bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2019–12–08
thirteen papers selected by
Joanna Zawacka-Pankau
  1. Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation.
  2. Genotype-phenotype correlation in BRCA1/2 mutation-associated pancreatic cancer.
  3. Risk Assessment and Genetic Testing for Inherited Gastrointestinal Syndromes.
  4. Genetic predisposition to MDS: diagnosis and management.
  5. Monitoring and treatment of MDS in genetically susceptible persons.
  6. Identification of germline pathogenic variants in DNA damage repair genes by a next-generation sequencing multigene panel in BRCAX patients.
  7. Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing.
  8. Cancer Susceptibility Mutations in Patients With Urothelial Malignancies.
  9. Renal cell carcinoma in young FH mutation carriers: case series and review of the literature.
  10. Screening Families of North Texans to Identify Persons with an Increased Risk for Cancer Due to Lynch Syndrome.
  11. The Current Practice of Lynch Syndrome Diagnosis and Management in Italy: A Qualitative Assessment.
  12. Racial and Ethnic Differences in BRCA1/2 and Multigene Panel Testing Among Young Breast Cancer Patients.
  13. A case report of a novel germline GNAS mutation in sonic hedgehog activated medulloblastoma.
  1. Br J Cancer. 2019 Dec 02.
    Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation.
    Max M Wattenberg, Daniella Asch, Shun Yu, Peter J O'Dwyer, Susan M Domchek, Katherine L Nathanson, Mark A Rosen, Gregory L Beatty, Evan S Siegelman, Kim A Reiss.
       BACKGROUND: Retrospective studies suggest a survival benefit when platinum-based chemotherapy is administered to patients with pancreatic cancer harbouring a germline mutation in BRCA1, BRCA2 or PALB2 (mut-positive PDAC). However, the objective response rate (ORR) and real-world progression free survival (rwPFS) achieved with such treatment remain ill-defined.
    METHODS: Twenty-six patients with advanced-stage mut-positive PDAC who had been treated with platinum-based therapy were matched by age, race and sex to 52 platinum-treated control PDAC patients. Responses to therapy were determined by RECIST v1.1, performed by blinded radiology review. Measured outcomes included ORR and rwPFS.
    RESULTS: The ORR in mut-positive patients was 58% compared to 21% in the control group (p = 0.0022). There was no significant difference in ORR between platinum regimens in mut-positive patients (p = 0.814), whereas in control patients, the only observed responses were to FOLFIRINOX. rwPFS was 10.1 mo. for mut-positive patients and 6.9 mo. for controls (HR 0.43; 95% CI 0.25-0.74; 0.0068).
    CONCLUSION: Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy. These findings may have implications particularly in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC.
    DOI:  https://doi.org/10.1038/s41416-019-0582-7
  2. Br J Cancer. 2019 Dec 02.
    Genotype-phenotype correlation in BRCA1/2 mutation-associated pancreatic cancer.
    Maeve A Lowery.
      Pancreatic cancers occurring in carriers of a pathogenic germline alteration in BRCA1/2 (gBRCA1/2) are assumed to demonstrate homologous recombination repair deficiency (HRD), associated with sensitivity to platinum-based chemotherapy and synthetic lethality with PARP inhibitors (PARPi). However, primary and secondary resistance to these agents occurs even in this highly selected population.
    DOI:  https://doi.org/10.1038/s41416-019-0645-9
  3. Gastroenterol Hepatol (N Y). 2019 Sep;15(9): 462-470
    Risk Assessment and Genetic Testing for Inherited Gastrointestinal Syndromes.
    Jessica Stoll, Sonia S Kupfer.
      A number of inherited syndromes affect the gastrointestinal tract, including Lynch syndrome and other hereditary colorectal cancers, hereditary polyposis, hereditary gastric cancer, hereditary pancreatic cancer, and hereditary pancreatitis. Recognition and diagnosis of these syndromes are paramount because affected individuals and family members can be offered life-saving screening, risk-reducing surgeries, and other therapies. Genetic counseling and testing are critical components of risk assessment and diagnosis of inherited syndromes. With the advent of next-generation sequencing, multigene panels have significantly changed the practice of genetic counseling and testing. Gastroenterology providers interface with patients who are at risk for inherited gastrointestinal syndromes; thus, providers should learn to recognize these syndromes and know when to refer their patients. Additionally, gastroenterology providers should have an understanding of genetic counseling and be able to interpret multigene panel test results. This article provides an overview of and practical tips for the assessment and diagnosis of hereditary gastrointestinal cancer syndromes and pancreatitis.
    Keywords:  Genetic counseling; direct-to-consumer testing; genetic testing; hereditary gastrointestinal cancers; hereditary pancreatitis
  4. Hematology Am Soc Hematol Educ Program. 2019 Dec 06. 2019(1): 110-119
    Genetic predisposition to MDS: diagnosis and management.
    Elissa Furutani, Akiko Shimamura.
      Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by clonal hematopoiesis with a propensity to evolve into acute myeloid leukemia. MDS presenting in children and young adults is associated with features clinically and biologically distinct from MDS arising in older adults. MDS presenting in children and young adults is associated with a higher likelihood of an underlying genetic predisposition; however, genetic predisposition is increasingly recognized in a subset of older adults. The diagnosis of a genetic predisposition to MDS informs clinical care and treatment selection. Early diagnosis allows a tailored approach to management and surveillance. Genetic testing now offers a powerful diagnostic approach but also poses new challenges and caveats. Clinical expertise in these disorders together with scientific expertise regarding the affected genes is essential for diagnosis. Understanding the basic mechanisms of genetic predisposition to myeloid malignancies may inform surveillance strategies and lead to novel therapies. The cases presented in this article illustrate challenges to the diagnosis of germline genetic predisposition to MDS and how the diagnosis affects clinical management and treatment.
    DOI:  https://doi.org/10.1182/hematology.2019000021
  5. Hematology Am Soc Hematol Educ Program. 2019 Dec 06. 2019(1): 105-109
    Monitoring and treatment of MDS in genetically susceptible persons.
    Stella M Davies.
      Genetic susceptibility to myelodysplastic syndrome (MDS) occurs in children with inherited bone marrow failure syndromes, including Fanconi anemia, Shwachman Diamond syndrome, and dyskeratosis congenita. Available evidence (although not perfect) supports annual surveillance of the blood count and bone marrow in affected persons. Optimal treatment of MDS in these persons is most commonly transplantation. Careful consideration must be given to host susceptibility to DNA damage when selecting a transplant strategy, because significant dose reductions and avoidance of radiation are necessary. Transplantation before evolution to acute myeloid leukemia (AML) is optimal, because outcomes of AML are extremely poor. Children and adults can present with germline mutations in GATA2 and RUNX1, both of which are associated with a 30% to 40% chance of evolution to MDS. GATA2 deficiency may be associated with a clinically important degree of immune suppression, which can cause severe infections that can complicate transplant strategies. GATA2 and RUNX1 deficiency is not associated with host susceptibility to DNA damage, and therefore, conventional treatment strategies for MDS and AML can be used. RUNX1 deficiency has a highly variable phenotype, and MDS can occur in childhood and later in adulthood within the same families, making annual surveillance with marrow examination burdensome; however, such strategies should be discussed with affected persons, allowing an informed choice.
    DOI:  https://doi.org/10.1182/hematology.2019000020
  6. Clin Biochem. 2019 Nov 28. pii: S0009-9120(19)30856-2. [Epub ahead of print]
    Identification of germline pathogenic variants in DNA damage repair genes by a next-generation sequencing multigene panel in BRCAX patients.
    Marta Rodríguez-Balada, Bàrbara Roig, Mireia Melé, Cinta Albacar, Sara Serrano, Mònica Salvat, Montserrat Querol, Joan Borràs, Lourdes Martorell, Josep Gumà.
       BACKGROUND: Approximately 5-10% of breast carcinomas have been related to hereditary conditions and are attributable to pathogenic variants in the BRCA1 and BRCA2 genes, which is referred to as hereditary breast and ovarian cancer (HBOC) syndrome. The inclusion of additional genes that can be related to HBOC syndrome is under intense evaluation due to the high proportion of patients with HBOC criteria who do not present pathogenic mutations in BRCA genes, named BRCAX, despite having high clinical suspicion of hereditary cancer. The main aim is to identify new potentially pathogenic gene variants that may contribute to HBOC to improve the efficiency of routine diagnostic tests in this hereditary condition.
    METHODS: A retrospective cohort of 77 HBOC BRCAX patients was analyzed by next-generation sequencing using a targeted multigene panel composed of 25 genes related to hereditary cancer and deficiencies in DNA repair pathways.
    RESULTS: We found 9 variants in 7 different genes, which were confirmed by automated sequencing. Six variants were classified as pathogenic or likely pathogenic. Three of them were located in the PALB2 gene, one in the BRIP1 gene, one in the BARD1 gene and 1 in the RAD50 gene. In addition, three variants of uncertain significance (VUS) were detected in the TP53, CHEK2, and CDH1 genes.
    CONCLUSIONS: We identified that 8% of BRCAX patients were carriers of pathogenic variants in genes other than BRCA1 and BRCA2. Therefore, wide gene panels, including clinically actionable genes, should be routinely used in the screening of HBOC in our population. We observed differences from other studies in the prevalence of mutated genes, most likely due to differences in the selection criteria of the probands and in the population analyzed. The high incidence of deleterious variant detection in PALB2 supports its significant role in breast cancer susceptibility and reinforces its inclusion in the HBOC genetic diagnostic process.
    Keywords:  BRCA1; BRCA2; DNA repair; Hereditary breast and ovarian cancer; genetic testing; next-generation sequencing
    DOI:  https://doi.org/10.1016/j.clinbiochem.2019.11.014
  7. Sci Rep. 2019 Dec 06. 9(1): 18555
    Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing.
    Mev Dominguez-Valentin, Sigve Nakken, Hélène Tubeuf, Daniel Vodak, Per Olaf Ekstrøm, Anke M Nissen, Monika Morak, Elke Holinski-Feder, Arild Holth, Gabriel Capella, Ben Davidson, D Gareth Evans, Alexandra Martins, Pål Møller, Eivind Hovig.
      We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes. In all, 138 breast cancer (BC) cases, 34 colorectal cancer (CRC) and 19 multiple early-onset cancers were included. A panel of 44 cancer-predisposing genes identified 5% (9/191) pathogenic or likely pathogenic variants and 87 variants of uncertain significance (VUS). Pathogenic or likely pathogenic variants were identified mostly in familial BC individuals (7/9) and were located in 5 genes: ATM (3), BRCA2 (1), CHEK2 (1), MSH6 (1) and MUTYH (1), followed by multiple early-onset (2/9) individuals, affecting the CHEK2 and ATM genes. Eleven of the 87 VUS were tested, and 4/11 were found to have an impact on splicing by using a minigene splicing assay. We here report for the first time the splicing anomalies using this assay for the variants ATM c.3806A > G and BUB1 c.677C > T, whereas CHEK1 c.61G > A did not result in any detectable splicing anomaly. Our study confirms the presence of pathogenic or likely pathogenic variants in genes that are not routinely tested in the context of the above-mentioned clinical phenotypes. Interestingly, more than half of the pathogenic germline variants were found in the moderately penetrant ATM and CHEK2 genes, where only truncating variants from these genes are recommended to be reported in clinical genetic testing practice.
    DOI:  https://doi.org/10.1038/s41598-019-54517-z
  8. J Clin Oncol. 2019 Dec 03. JCO1901395
    Cancer Susceptibility Mutations in Patients With Urothelial Malignancies.
    Maria I Carlo, Vignesh Ravichandran, Preethi Srinavasan, Chaitanya Bandlamudi, Yelena Kemel, Ozge Ceyhan-Birsoy, Semanti Mukherjee, Diana Mandelker, Joshua Chaim, Andrea Knezevic, Satshil Rana, Zarina Fnu, Kelsey Breen, Angela G Arnold, Aliya Khurram, Kaitlyn Tkachuk, Catharine K Cipolla, Ashley Regazzi, A Ari Hakimi, Hikmat Al-Ahmadie, Guido Dalbagni, Karen A Cadoo, Michael F Walsh, Min-Yuen Teo, Samuel A Funt, Jonathan A Coleman, Bernard H Bochner, Gopa Iyer, David B Solit, Zsofia K Stadler, Liying Zhang, Jonathan E Rosenberg, Barry S Taylor, Mark E Robson, Michael F Berger, Joseph Vijai, Dean F Bajorin, Kenneth Offit.
       PURPOSE: Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors.
    PATIENTS AND METHODS: Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database.
    RESULTS: P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [P = .004] and 4.6 [P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants.
    CONCLUSION: Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.
    DOI:  https://doi.org/10.1200/JCO.19.01395
  9. Fam Cancer. 2019 Dec 02.
    Renal cell carcinoma in young FH mutation carriers: case series and review of the literature.
    J A Hol, M C J Jongmans, A S Littooij, R R de Krijger, R P Kuiper, J J T van Harssel, A Mensenkamp, M Simons, G A M Tytgat, M M van den Heuvel-Eibrink, M van Grotel.
      Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant syndrome caused by heterozygous pathogenic germline variants in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and an increased risk of developing renal cell carcinoma (RCC), which is usually adult-onset. HLRCC-related RCC tends to be aggressive and can metastasize even when the primary tumor is small. Data on children and adolescents are scarce. Herein, we report two patients from unrelated Dutch families, with HLRCC-related RCC at the ages of 15 and 18 years, and a third patient with an FH mutation and complex renal cysts at the age of 13. Both RCC's were localized and successfully resected, and careful MRI surveillance was initiated to monitor the renal cysts. One of the patients with RCC subsequently developed an ovarian Leydig cell tumor. A review of the literature identified 10 previously reported cases of HLRCC-related RCC in patients aged younger than 20 years, five of them presenting with metastatic disease. These data emphasize the importance of recognizing HLRCC in young patients to enable early detection of RCC, albeit rare. They support the recommendations from the 2014 consensus guideline, in which genetic testing for FH mutations, and renal MRI surveillance, is advised for HLRCC family members from the age of 8-10 years onwards.
    Keywords:  Adolescents; Children; FH mutation; Fumarate hydratase; HLRCC; Hereditary leiomyomatosis; Renal cell carcinoma
    DOI:  https://doi.org/10.1007/s10689-019-00155-3
  10. Tex Med. 2019 Dec 01. 115(12): e1
    Screening Families of North Texans to Identify Persons with an Increased Risk for Cancer Due to Lynch Syndrome.
    Theodora Ross, Sara Pirzadeh-Miller, Sayoni Lahiri, Amber Gemmell.
      In 2016, the UT Southwestern Medical Center's Cancer Genetics Program was awarded a grant (PP160103) by the Cancer Prevention and Research Institute of Texas (CPRIT) to increase awareness of hereditary cancer syndromes, particularly Lynch syndrome (LS), and implement a population-based genetic screening program to identify those at high genetic risk for cancer.
  11. Public Health Genomics. 2019 Dec 05. 1-19
    The Current Practice of Lynch Syndrome Diagnosis and Management in Italy: A Qualitative Assessment.
    Alessia Tognetto, Roberta Pastorino, Sergio Castorina, Daniele Filippo Condorelli, Andrea DeCensi, Corrado De Vito, Antonio Magnano, Franco Scaldaferri, Paolo Villari, Maurizio Genuardi, Stefania Boccia.
       BACKGROUND: Lynch syndrome (LS) is the most frequent form of hereditary colorectal cancer (CRC; up to 3-5% of the total CRC burden) and predisposes to the development of other cancers. Multidisciplinary diagnostic strategies are relevant both to the index cases and to their at-risk relatives, but their implementation is still limited. Our study aimed to explore LS testing practices in Italy.
    METHODS: In order to ascertain the current practice of LS diagnosis and management, we conducted a qualitative assessment by sending a questionnaire to health care professionals at 4 Italian hospitals selected as "models" representing different hospital settings. Based on the surveys, we reconstructed the management pathways for CRC patients in terms of diagnostic strategies and health professionals involved.
    RESULTS: Seven of the 8 invited professionals filled in the questionnaire. Noncompliance with the latest guidelines was reported, as no tumor "screening" was performed on CRC cases. The lack of a structured multidisciplinary team who manages CRC patients from risk assessment to diagnosis and follow-up was reported. The availability of professionals and laboratory technologies differ widely between hospitals. As for cascade testing of at-risk relatives, a systematic and active approach was absent in all the considered hospitals.
    CONCLUSIONS: Our study shows that no structured and standardized pathways for the diagnosis and management of LS patients are currently in place in Italy. We envisage that by extending our research to further experiences and countries, an increasing awareness of the topic can be translated into a health gain for hereditary CRC patients and their at-risk relatives.
    Keywords:  Cancer genetics; Carrier screening; Genetic testing; Hereditary colorectal cancer; Lynch syndrome; Molecular genetics
    DOI:  https://doi.org/10.1159/000504305
  12. J Cancer Educ. 2019 Dec 04.
    Racial and Ethnic Differences in BRCA1/2 and Multigene Panel Testing Among Young Breast Cancer Patients.
    T Jones, M S Trivedi, X Jiang, T Silverman, M Underhill, W K Chung, R Kukafka, K D Crew.
      Genetic testing for hereditary breast and ovarian cancer (HBOC) is recommended for breast cancer patients diagnosed at age ≤ 50 years. Our objective was to examine racial/ethnic differences in genetic testing frequency and results among diverse breast cancer patients. A retrospective cohort study among women diagnosed with breast cancer at age ≤ 50 years from January 2007 to December 2017 at Columbia University in New York, NY. Among 1503 diverse young breast cancer patients, nearly half (46.2%) completed HBOC genetic testing. Genetic testing completion was associated with younger age, family history of breast cancer, and earlier stage, but not race/ethnicity or health insurance status. Blacks had the highest frequency of pathogenic/likely pathogenic (P/LP) variants (18.6%), and Hispanics and Asians had the most variants of uncertain significance (VUS), 19.0% and 21.9%, respectively. The percentage of women undergoing genetic testing increased over time from 15.3% in 2007 to a peak of 72.8% in 2015. Over the same time period, there was a significant increase in P/LP and VUS results. Due to uncertainty about the clinical implications of P/LP variants in moderate penetrance genes and VUSs, our findings underscore the need for targeted genetic counseling education, particularly among young minority breast cancer patients.
    Keywords:  BRCA1/2 genetic testing; Multigene panel testing; Racial/ethnic minorities; Young breast cancer patients
    DOI:  https://doi.org/10.1007/s13187-019-01646-8
  13. Pediatr Blood Cancer. 2019 Dec 02. e28103
    A case report of a novel germline GNAS mutation in sonic hedgehog activated medulloblastoma.
    Hane Lee for UCLA Clinical Genomics Center
      
    DOI:  https://doi.org/10.1002/pbc.28103
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