bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022‒10‒09
six papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. BRCA1/2 Variants Identified Through Tumor Genomic Profiling: Assessing Genetic Counseling Outcomes.
  2. Initial outcomes and insights from a novel high-risk prostate cancer screening clinic.
  3. Adult-onset hereditary myeloid malignancy and allogeneic stem cell transplantation.
  4. Clinically relevant germline variants in allogeneic hematopoietic stem cell transplant recipients.
  5. Temporal Patterns and Adoption of Germline and Somatic BRCA Testing in Ovarian Cancer.
  6. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium.
  1. JCO Precis Oncol. 2022 Oct;6 e2100375
    BRCA1/2 Variants Identified Through Tumor Genomic Profiling: Assessing Genetic Counseling Outcomes.
    Jamie W Harriman, Whitney F Espinel, Jennie Vagher, Amanda Gammon.
      PURPOSE: As tumor genomic profiling (TGP) is increasingly used to help guide cancer treatment, BRCA variants, which may or may not be reflective of the germline genome, are being identified. As TGP use increases, it is becoming an important tool for referral to genetic counseling and identifying patients with hereditary cancer syndromes such as hereditary breast and ovarian cancer. This study explores genetic counseling referral patterns and germline implications of patients found to have pathogenic BRCA1/2 variants identified through TGP.METHODS: Participants include patients at Huntsman Cancer Institute undergoing TGP through a single commercial laboratory between March 2014 and July 2018. A retrospective chart review was conducted for 62 patients found to have pathogenic variants (PVs) in BRCA1/2 on TGP. Data on genetic counseling referrals and uptake, germline test results, family history, and patient demographics were collected.
    RESULTS: In the study time frame, 1,899 patients underwent TGP. Testing identified 67 PVs in BRCA1 (23 variants) or BRCA2 (44 variants) in 62 patients. Thirty-five patients first received a referral to a genetic counselor following TGP with 33 patients completing genetic counseling. Of the 30 patients who pursued germline genetic testing following TGP, 11 were discovered to have a previously unknown germline BRCA PV. Nine of these patients were the first in their family diagnosed with hereditary breast and ovarian cancer.
    CONCLUSION: This study represents one institution's experience with genetic counseling referrals, uptake, and germline results following TGP. For some patients, TGP will be the first indicator of an underlying hereditary condition. Identifying patients with PVs (which may be germline) through TGP is an important new genetic counseling referral tool that can have important implications for the patient and their family.
    DOI:  https://doi.org/10.1200/PO.21.00375
  2. Prostate. 2022 Oct 07.
    Initial outcomes and insights from a novel high-risk prostate cancer screening clinic.
    Jonathan B Harper, Samantha E Greenberg, Trevor C Hunt, Kathleen A Cooney, Brock B O'Neil.
      INTRODUCTION: Guidelines for germline testing in patients with prostate cancer (PCa) are identifying family members who require additional surveillance given pathogenic variants (PVs) that confer increased PCa risk. We established an interdisciplinary clinic for cancer surveillance in high-risk individuals aimed to implement screening recommendations. This study aimed to characterize the clinical features of this cohort.PATIENTS AND METHODS: The Prostate Cancer Risk Clinic (PCRC) was established for unaffected individuals with germline PVs or a strong PCa family history. PCa screening, urine labs, and questionnaires were included in the visit. Individuals with BRCA1/2 PVs underwent clinical breast exam as well. Data from the initial visit were abstracted from the medical record and questionnaires for analysis.
    RESULTS: Thirty-five individuals with increased PCa risk were followed by the PCRC with a median age of 47 years of age. Twenty individuals (57%) had a family history of PCa, and 34 (97%) had a germline PV associated with an increased risk for developing PCa. Four individuals underwent biopsy due to care in the PCRC, with one PCa identified in an individual with TP53 PV. Median patient response scores indicated mild symptoms of an enlarged prostate (AUASS), normal erectile function (SHIM), and relatively low anxiety about developing PCa (MAX-PC). However, there were notable "outlier" scores on each questionnaire.
    CONCLUSIONS: Individuals with prostates and BRCA1/2 PVs, among other germline PVs, can benefit from a comprehensive interdisciplinary approach to high-risk management. PCa was identified in an individual with a non-BRCA PV, emphasizing the importance and need for high-risk screening guidelines across all genes with increased risk for PCa. "Outlier" patient response scores demonstrate that some participants experienced worse symptoms or anxiety than was indicated by median scores alone.
    Keywords:  early detection of cancer; genetic counseling; patient-reported outcome measures; prostate cancer-familial; prostate cancer-hereditary; prostatic neoplasms
    DOI:  https://doi.org/10.1002/pros.24447
  3. Front Oncol. 2022 ;12 997530
    Adult-onset hereditary myeloid malignancy and allogeneic stem cell transplantation.
    Takashi Toya, Hironori Harada, Yuka Harada, Noriko Doki.
      Hereditary myeloid malignancies, especially in adults or elderly persons, had been considered quite rare before the next-generation sequencing era; however, increased usage of clinical sequencing has revealed much higher prevalence of inherited myeloid malignancies. DDX41 and various pathogenic germline mutations have newly been recognized as the cause of adult-onset familial leukemia and myeloid malignancies. Although germline predisposition to myeloid neoplasms had been categorized as a provisional entity in the World Health Organization classification of hematopoietic neoplasms in 2016, methodology for the identification of hereditary myeloid malignancies has not been fully established yet. In addition, many unresolved problems, such as epidemiology, the exact pathogenic mechanisms, and ideal treatment strategy, including indications of allogeneic hematopoietic stem cell transplantation, still remain. Related donor selection for stem cell transplant is a particularly sensitive issue due to the possibility of germline mutation of the candidate relatives and the risk of donor cell leukemia after transplantation. Here, we reviewed the current evidence regarding epidemiology, diagnosis, mechanisms of progression, and transplantation strategy for hereditary myeloid malignancies.
    Keywords:  allogeneic stem cell transplantation; donor cell leukemia; genetic testing; germline mutation; hereditary myeloid malignancy
    DOI:  https://doi.org/10.3389/fonc.2022.997530
  4. Bone Marrow Transplant. 2022 Oct 04.
    Clinically relevant germline variants in allogeneic hematopoietic stem cell transplant recipients.
    Atte K Lahtinen, Jessica Koski, Jarmo Ritari, Kati Hyvärinen, Satu Koskela, Jukka Partanen, Kim Vettenranta, Minna Koskenvuo, Riitta Niittyvuopio, Urpu Salmenniemi, Maija Itälä-Remes, Kirsi Jahnukainen, Outi Kilpivaara, Ulla Wartiovaara-Kautto.
      Allogeneic hematopoietic stem cell transplantation (HSCT) provides patients with severe hematologic disease a well-established potential for curation. Incorporation of germline analyses in the workup of HSCT patients is not a common practice. Recognizing rare harmful germline variants may however affect patients' pre-transplantation care, choice of the stem cell donor, and complication risks. We analyzed a population-based series of germline exome data of 432 patients who had undergone HSCT. Our aim was to identify clinically relevant variants that may challenge the outcome of the HSCT. We focused on genes predisposing to hematological diseases, or solid tumors, and genes included in the American College of Medical Genetics secondary findings list v3.0. As population-specific controls, we used GnomAD non-cancer Finns (n = 10,816). We identified in our population-based analysis rare harmful germline variants in disease-predisposing or actionable toxicity-increasing genes in 17.8% of adult and pediatric patients that have undergone HSCT (15.1% and 22.9%, respectively). More than half of the patients with a family member as a donor had not received genetic diagnosis prior to the HSCT. Our results encourage clinicians to incorporate germline genetic testing in the HSCT protocol in the future in order to reach optimal long-term outcome for the patients.
    DOI:  https://doi.org/10.1038/s41409-022-01828-x
  5. Obstet Gynecol. 2022 Oct 06.
    Temporal Patterns and Adoption of Germline and Somatic BRCA Testing in Ovarian Cancer.
    Sarah P Huepenbecker, Jason D Wright, Mary K Downer, Devin Incerti, Patricia Luhn, Ignacio Dolado, Lydie Bastiere-Truchot, Yvonne G Lin, John K Chan, Larissa A Meyer.
      OBJECTIVE: To describe the testing rate, patient characteristics, temporal trends, timing, and results of germline and somatic BRCA testing in patients with ovarian cancer using real-world data.METHODS: We included a cross-sectional subset of adult patients diagnosed with ovarian cancer between January 1, 2011, and November 30, 2018, who received frontline treatment and were followed for at least 1 year in a real-world database. The primary outcome was receipt of BRCA testing, classified by biosample source as germline (blood or saliva) or somatic (tissue). Lines of therapy (frontline, second line, third line) were derived based on dates of surgery and chemotherapy. Descriptive statistics were analyzed.
    RESULTS: Among 2,557 patients, 72.2% (n=1,846) had at least one documented BRCA test. Among tested patients, 62.5% (n=1,154) had only germline testing, 10.6% (n=197) had only somatic testing, and 19.9% (n=368) had both. Most patients had testing before (9.7%, n=276) or during (48.6%, n=1,521) frontline therapy, with 17.6% (n=273) tested during second-line and 12.7% (n=129) tested during third-line therapy. Patients who received BRCA testing, compared with patients without testing, were younger (mean age 63 years vs 66 years, P<.001) and were more likely to be treated at an academic practice (10.4% vs 7.0%, P=.01), with differences by Eastern Cooperative Oncology Group performance score (P<.001), stage of disease (P<.001), histology (P<.001), geography (P<.001), and type of frontline therapy (P<.001), but no differences based on race or ethnicity. The proportion of patients who received BRCA testing within 1 year of diagnosis increased from 24.6% of patients in 2011 to 75.6% of patients in 2018.
    CONCLUSION: In a large cohort of patients with ovarian cancer, significant practice disparities existed in testing for actionable BRCA mutations. Despite increased testing over time, many patients did not receive testing, suggesting missed opportunities to identify patients appropriate for targeted therapy and genetic counseling.
    DOI:  https://doi.org/10.1097/AOG.0000000000004958
  6. Hered Cancer Clin Pract. 2022 Oct 01. 20(1): 36
    Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium.
    European Hereditary Tumour Group (EHTG) and the International Mismatch Repair Consortium (IMRC)
      OBJECTIVE: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants.METHODS: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands.
    RESULTS: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups.
    CONCLUSIONS: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
    Keywords:  Colonoscopy; Colorectal cancer; Epidemiology; Incidence; Lynch Syndrome; Over-diagnosis; Penetrance; Prevention; Prospective; Segregation analysis
    DOI:  https://doi.org/10.1186/s13053-022-00241-1
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