bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2019‒10‒27
seventeen papers selected by
Joanna Zawacka-Pankau



  1. Urol Oncol. 2019 Oct 17. pii: S1078-1439(19)30361-8. [Epub ahead of print]
    Kwon DH, Borno HT, Cheng HH, Zhou AY, Small EJ.
      BACKGROUND: Prostate cancer is among the most heritable cancers, and clinical testing for germline genetic variants based on ethnicity, disease features, and family history has recently become standard of care for men with advanced disease. It is not established whether prevalence of germline variants varies based on ethnicity or race.METHODS: We retrospectively examined germline genetic and clinical data of men reporting a diagnosis of prostate cancer referred to Color Genomics by a healthcare provider for testing of 30 genes associated with hereditary cancer risk. Variants were classified as pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign, or benign. P/LP and VUS prevalence was compared among subgroups classified by age at diagnosis, self-reported ethnicity, family history, and history of other cancer.
    RESULTS: We identified 1,351 men reporting a diagnosis of prostate cancer of any stage who underwent germline testing. Overall, 78% of men were Caucasian, 11% Ashkenazi Jewish, 3% African-American/Canadian (AAC), 2% Hispanic, 2% Asian/Pacific Islander (API), and 4% Other (multiple, unknown, Native-American). One-hundred eighty-seven men (13.8%) carried a P/LP variant, and the most prevalent P/LP variants were in BRCA2 (3.4%), CHEK2 (2.8%), MUTYH (1.8%), and ATM (1.7%). Age at diagnosis, ethnicity, type of family member with prostate cancer, and type of second cancer were not associated with risk of carrying any P/LP variant. Ashkenazi Jewish men (6.7%) were more likely to carry P/LP BRCA2 variants than Caucasian men (2.8%) (P < 0.05). Two-hundred eighty-four men (21.0%) carried a VUS, and AAC (36.6%) and API (33.3%) men were most likely to carry a VUS (P < 0.01).
    CONCLUSIONS: P/LP germline variants are prevalent in men with prostate cancer. AAC, Hispanic, and API men with prostate cancer are under-represented in studies of germline testing, potentially contributing to higher rates of VUS relative to Caucasian and Ashkenazi Jewish men. Further studies in these groups will facilitate reclassification of VUS, increasing opportunities for early detection, cancer risk modification, and targeted therapeutics.
    Keywords:  Disparities; Germline mutation; Prostate cancer
    DOI:  https://doi.org/10.1016/j.urolonc.2019.09.010
  2. Fam Process. 2019 Oct 24.
    Pantaleao A, Young JL, Epstein NB, Carlson M, Bremer RC, Khincha PP, Peters JA, Greene MH, Roy K, Achatz MI, Savage SA, Werner-Lin A.
      Li-Fraumeni Syndrome (LFS) is a hereditary disorder that confers an approximately 90% lifetime risk of cancer and requires comprehensive lifetime cancer screening. We explored healthcare roles for managing LFS-related cancer risks and treatments that were assumed by parents, adolescents, and adult children. Semi-structured interviews were conducted with 23 families. Family groupings were comprised of 2-5 members, with the younger generation in each family ranging in age from 7 to 40 years. Using grounded theory methods, we conducted open and focused coding of interview transcript content. Family members described how the role of health leader was implemented in their family, as well as factors such as maturation of a child or death of a member that determined who assumed particular roles and how these roles shifted over time. They often expressed collective responsibility for helping relatives understand LFS and implement appropriate cancer risk management. Members demonstrated their health role by attending others' medical appointments for support or information gathering. The health leader role was intergenerational and provided the family necessary support in navigating complicated healthcare decisions. Our findings provide insight into healthcare providers regarding how LFS patients and their relatives develop unique medical decision-making and caring roles influenced by the hereditary nature of LFS, and how these roles change over time. Providers who are attuned to family role dynamics may be better able to meet relatives' psychosocial and medical needs by understanding how living with LFS influences the family system's functioning and facilitating members' support for each other.
    Keywords:  Family; Hereditary Cancer; Li-Fraumeni Syndrome; Psychosocial; Roles; cáncer hereditario; familia; psicosocial; roles; síndrome de Li-Fraumeni; 作用; 家庭; 李-佛美尼综合症; 社会心理; 遗传性癌症
    DOI:  https://doi.org/10.1111/famp.12497
  3. Ann Intern Med. 2019 Oct 22.
    Tischler J, Crew KD, Chung WK.
      Personalization of care through precision medicine and, more specifically, genetic testing is altering the treatment of breast cancer. Genetic testing is used in germline and tumor testing, with each providing distinct data to guide management. Germline testing supports more accurate risk evaluation to inform screening and risk-reducing medical and surgical strategies. Tumor testing can inform cancer recurrence risk assessment and cancer treatment options. This article reviews how genetic testing informs treatment and potential risks for a patient with breast cancer and her family. Hereditary cancer genetic testing of family members should include a discussion of potential results, adverse effects, clinical management options, and insurance coverage and address concerns about privacy or discrimination. Genetic professionals are available to assist with educating, testing, and treating patients with increased cancer risk.
    DOI:  https://doi.org/10.7326/M18-2417
  4. Can J Urol. 2019 Oct;26(5S2): 24-26
    Pritchard CC.
      Germline and tumor genetic testing of DNA repair genes in men with advanced prostate is increasingly recommended by U.S. and international guidelines as part of standard of care. Damaging mutations in homologous DNA repair pathways genes including BRCA2, BRCA1, PALB2, and ATM, and mismatch DNA repair genes including MSH2 and MSH6 have emerging clinical utility for risk assessment and treatment decision-making. This article summarizes a presentation at the 2019 Philadelphia Consensus Conference focused on the latest data at the intersection of germline and tumor genetic testing for prostate cancer patients.
  5. Can J Urol. 2019 Oct;26(5S2): 31-33
    Carroll PR, Witte JS, Parsons JK.
      Men with germline mutations in DNA repair genes are at an increased risk of prostate cancer. These germline mutations are commonly seen in conjunction with somatic DNA repair gene mutations in prostate tumors. This indicates that men with a personal or family history of prostate cancer-as well as other cancer syndromes arising from mutations in DNA repair genes-should be considered for genetic testing and counseling.
  6. Can J Urol. 2019 Oct;26(5S2): 46-47
    Polascik TJ, Orabi H.
      Prostate cancer screening remains controversial in the medical field. While screening men above 50 years can impose overdiagnosis and overtreatment, targeted screening of males with pathologic variants of genetic mutations is evolving and viewed as sensible. Identifying such patients requires genetic testing in males having family history of prostate cancer or certain ethnicity. Such strategies will likely occur as routine practice once favorable results of ongoing studies assessing genetic predisposition are released.
  7. Can J Urol. 2019 Oct;26(5S2): 5-6
    Cookson MS.
      The management of high-risk prostate cancer is evolving. Currently, most decisions are based on traditional factors such as tumor grade and stage. However, we are in a state of evolution. A new understanding of the value of both genetic and somatic germline testing is upon us. Perhaps even more exciting is the recognition that genomic testing can and should be moved up in certain high-risk patients so more effective and targeted therapy can be applied earlier in the disease state.
  8. PLoS One. 2019 ;14(10): e0224023
    Katsidzira L, Vorster A, Gangaidzo IT, Makunike-Mutasa R, Govender D, Rusakaniko S, Thomson S, Matenga JA, Ramesar R.
      BACKGROUND: Approximately 25% of colorectal cancer patients in sub-Saharan Africa are younger than 40 years, and hereditary factors may contribute. We investigated the frequency and patterns of inherited colorectal cancer among black Zimbabweans.METHODS: A population-based cross-sectional study of ninety individuals with a new diagnosis of colorectal cancer was carried out in Harare, Zimbabwe between November 2012 and December 2015. Phenotypic data was obtained using interviewer administered questionnaires, and reviewing clinical and pathology data. Cases were screened for mismatch repair deficiency by immunohistochemistry and/or microsatellite instability testing, and for MLH1, MSH2 and EPCAM deletions using multiplex ligation-dependent probe amplification. Next generation sequencing using a 16-gene panel was performed for cases with phenotypic features consistent with familial colorectal cancer. Variants were assessed for pathogenicity using the mean allele frequency, phenotypic features and searching online databases.
    RESULTS: Three Lynch syndrome cases were identified: MSH2 c.2634G>A pathogenic mutation, c.(1896+1_1897-1)_(*193_?)del , and one fulfilling the Amsterdam criteria, with MLH1 and PMS2 deficiency, but no identifiable pathogenic mutation. Two other cases had a strong family history of cancers, but the exact syndrome was not identified. The prevalence of Lynch syndrome was 3·3% (95% CI 0·7-9·4), and that of familial colorectal cancer was 5·6% (95% CI, 1·8-12·5).
    CONCLUSIONS: Identifying cases of inherited colorectal cancer in sub-Saharan Africa is feasible, and our findings can inform screening guidelines appropriate to this setting.
    DOI:  https://doi.org/10.1371/journal.pone.0224023
  9. Can J Urol. 2019 Oct;26(5S2): 19-21
    Cheng HH.
      Recent studies demonstrate that the prevalence of germline mutations in DNA repair genes in metastatic prostate cancer is higher than previously recognized, and is higher than in localized disease and in unaffected men. This is compelling evidence that specific gene dysfunction is critical in prostate cancer initiation and/or evolution to metastases. Applications to treatment in advanced disease are imminent, and further investigation in early-stage disease, as well as in diverse and at-risk populations will help maximize clinical benefit.
  10. Can J Urol. 2019 Oct;26(5S2): 50-51
    Concepcion RS.
      In an attempt to better understand how community urology practices would begin to incorporate hereditary testing in prostate cancer patients, we developed an eight-question on line survey to identify current testing patterns, utilization of genetic counseling and barriers that practices face. Fifty-two large community urology practices participated. A total of 32/52 (63%) of the responders were already offering testing to select patients. The big hurdles practices were concerned when initiating testing were fear of medical/legal liability (22%), concerns over reimbursement and out of pocket patient expense (20%) and the complexity, time and difficulty to enter a complete family history/pedigree into the EHR (18%).
  11. Clin Gastroenterol Hepatol. 2019 Oct 17. pii: S1542-3565(19)31165-6. [Epub ahead of print]
    Peterse EFP, Naber SK, Daly C, Pollett A, Paszat LF, Spaander MCW, Aronson M, Gryfe R, Rabeneck L, Lansdorp-Vogelaar I, Baxter NN.
      BACKGROUND & AIMS: The province of Ontario, Canada, is considering immunohistochemical followed by cascade analyses of all patients who received a diagnosis of colorectal cancer (CRC) at an age younger than 70 years to identify individuals with Lynch syndrome. We evaluated the costs and benefits of testing for Lynch syndrome and determined the optimal surveillance interval for first-degree relatives (FDRs) found to have Lynch syndrome.METHODS: We developed a patient flow diagram to determine costs and yield of immunohistochemical testing for Lynch syndrome in CRC cases and, for those found to have Lynch syndrome, their FDRs, accounting for realistic uptake. Subsequently, we used the MISCAN-colon model to compare costs and benefits of annual, biennial, and triennial surveillance in FDRs identified with Lynch syndrome vs colonoscopy screening every 10 years (usual care for individuals without a diagnosis of Lynch syndrome).
    RESULTS: Testing 1000 CRC cases was estimated to identify 20 CRC index cases and 29 FDRs with Lynch syndrome at a cost of $310,274. Despite the high cost of Lynch syndrome tests, offering the FDRs with Lynch syndrome biennial colonoscopy surveillance was cost effective at $8785 per life-year gained compared with usual care, due to a substantial increase in life-years gained (+122%) and cost savings in CRC care. Triennial surveillance was more costly and less effective, and annual surveillance showed limited additional benefit compared with biennial surveillance.
    CONCLUSIONS: Immunohistochemical testing for Lynch syndrome in persons younger than 70 years who received a diagnosis of colorectal cancer, and then testing first-degree relatives of those found to have Lynch syndrome, provides a good balance between costs and long-term benefits. Colonoscopy surveillance every 2 years is the optimal surveillance interval for patients with Lynch syndrome.
    Keywords:  colon; family; polyp; risk
    DOI:  https://doi.org/10.1016/j.cgh.2019.10.021
  12. Cancer Discov. 2019 Oct 25.
      Germline mutations in GPR161, encoding a Sonic Hedgehog regulator, predispose to medulloblastoma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2019-162
  13. Am J Surg. 2019 Oct 11. pii: S0002-9610(19)30840-2. [Epub ahead of print]
    Breit C, Ablah E, Ward M, Okut H, Tenofsky PL.
      BACKGROUND: The majority of women who undergo genetic testing due to a significant family history of breast cancer will receive a negative result. The purpose of this study was to calculate the lifetime risk of breast cancer in women undergoing genetic counseling who received an uninformative genetic test result.METHODS: A retrospective chart review of mutation-negative women presenting to a cancer risk assessment clinic was performed. Lifetime risks of breast cancer were calculated using the Claus, Gail, and Tyrer-Cuzick risk assessment models.
    RESULTS: Approximately half (51%) of the women were classified as high-risk by at least one risk assessment model. The Tyrer-Cuzick model identified the highest proportion (43.2%) of patients as high-risk. Four percent (n = 4) of the sample was considered high-risk by all three models.
    CONCLUSIONS: More than half (51%) of women who underwent genetic counseling and received an uninformative negative genetic test result had a significantly elevated risk for the development of breast cancer. It is, therefore, imperative that women do not conclude that a negative genetic test result represents a lack of risk.
    Keywords:  Breast cancer risk assessment; Genetic counseling; High-risk; Negative result; Uninformative result
    DOI:  https://doi.org/10.1016/j.amjsurg.2019.10.015
  14. JAMA Netw Open. 2019 Oct 02. 2(10): e1913900
    Karam R, Conner B, LaDuca H, McGoldrick K, Krempely K, Richardson ME, Zimmermann H, Gutierrez S, Reineke P, Hoang L, Allen K, Yussuf A, Farber-Katz S, Rana HQ, Culver S, Lee J, Nashed S, Toppmeyer D, Collins D, Haynes G, Pesaran T, Dolinsky JS, Tippin Davis B, Elliott A, Chao E.
      Importance: Performing DNA genetic testing (DGT) for hereditary cancer genes is now a well-accepted clinical practice; however, the interpretation of DNA variation remains a challenge for laboratories and clinicians. Adding RNA genetic testing (RGT) enhances DGT by clarifying the clinical actionability of hereditary cancer gene variants, thus improving clinicians' ability to accurately apply strategies for cancer risk reduction and treatment.Objective: To evaluate whether RGT is associated with improvement in the diagnostic outcome of DGT and in the delivery of personalized cancer risk management for patients with hereditary cancer predisposition.
    Design, Setting, and Participants: Diagnostic study in which patients and/or families with inconclusive variants detected by DGT in genes associated with hereditary breast and ovarian cancer, Lynch syndrome, and hereditary diffuse gastric cancer sent blood samples for RGT from March 2016 to April 2018. Clinicians who ordered genetic testing and received a reclassification report for these variants were surveyed to assess whether RGT-related variant reclassifications changed clinical management of these patients. To quantify the potential number of tested individuals who could benefit from RGT, a cohort of 307 812 patients who underwent DGT for hereditary cancer were separately queried to identify variants predicted to affect splicing. Data analysis was conducted from March 2016 and September 2018.
    Main Outcomes and Measures: Variant reclassification outcomes following RGT, clinical management changes associated with RGT-related variant reclassifications, and the proportion of patients who would likely be affected by a concurrent DGT and RGT multigene panel testing approach.
    Results: In total, 93 if 909 eligible families (10.2%) submitted samples for RGT. Evidence from RGT clarified the interpretation of 49 of 56 inconclusive cases (88%) studied; 26 (47%) were reclassified as clinically actionable and 23 (41%) were clarified as benign. Variant reclassifications based on RGT results changed clinical management recommendations for 8 of 18 patients (44%) and 14 of 18 families (78%), based on responses from 18 of 45 clinicians (40%) surveyed. A total of 7265 of 307 812 patients who underwent DGT had likely pathogenic variants or variants of uncertain significance potentially affecting splicing, indicating that approximately 1 in 43 individuals could benefit from RGT.
    Conclusions and Relevance: In this diagnostic study, conducting RNA testing resolved a substantial proportion of variants of uncertain significance in a cohort of individuals previously tested for cancer predisposition by DGT. Performing RGT might change the diagnostic outcome of at least 1 in 43 patients if performed in all individuals undergoing genetic evaluation for hereditary cancer.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2019.13900
  15. J Clin Pathol. 2019 Oct 24. pii: jclinpath-2019-206234. [Epub ahead of print]
    Serra S, Capo-Chichi JM, McCarthy AJ, Sabatini P, Chetty R.
      BACKGROUND: An obligate germline Lynch syndrome carrier had four colonic adenomas removed.MATERIALS AND METHODS: The adenomas were evaluated for grade of dysplasia, MLH1, PMS2, MSH2 and MSH6 protein expression, microsatellite instability (MSI), BRAF, methylation status and a next-generation sequencing (NGS) panel of 52 cancer genes.
    RESULTS: There were four tubular or tubulovillous adenomas from the hepatic flexure, rectosigmoid and rectum; one with low-grade and high-grade dysplasia, one with high-grade dysplasia only and two with low-grade dysplasia. All four adenomas showed retention of MLH1, MHS2 and MSH6 but complete loss of PMS2 in both low-grade and high-grade dysplasia areas.Two of the four adenomas were MSI-high, BRAF V600E wild type and were not MLH1 methylated. NGS identified an MLH1 germline variant: NM_000249.3: c.1558+1 G>A, p.(?) in all tissue (adenomas and normal), which likely explains the pathophysiology of Lynch syndrome in this patient. Other variants were also detected in MLH1 and MSH6 in all four adenomas tested; these being reported previously in somatic colorectal cancers.
    CONCLUSION: We highlight an MLH1 variant in the colonic adenomas in an obligate Lynch syndrome carrier that resulted in PMS2 protein loss in the absence of mutations of the PMS2 gene.
    Keywords:  Lynch syndrome carrier; MLH1 variants; PMS2 loss; mismatch repair
    DOI:  https://doi.org/10.1136/jclinpath-2019-206234
  16. Can J Urol. 2019 Oct;26(5S2): 9
    Soule HR, Miyahira AK.
      The Prostate Cancer Foundation (PCF) is the world's largest non-profit organization that funds patient-centric prostate cancer research. PCF has funded numerous critical studies surrounding the identification, biology, and clinical significance of prostate cancer germline and somatic genetic alterations, and is accelerating the application of these findings to improving outcomes for patients and their families.