bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–09–18
thirteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes.
  2. Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer.
  3. Addition of Germline Testing to Tumor-Only Sequencing Improves Detection of Pathogenic Germline Variants in Men With Advanced Prostate Cancer.
  4. ATM serine/threonine kinase germline mutations in chronic lymphocytic leukaemia come in different flavours.
  5. A novel case of hereditary leiomyomatosis- associated renal cell carcinoma with metastasis to pituitary gland.
  6. Clinical implementation of genetic testing in adults for hereditary hematologic malignancy syndromes.
  7. Other Primary Malignancies in Patients with Breast Cancer Who Undergo Germline Panel Testing.
  8. Heritable cancer predisposition testing in pediatric cancer patients excluding retinoblastoma in a middle-income country.
  9. Eligibility, uptake and response to germline genetic testing in women with DCIS.
  10. CT imaging phenotypes linked to CA125 and HE4 biomarkers are highly predictive in discriminating between hereditary and sporadic ovarian cancer patients.
  11. Identifying the BRCA1 c.-107A > T variant in Dutch patients with a tumor BRCA1 promoter hypermethylation.
  12. Fanconi anemia and dyskeratosis congenita/telomere biology disorders: Two inherited bone marrow failure syndromes with genomic instability.
  13. Generation of heterozygous SAMD9 CRISPR/Cas9-edited iPSC line (ESi086-A-3), carrying p.I1567M mutation.
  1. Front Oncol. 2022 ;12 942741
    An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes.
    Alison Schwartz, Danielle K Manning, Diane R Koeller, Anu Chittenden, Raymond A Isidro, Connor P Hayes, Feruza Abraamyan, Monica Devi Manam, Meaghan Dwan, Justine A Barletta, Lynette M Sholl, Matthew B Yurgelun, Huma Q Rana, Judy E Garber, Arezou A Ghazani.
      Genomic profiles of tumors are often unique and represent characteristic mutational signatures defined by DNA damage or DNA repair response processes. The tumor-derived somatic information has been widely used in therapeutic applications, but it is grossly underutilized in the assessment of germline genetic variants. Here, we present a comprehensive approach for evaluating the pathogenicity of germline variants in cancer using an integrated interpretation of somatic and germline genomic data. We have previously demonstrated the utility of this integrated approach in the reassessment of pathogenic germline variants in selected cancer patients with unexpected or non-syndromic phenotypes. The application of this approach is presented in the assessment of rare variants of uncertain significance (VUS) in Lynch-related colon cancer, hereditary paraganglioma-pheochromocytoma syndrome, and Li-Fraumeni syndrome. Using this integrated method, germline VUS in PMS2, MSH6, SDHC, SHDA, and TP53 were assessed in 16 cancer patients after genetic evaluation. Comprehensive clinical criteria, somatic signature profiles, and tumor immunohistochemistry were used to re-classify VUS by upgrading or downgrading the variants to likely or unlikely actionable categories, respectively. Going forward, collation of such germline variants and creation of cross-institutional knowledgebase datasets that include integrated somatic and germline data will be crucial for the assessment of these variants in a larger cancer cohort.
    Keywords:  Li-Fraumeni syndrome; germline VUS; lynch syndrome; paraganglioma; somatic and germline integration; tumor signature profile
    DOI:  https://doi.org/10.3389/fonc.2022.942741
  2. JCO Precis Oncol. 2022 Sep;6 e2100516
    Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer.
    Edward D Esplin, Sarah M Nielsen, Sara L Bristow, Judy E Garber, Heather Hampel, Huma Q Rana, N Jewel Samadder, Neal D Shore, Robert L Nussbaum.
      
    DOI:  https://doi.org/10.1200/PO.21.00516
  3. JCO Precis Oncol. 2022 Aug;6 e2200329
    Addition of Germline Testing to Tumor-Only Sequencing Improves Detection of Pathogenic Germline Variants in Men With Advanced Prostate Cancer.
    Jacob E Berchuck, Daniel Boiarsky, Rebecca Silver, Rajitha Sunkara, Heather M McClure, Harrison K Tsai, Stephanie Siegmund, Alok K Tewari, Jonathan A Nowak, Neal I Lindeman, Huma Q Rana, Atish D Choudhury, Mark M Pomerantz, Matthew L Freedman, Eliezer M Van Allen, Mary-Ellen Taplin.
       PURPOSE: Guidelines recommend somatic and germline testing for men with advanced prostate cancer (PCa). Barriers to widespread implementation result in underutilization of germline testing. Somatic testing alone risks missing pathogenic germline variants (PGVs). We sought to determine whether the addition of germline testing to tumor-only sequencing improves detection of PGVs in men with advanced PCa. Secondarily, we sought to define the added value of combining somatic and germline testing to optimize detection of clinically actionable alterations.
    PATIENTS AND METHODS: We analyzed results of independent germline testing and tumor-only sequencing from 100 men with advanced PCa from a prospective clinical trial (ClinicalTrials.gov identifier: NCT03328091). The primary outcome was the proportion of PGVs not reported with tumor-only sequencing. The secondary outcome was the association of locus-specific loss of heterozygosity for PGVs in homologous recombination genes with clinical-genomic features.
    RESULTS: In the 100 men who underwent germline testing and tumor-only sequencing, 24 PGVs were identified, 17 of which were clinically actionable, in 23 patients. Tumor-only sequencing failed to report four (17%) of the PGVs. One additional PGV (4.2%) had variant allele frequency on tumor-sequencing below the threshold for follow-up germline testing. When integrating tumor-only sequencing with germling testing results, 33% of patients harbored clinically actionable alterations. Rates of locus-specific loss of heterozygosity were higher for BRCA2 PGVs in castration-resistant PCa than PGVs in other homologous recombination genes in hormone-sensitive PCa (P = .029).
    CONCLUSION: Tumor-only sequencing failed to report more than 20% of PGVs in men with advanced PCa. These findings strongly support guideline recommendations for universal germline and somatic testing in this population. Combining tumor and germline sequencing doubled the chance of detecting a clinically actionable alteration.
    DOI:  https://doi.org/10.1200/PO.22.00329
  4. Br J Haematol. 2022 Sep 16.
    ATM serine/threonine kinase germline mutations in chronic lymphocytic leukaemia come in different flavours.
    Ana Rio-Machin.
      
    Keywords:  cancer genetics; chronic lymphocytic leukaemia; germline variants; variants of unknown significance (VUS)
    DOI:  https://doi.org/10.1111/bjh.18458
  5. Urol Case Rep. 2022 Nov;45 102206
    A novel case of hereditary leiomyomatosis- associated renal cell carcinoma with metastasis to pituitary gland.
    Catalina A Palma, Geoffrey Watson, Peter Earls, Nitya Patanjali, Jerome Laurence, Scott Leslie.
      Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare genetic disorder characterised by a germline mutation of the fumarate hydratase (FH) gene, in which affected individuals have a high likelihood of developing cutaneous leiomyomas, uterine leiomyomas and renal cell cancer (RCC). HLRCC-associated RCC is characterised by presentation at a younger age than the sporadic form, its aggressive nature and rapid metastatic potential. We present the case of a 50 year old woman with FH mutation, a history of early onset symptomatic uterine leiomyomas, and RCC with the first reported case of an isolated metastasis to the pituitary gland.
    Keywords:  HLRCC, Hereditary Leiomyomatosis and renal cell cancer; Hereditary leiomyomatosis and renal cell cancer; IVC, Inferior vena cava; Metastasis; Pituitary gland; RCC, Renal cell carcinoma
    DOI:  https://doi.org/10.1016/j.eucr.2022.102206
  6. Genet Med. 2022 Sep 16. pii: S1098-3600(22)00901-7. [Epub ahead of print]
    Clinical implementation of genetic testing in adults for hereditary hematologic malignancy syndromes.
    Safa Ansar, Janet Malcolmson, Kirsten M Farncombe, Karen Yee, Raymond H Kim, Hassan Sibai.
       PURPOSE: As research on hereditary hematologic malignancy syndromes (HHMS) are accumulating, cancer genetics clinics are identifying more adult hematology patients with an inherited component to their disease. However, investigations for HHMS are complex, and there is no formal consensus on genetic testing criteria.
    METHODS: We developed genetic testing criteria for adult hematology patients through a comprehensive literature review and our experience at the Princess Margaret Cancer Centre. We validated our criteria by applying them retrospectively to patients referred to our clinic for HHMS assessment.
    RESULTS: Our genetic testing criteria are comprehensive of myeloid malignancies, lymphoid malignancies, and bone marrow failure, including age at diagnosis, family history, and genetic test results in blood and bone marrow. Of the 104 patients who met the criteria, 26% had at least 1 actionable variant in any gene associated with an increased risk of cancer and 13% had an actionable variant resulting in an HHMS diagnosis. A total of 15 patients had incidental findings, including 11 patients with a pathogenic variant associated with carrier status for an autosomal recessive disorder and 4 patients with a mosaic result.
    CONCLUSION: Our high gene positivity rate shows the utility of a broad approach to germline testing in an adult hematology population.
    Keywords:  Genetic testing; Germline; Hematologic malignancy; Hereditary
    DOI:  https://doi.org/10.1016/j.gim.2022.08.010
  7. Ann Surg Oncol. 2022 Sep 12.
    Other Primary Malignancies in Patients with Breast Cancer Who Undergo Germline Panel Testing.
    Brittany L Murphy, Min Yi, Angelica M Gutierrez Barrera, Debu Tripathy, Kelly K Hunt, Banu K Arun.
       BACKGROUND: Women with a history of breast cancer (BC) more commonly have a diagnosis of other primary malignancies (OPMs) than the general population. This study sought to evaluate OPMs among patients with BC who underwent germline testing with a hereditary BC gene panel.
    METHODS: The study identified women 18 years of age or older with a history of unilateral BC who underwent multi-gene panel testing between January 2014 and August 2019 at the authors' institution. Patient, tumor, and treatment factors for BC and OPM diagnoses were collected for descriptive, univariate, and overall survival (OS) analyses.
    RESULTS: Among 1163 patients, 330 (28.4%) had an OPM. The median follow-up period was 4.1 years from BC diagnosis. Of the 1163 patients, 209 (18%) had a BRCA pathogenic variant (PV), 306 (26.4%) had a non-BRCA PV, and 648 (55.7%) had no PV. Development of an OPM varied according to germline testing result, with an OPM developing for 18.6% (39/209) of the patients with a BRCA PV, 31.8% (204/648) of the patients with no PV, and 28.4% (87/306) of the patients with a non-BRCA PV (p < 0.0001). The most common OPMs were ovarian (n = 60), uterine (n = 44), sarcoma (n = 36), melanoma (n = 27), colorectal (n = 22), and lymphoma (n = 20) malignancies. The 5-year OS was 96%. The patients with an OPM 5 years after BC diagnosis had a shorter OS than those who did not (93.4% vs 97.5%; p = 0.002).
    CONCLUSION: More than 25% of women with BC who underwent germline panel testing had an OPM diagnosed during the short-term follow-up period, and the diagnosis of an OPM was associated with reduced OS. These data have implications for counseling BC patients who undergo germline testing regarding future cancer screening.
    DOI:  https://doi.org/10.1245/s10434-022-12468-2
  8. Pediatr Blood Cancer. 2022 Sep 12. e29982
    Heritable cancer predisposition testing in pediatric cancer patients excluding retinoblastoma in a middle-income country.
    Omar El Khatib, Yasser Yahya, Rami Mahfouz, Lama Hamadeh, Maya Basbous, Miguel R Abboud, Samar Muwakkit, Carlos Rodriguez-Galindo, Sima Jeha, Raya Saab.
      Resource-limited settings often have financial barriers to genetic testing for heritable cancer. This retrospective study investigated the pattern of heritable cancer predisposition testing in a middle-income country over the period 2014-2021, excluding retinoblastoma. After establishing a specific fund in 2019, rate of tests increased from 1.1% to 10.9% of new diagnoses. Most common testing was for constitutional mismatch repair deficiency (CMMRD), rhabdoid predisposition syndrome, TP53 (tumor protein 53) mutation, and hereditary cancer panel. Of 33 patients, 13 (39%) tested positive, 12 (36%) negative, and eight (24%) had variants of unknown significance. Positivity rate was 43% for a clinical phenotype and 44% for a tumor type indication.
    Keywords:  cancer predisposition; genetic testing; heritable cancer; pediatric oncology
    DOI:  https://doi.org/10.1002/pbc.29982
  9. Front Oncol. 2022 ;12 918757
    Eligibility, uptake and response to germline genetic testing in women with DCIS.
    Lauren Turza, Leann A Lovejoy, Clesson E Turner, Craig D Shriver, Rachel E Ellsworth.
       Background: Ductal carcinoma in situ (DCIS) is a malignant, yet pre-invasive disease of the breast. While the majority of DCIS have low risk of recurrence, a subset of women with germline pathogenic variants (PV) in cancer predisposition genes are at increased risk for recurrence. Uptake of genetic testing and subsequent surgical intervention in women with DCIS has not been well-studied. The aim of this study was to evaluate test eligibility parameters, uptake of clinical testing, impact on surgical decision making and second cancer events (SCE) in women with DCIS.
    Methods: Four-hundred eighty-four women diagnosed with unilateral DCIS 2001-2020 were eligible for this study. Demographic, commercial genetic test results and surgical procedures were extracted from the database. Test-eligibility was assigned using National Comprehensive Cancer Network (NCCN) criteria. Panel genetic testing was performed in the research laboratory across 94 cancer predisposition genes. Statistical analyses were performed using Fisher's exact tests and Chi-square analyses with p < 0.05 defining significance.
    Results: Forty-four percent of women were test-eligible at diagnosis of which 63.4% pursued genetic testing before definitive surgery; 9.9% pursued testing only after a second cancer event. Bilateral mastectomy (BM) was significantly higher (p<0.001) in women who had testing before definitive surgery (46.9%) compared to those who had testing afterword (10.8%) and in women who underwent testing before definitive surgery with PV (75%) compared to those without PV (37.5%. p=0.045). Of the 39 women with PV, 20 (51.3%) were detected only in the research setting, with 7 (17.9%) of these women not eligible for genetic testing based on NCCN criteria. In women who did not undergo BM at diagnosis, SCE were significantly higher (p=0.001) in women with PV (33.3%) compared to those without PV (11.9%).
    Conclusion: Pursuit of genetic testing and subsequent use of risk-reducing surgeries in women with PV was suboptimal in women with a primary diagnosis of DCIS. In conjunction, >50% of PV were detected only in the research setting. Because omission of genetic testing in women with DCIS may represent a lost opportunity for prevention, genetic testing at the time of diagnosis should be standard for all women with DCIS.
    Keywords:  ductal carcinoma in situ; genetic testing; germline mutation; recurrence; risk-reducing surgery
    DOI:  https://doi.org/10.3389/fonc.2022.918757
  10. Tumour Biol. 2022 ;44(1): 171-185
    CT imaging phenotypes linked to CA125 and HE4 biomarkers are highly predictive in discriminating between hereditary and sporadic ovarian cancer patients.
    Lucia Manganaro, Veronica Celli, Valentina Viggiani, Elena Berardelli, Teresa Granato, Sara Tartaglione, Antonella Farina, Carlo Catalano, Antonio Angeloni, Emanuela Anastasi.
       BACKGROUND: Hereditary ovarian cancers (HOC) represent about 23% of ovarian cancer (OC) cases: they are most frequently related to germline mutations in the BRCA genes.
    OBJECTIVE: We aimed to compare CA125/HE4 serum levels and Computed Tomography (CT) features at time of ovarian cancer (OC) diagnosis in two populations: BRCA mutant and BRCA wild-type (WT) OC, and to investigate the relationship between this laboratory and radiological biomarker and BRCA mutation status.
    METHODS: This retrospective study included 60 newly diagnosed OC patients with FIGO stage IIIC-IV disease, tested for BRCA1/2 germline mutation status of which preoperative CT scan and serum tumor marker assay were available.
    RESULTS: The median level of CA125 (708 U/mL) was significantly higher (p < 0.002) in BRCA1/2 mutated patients than in WT patients (176 U/mL), whereas the median level of HE4 (492 pmol/L) was significantly higher (p < 0.002) in WT than in BRCA-mutated patients (252 pmol/L). BRCA mutation carriers showed a higher incidence of bilateral ovarian masses (p = 0.0303) characterized by solid structures (p < 0.00001), higher peritoneal tumor load, macronodular implants >2 cm (p = 0.000099), increased frequency of lymphadenopathies (p = 0.019), and metastasis (p = 0.052) compared to patients with BRCA WT.
    CONCLUSIONS: Tumor markers and CT patterns may help in identifying BRCA mutation status in OC directing patients towards a personalized treatment.
    Keywords:  BRCA; HE4-CA125; Ovarian cancer; computed tomography
    DOI:  https://doi.org/10.3233/TUB-211557
  11. Fam Cancer. 2022 Sep 16.
    Identifying the BRCA1 c.-107A > T variant in Dutch patients with a tumor BRCA1 promoter hypermethylation.
    Vincent M T de Jong, Roelof Pruntel, Tessa G Steenbruggen, Fonnet E Bleeker, Petra Nederlof, Frans B L Hogervorst, Sabine C Linn.
      An inherited single nucleotide variant (SNV) in the 5'UTR of the BRCA1 gene c.-107A > T was identified to be related to BRCA1 promoter hypermethylation and a hereditary breast and ovarian cancer phenotype in two UK families. We investigated whether this BRCA1 variant was also present in a Dutch cohort of breast and ovarian cancer patients with tumor BRCA1 promoter hypermethylation. We selected all breast and ovarian cancer cases that tested positive for tumor BRCA1 promoter hypermethylation at the Netherlands Cancer Institute and Sanger sequenced the specific mutation in the tumor DNA. In total, we identified 193 tumors with BRCA1 promoter hypermethylation in 178 unique patients. The wild-type allele was identified in 100% (193/193) of sequenced tumor samples. In a large cohort of 178 patients, none had tumors harboring the previously identified c.-107A > T SNV in BRCA1. We therefore can conclude that the germline SNV is not pervasive in patients with tumor BRCA1 promoter hypermethylation.
    Keywords:  BRCA1; Breast cancer; Methylation
    DOI:  https://doi.org/10.1007/s10689-022-00314-z
  12. Front Oncol. 2022 ;12 949435
    Fanconi anemia and dyskeratosis congenita/telomere biology disorders: Two inherited bone marrow failure syndromes with genomic instability.
    Moisés Ó Fiesco-Roa, Benilde García-de Teresa, Paula Leal-Anaya, Renée van 't Hek, Talia Wegman-Ostrosky, Sara Frías, Alfredo Rodríguez.
      Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.
    Keywords:  Fanconi anemia (FA)/BRCA pathway; GINPOD; PHENOS; VACTERL-H; cancer risk; dyskeratosis congenita (DC); genomic instability; telomere biology disorders
    DOI:  https://doi.org/10.3389/fonc.2022.949435
  13. Stem Cell Res. 2022 Sep 03. pii: S1873-5061(22)00255-0. [Epub ahead of print]64 102906
    Generation of heterozygous SAMD9 CRISPR/Cas9-edited iPSC line (ESi086-A-3), carrying p.I1567M mutation.
    Joan Pera, Julio Castaño, Joan Casamitjana, Alessandra Giorgetti, Damia Romero-Moya.
      Germline SAMD9 mutations are one of the most common alterations that predispose to pediatric myelodysplastic syndrome (MDS), a clonal disorder characterized by ineffective hematopoiesis, increasing the risk of developing acute myeloid leukemia (AML). Up to date, a disease model to study the role of SAMD9 mutation in MDS is still lacking. Here, we have generated a human induced pluripotent stem cell (hiPSC) line carrying SAMD9mut (p.I1567M), taking advantage of CRISPR/Cas9 system. As a result, the genetic engineered hiPSC line represent a new in vitro disease model to understand the impact of SAMD9 mutation at molecular and cellular level during hematopoiesis.
    DOI:  https://doi.org/10.1016/j.scr.2022.102906
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