Ukaegbu, Miki Horiguchi, Amal Yussuf, Holly LaDuca, Anu Chittenden, Judy E Garber, Sapna Syngal.
       PURPOSE: With the availability of multigene panel testing (MGPT) for hereditary cancer risk assessment, clinicians need to assess the likelihood of pathogenic germline variants (PGVs) across numerous genes in parallel. This study's aim was to develop and validate a clinical prediction model (PREMMplus) for MGPT risk assessment.
    MATERIALS AND METHODS: PREMMplus was developed in a single-institution cohort of 7,280 individuals who had undergone MGPT. Logistic regression models with Least Absolute Shrinkage and Selection Operator regularization were used to examine candidate predictors (age, sex, ethnicity, and personal/family history of 18 cancers/neoplasms) to estimate one's likelihood of carrying PGVs in 19 genes (broadly categorized by phenotypic overlap and/or relative penetrance: 11 category A [APC, BRCA1/2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53] and eight category B genes [ATM, BRIP1, CDKN2A, CHEK2, PALB2, PTEN, RAD51C, and RAD51D]). Model performance was validated in nonoverlapping data sets of 8,691 and 14,849 individuals with prior MGPT ascertained from clinic- and laboratory-based settings, respectively.
    RESULTS: PREMMplus (score ≥ 2.5%) had 93.9%, 91.7%, and 89.3% sensitivity and 98.3%, 97.5%, and 97.8% negative-predictive value (NPV) for identifying category A gene PGV carriers in the development and validation cohorts, respectively. PREMMplus assessment (score ≥ 2.5%) had 89.9%, 85.6%, and 84.2% sensitivity and 95.0%, 93.5%, and 93.5% NPV, respectively, for identifying category A/B gene PGV carriers. Decision curve analyses support MGPT for individuals predicted to have ≥ 2.5% probability of a PGV.
    CONCLUSION: PREMMplus accurately identifies individuals with PGVs in a diverse spectrum of cancer susceptibility genes with high sensitivity/NPV. Individuals with PREMMplus scores ≥ 2.5% should be considered for MGPT.
    DOI:  https://doi.org/10.1200/JCO.22.00120
  4. Oncol Lett. 2022 Sep;24(3): 325
    HBOC syndrome with an uncharacterized variant in the BRCA1 gene in a patient diagnosed with endometrial cancer after surgery for bilateral breast cancer: A case report.
    Yasushi Mabuchi, Yuta Hamano, Sawako Minami, Nami Ota, Kazuhiko Ino.
      The association between endometrial cancer and the BRCA1 and BRCA2 genes is not fully understood, and the risk elevation of endometrial cancer in patients with hereditary breast and ovarian cancer (HBOC) is not understood. The present report examines a rare case of HBOC syndrome and an uncharacterized variant of the BRCA1 gene in a patient diagnosed with endometrial cancer. A 46-year-old woman, gravida 1 para 1, was referred to Wakayama Medical University Hospital (Wakayama, Japan) because positron emission tomography/computed tomography (PET/CT) showed a high FDG uptake in the corpus uteri and the left ovary. PET/CT was performed just after mastectomy for left-sided breast cancer (triple negative). The patient had previously undergone partial mastectomy for right-sided breast cancer (triple negative) and was treated with radiation therapy to the right residual breast when she was 39 years old. Laparoscopic hysterectomy and bilateral adnexectomy were performed, and the histological diagnosis was endometrioid carcinoma, grade 1. Her germline BRCA status was tested by blood examination and the result was 'NM_007294.4(BRCA1):c.49G>C (p.Ala17Pro)'. The variant was evaluated as 'likely pathogenic'. The patient was diagnosed with HBOC syndrome and endometrial cancer, pT1ANxM0. The patient had no recurrence of breast or endometrial cancer 16 months after gynecologic surgery.
    Keywords:  BRCA; breast cancer; endometrial cancer; hereditary breast and ovarian cancer syndrome; variant
    DOI:  https://doi.org/10.3892/ol.2022.13445
  5. Cancers (Basel). 2022 Jul 28. pii: 3680. [Epub ahead of print]14(15):
    Germline Variants Associated with Nasopharyngeal Carcinoma Predisposition Identified through Whole-Exome Sequencing.
    Ning-Yuan Lee, Melissa Hum, Pei-Yi Ong, Matthew Khine Myint, Enya H W Ong, Kar-Perng Low, Zheng Li, Boon-Cher Goh, Joshua K Tay, Kwok-Seng Loh, Melvin L K Chua, Soo-Chin Lee, Chiea-Chuen Khor, Ann S G Lee.
      The current understanding of genetic susceptibility factors for nasopharyngeal carcinoma (NPC) is still incomplete. To identify novel germline variants associated with NPC predisposition, we analysed whole-exome sequencing data from 119 NPC patients from Singapore with a family history of NPC and/or with early-onset NPC, together with 1337 Singaporean participants without NPC. Variants were prioritised and filtered by selecting variants with minor allele frequencies of <1% in both local control (n = 1337) and gnomAD non-cancer (EAS) (n = 9626) cohorts and a high pathogenicity prediction (CADD score > 20). Using single-variant testing, we identified 17 rare pathogenic variants in 17 genes that were associated with NPC. Consistent evidence of enrichment in NPC patients was observed for five of these variants (in JAK2, PRDM16, LRP1B, NIN, and NKX2-1) from an independent case-control comparison of 156 NPC patients and 9770 unaffected individuals. In a family with five siblings, a FANCE variant (p. P445S) was detected in two affected members, but not in three unaffected members. Gene-based burden testing recapitulated variants in NKX2-1 and FANCE as being associated with NPC risk. Using pathway analysis, endocytosis and immune-modulating pathways were found to be enriched for mutation burden. This study has identified NPC-predisposing variants and genes which could shed new insights into the genetic predisposition of NPC.
    Keywords:  exome sequencing; genetic predisposition; germline variants; nasopharyngeal carcinoma
    DOI:  https://doi.org/10.3390/cancers14153680
  6. Perm J. 2022 Jul 27. 1-9
    Hereditary Breast and Ovarian Cancer Genetic Risk: Screening and Treatment Among Transgender and Gender Diverse Patients.
    Maia Sakradse, Shiyun Zhu, Miranda Ritterman Weintraub, Julia Jung, Eve Zaritsky.
      Introduction Transgender and gender diverse (TGD) populations with hereditary cancer syndromes face unique barriers to care and thus may not be accessing appropriate cancer screening or risk-reducing procedures. Our objective was to evaluate health care utilization of TGD patients with hereditary cancer syndromes. This includes counseling received, cancer screenings conducted, and risk-reducing procedures performed. Methods A case series of TGD patients (N = 11) with hereditary breast and ovarian cancer (n = 9) or Lynch syndrome (n = 2) who received care within Kaiser Permanente Northern California between 2009 and 2019. Results All patients received counseling and prophylactic options. Three patients (27%) completed all recommended screening, 6 (54%) had partial screening, 1 (9%) received no screening, and 1 (9%) did not require any screening. Six (55%) underwent a risk-reducing procedure. Discussion This case series highlights that despite all the study participants being appropriately counseled by practitioners about their risk of cancer, screening, and prophylactic options, in many cases, the screening received was partial or absent. Relatively few completed all the recommended screenings based on their clinical risk factors. Conclusion Many of the TGD patients with hereditary cancer syndromes in this cohort did not complete all the recommended cancer screening. This can be an area of focus in order to improve the quality of care provided to this vulnerable population.
    Keywords:  cancer screening; hereditary cancer syndrome; prophylactic surgery; transgender
    DOI:  https://doi.org/10.7812/TPP/21.133
  7. Leukemia. 2022 Aug 08.
    Germline GATA1 exon 2 mutation associated with chronic cytopenia and a non-down syndrome transient abnormal myelopoiesis with clonal trisomy 21.
    Ricardo Camargo, Sushree S Sahoo, José Carlos Córdoba, Isis Quezado Magalhães.
      
    DOI:  https://doi.org/10.1038/s41375-022-01638-6
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