bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒08‒16
ten papers selected by
Joanna Zawacka-Pankau
University of Warsaw


  1. Hered Cancer Clin Pract. 2020 ;18 17
    Macklin-Mantia SK, Hines SL, Kasi PM.
      Background: Patients with DNA-damage response genes (DDR)-related pancreas cancer (BRCA1/2 or other DNA-damage related genes) may have improved outcomes secondary to increased sensitivity to DNA-damaging drugs (platinum chemotherapy/ poly ADP ribose polymerase (PARP)-inhibitors). However, data is scarce pertaining to outcomes in this subset of patients. Our objective was to retrospectively identify DDR-related pancreas cancer patients and report on clinical outcomes.Methods: Pancreas cancer patients with a germline pathogenic variant in BRCA1/2 or other DDR gene were identified retrospectively through review of medical records (medical genetics/oncology) and genetic testing results at our institution. Data regarding clinical outcomes, therapy received, and survival was subsequently extracted.
    Results: A total of 11 patients with pancreas cancer were identified to carry a pathogenic DDR-variant: BRCA1 (3), ATM (4), BRCA2 (2), PALB2 (1) and FANCC (1). Five of these individuals had prior history of other cancers. Clinically these tumors were localized (4), locally advanced (3), and metastatic (4) at diagnosis. Four out of 11 patients were still alive at time of data review. Survival in the 7 patients who had died was 13.7, 140.0, 20.5, 22.3, 23.5, 25.8, and 111.5 months. All patients with advanced disease had exposure to platinum chemotherapy.
    Conclusions: Historical survival in patients with advanced and metastatic pancreas cancer is poor. Results of this DDR-subset of patients do show significantly superior outcomes, likely secondary to exposure to platinum drugs. This data, alongside other similar cohorts, would favor the DDR-genes being a predictive marker with improved survival if exposed to these drugs and the new class of drugs, PARP-inhibitors.
    Keywords:  BRCA1/2; Genetic testing; Hereditary cancer; PARP inhibitors; Pancreatic cancer; Platinum chemotherapy
    DOI:  https://doi.org/10.1186/s13053-020-00148-9
  2. JCO Precis Oncol. 2019 ;3
    Cadoo KA, Mandelker DL, Mukherjee S, Stewart C, DeLair D, Ravichandran V, Srinivasan P, Hurley D, Kemel Y, Arnold AG, Sheehan M, Pradhan N, Joseph V, Chi DS, Gardner GJ, Jewell EL, Leitao MM, Roche KL, Mueller JJ, Sonoda Y, Zivanovic O, Walsh M, Carlo MI, Berger MF, Hyman D, Zhang L, Robson ME, Offit K, Aghajanian C, Rustum NRA, Stadler Z.
      Purpose: Mutations in DNA mismatch repair (MMR) genes and PTEN, diagnostic of Lynch and Cowden syndromes, respectively, represent the only established inherited predisposition genes in endometrial cancer to date. The prevalence of other cancer predisposition genes remains unclear. We sought the prevalence of pathogenic germline variants in unselected patients with endometrial cancer attending for surgical consultation.Patients and Methods: Patients were prospectively consented (4/2016-5/2017) to an IRB-approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel (MSK-IMPACT) with return of germline results for >75 cancer predisposition genes. Tumors were assessed for microsatellite instability (MSI). Per institutional standards, all tumors underwent Lynch syndrome screening via IHC for MMR proteins.
    Results: Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. Tumors were endometrioid in 104 (67%), of which 60 (58%) were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%)-7 (4.5%) with highly penetrant cancer syndromes and 15 (9.6%) with variants in moderate-, low-penetrance, or recessive genes. Of these, 5 (21%) were in Lynch syndrome genes (2 MSH6, 2 PMS2, and 1 MLH1). All 5 tumors had concordant IHC staining; 2 (40%) were definitively MSI-high by next-generation sequencing. One patient had a known BRCA1 mutation; 1 had SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in moderate- and low-penetrance variants or genes associated with recessive disease.
    Conclusion: In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multi-gene panel testing identifies cancer predisposition gene variants in 14%. This finding may have implications for future cancer screening and risk-reduction recommendations. Universal IHC screening for Lynch syndrome successfully identifies the majority (71%) of high-penetrance germline mutations.
    DOI:  https://doi.org/10.1200/po.18.00338
  3. Cancers (Basel). 2020 Aug 09. pii: E2225. [Epub ahead of print]12(8):
    Picó MD, Sánchez-Heras AB, Castillejo A, Giner-Calabuig M, Alustiza M, Sánchez A, Moreira L, Pellise M, Castells A, Llort G, Yagüe C, Ramon Y Cajal T, Gisbert-Beamud A, Cubiella J, Rivas L, Herraiz M, Garau C, Salces I, Carrillo-Palau M, Bujanda L, López-Fernández A, Alvarez-Urturi C, López MJ, Alenda C, Zapater P, Lacueva FJ, Balaguer F, Soto JL, Murcia Ó, Jover R.
      Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56-2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67-4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44-2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26-5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk.
    Keywords:  colorectal cancer; genetic; risk; surveillance
    DOI:  https://doi.org/10.3390/cancers12082225
  4. Hum Mutat. 2020 Aug 12.
    Bhar S, Zhou F, Reineke LC, Morris DK, Khincha PP, Giri N, Mirabello L, Bergstrom K, Lemon LD, Williams CL, Toh Y, Tarek Elghetany M, Lloyd RE, Alter BP, Savage SA, Bertuch AA.
      Diamond Blackfan anemia (DBA) is a ribosomopathy of variable expressivity and penetrance characterized by red cell aplasia, congenital anomalies, and predisposition to certain cancers, including early onset colorectal cancer (CRC). DBA is primarily caused by a dominant mutation of a ribosomal protein (RP) gene, although approximately 20% of patients remain genetically uncharacterized despite exome sequencing and copy number analysis. While somatic loss-of-function mutations in RP genes have been reported in sporadic cancers, with the exceptions of 5q- myelodysplastic syndrome (RPS14) and microsatellite unstable CRC (RPL22), these cancers are not enriched in DBA. Conversely, pathogenic variants in RPS20 were previously implicated in familial CRC; however, none of the reported individuals had classical DBA features. We describe two unrelated children with DBA lacking variants in known DBA genes who were found by exome sequencing to have de novo novel missense variants in RPS20. The variants affect the same amino acid but result in different substitutions and reduce RPS20 protein level. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. These findings expand the phenotypic spectrum of RPS20 mutation beyond familial CRC to include DBA, which itself is associated with increased risk of CRC. This article is protected by copyright. All rights reserved.
    Keywords:  Diamond Blackfan anemia; RPS20; familial colorectal cancer; ribosomopathy; yeast model
    DOI:  https://doi.org/10.1002/humu.24092
  5. Genet Med. 2020 Aug 10.
    Perez-Valencia JA, Gallon R, Chen Y, Koch J, Keller M, Oberhuber K, Gomes A, Zschocke J, Burn J, Jackson MS, Santibanez-Koref M, Messiaen L, Wimmer K.
      PURPOSE: Biallelic germline mismatch repair (MMR) gene pathogenic variants (PVs) cause constitutional MMR deficiency (CMMRD), a highly penetrant childhood cancer syndrome phenotypically overlapping with neurofibromatosis type 1 (NF1). CMMRD testing in suspected NF1 children without NF1/SPRED1 PVs enables inclusion of CMMRD positives into monitoring programs prior to tumor onset. However, testing is associated with potential harms and the prevalence of CMMRD among these children is unknown.METHODS: Using a simple and scalable microsatellite instability (MSI) assay of non-neoplastic leukocyte DNA to detect CMMRD, we retrospectively screened >700 children suspected of sporadic NF1 but lacking NF1/SPRED1 PVs.
    RESULTS: For three of seven MSI-positive patients germline MMR gene PVs confirmed the diagnosis of CMMRD. Founder variants NM_000535.5(PMS2):c.736_741delinsTGTGTGTGAAG, prevalent in Europe and North America, and NM_000179.2(MSH6):c.10C>G, affecting 1:400 French Canadians, represented two of five PVs. The prevalence of CMMRD was 3/735 (0.41%, 95% confidence interval [CI]: 0.08-1.19%).
    CONCLUSION: Our empirical data provide reliable numbers for genetic counseling and confirm previous prevalence estimations, on which Care for CMMRD consortium guidelines are based. These advocate CMMRD testing of preselected patients rather than offering reflex testing to all suspected sporadic NF1 children lacking NF1/SPRED1 PVs. The possibility of founder effects should be considered alongside these testing guidelines.
    Keywords:  childhood cancer; constitutional mismatch repair deficiency; founder variant; microsatellite instability; neurofibromatosis type 1
    DOI:  https://doi.org/10.1038/s41436-020-0925-z
  6. Br J Haematol. 2020 Aug 07.
    Yoshida M, Tanase-Nakao K, Shima H, Shirai R, Yoshida K, Osumi T, Deguchi T, Mori M, Arakawa Y, Takagi M, Miyamura T, Sakaguchi K, Toyoda H, Ishida H, Sakata N, Imamura T, Kawahara Y, Morimoto A, Koike T, Yagasaki H, Ito S, Tomizawa D, Kiyokawa N, Narumi S, Kato M.
      Monosomy 7 (-7) occurs in various types of paediatric myeloid disorders and has a poor prognosis. Recent studies have demonstrated that patients with germline gain-of-function SAMD9/9L variants and loss-of-function GATA2 variants are prone to developing myelodysplastic syndrome (MDS) associated with -7. However, the prevalence of the genetic variants among paediatric haematologic disorders with -7 is unknown. The present study screened germline variants of GATA2 and SAMD9/9L in 25 patients with various types of paediatric haematological disorders associated with -7. The diagnoses of the 25 patients included MDS (n = 10), acute myeloid leukaemia (AML) and myeloid sarcomas (n = 9), juvenile myelomonocytic leukaemia (n = 3) and other disorders (n = 3). Seven patients with a germline pathogenic GATA2 variant were found. For SAMD9/9L screening, next-generation sequencing was used to detect low-abundance variants and found four novel germline variants. Functional analysis revealed that three out of the four variants showed growth-restricting capacity in vitro and thus, were judged to be pathogenic. Cases with GATA2 mutation tended to be older, compared to those with SAMD9/9L mutations. In conclusion, GATA2 and SAMD9/9L were sequenced in 25 patients with paediatric haematologic disorders associated with -7, and 40% of them were found to have some pathogenic germline variants in the three genes.
    Keywords:   GATA2 ; SAMD9 ; SAMD9L ; monosomy 7; pediatrics
    DOI:  https://doi.org/10.1111/bjh.17006
  7. BMC Cancer. 2020 Aug 10. 20(1): 747
    El Ansari FZ, Jouali F, Marchoudi N, Bennani MM, Ghailani NN, Barakat A, Fekkak J.
      BACKGROUND: Hereditary breast and ovarian cancer (HBOC) is an autosomal dominant inherited cancer susceptibility disorder. Both BRCA1 and BRCA2 genes are considered as high penetrance genes of this syndrome. The identification of BRCA1/2 genetic alterations before cancer development, grant patients the chance to benefit from various medical cancer prevention approaches. Therefore, the appearance of recent advanced technologies in molecular analysis such as next generation sequencing has simplified full BRCA1/2 analysis. Many attempts took place in hope of understanding the molecular germline spectrum of these two genes in Moroccan HBOC patients. However, most of the past projects focused only on young breast cancer cases, lacked ovarian cancer cases in their cohort and only a limited number of these studies were able to analyze the entire exons or copy number variations for both genes. In attempt of gaining more information regarding the molecular profile of BRCA1/2 in HBOC, we conducted a study in which we analyze their molecular profile on selected Moroccan patients suspected of having HBOC syndrome.METHODS: In this study we obtained blood samples from 64 selected Moroccan patients, who suffered from Breast and/or ovarian cancer and had a strong family history for cancer. To analyze BRCA1/2 punctual variants and copy number variations, we used the Ion Personal Genome Machine (PGM) and Oncomine BRCA1/2 research assay panel. Afterward, we correlated the molecular results with the clinic-pathologic data using IBM SPSS Statistics ver 2.
    RESULTS: From the 64 selected cases, Forty-six had breast cancer, fifteen had ovarian cancer and three had both breast and ovarian cancer. The molecular analysis revealed that 18 patients from the 64 harbored a pathogenic variant (28%). Twelve had six different BRCA1 pathogenic variants and six had six different BRCA2 pathogenic variants. In this study, we report four pathogenic variants that to the best of our knowledge has never been reported in the Moroccan population before. Regarding copy number variation analysis, No CNV was detected in both genes for all the 64 successfully sequenced and analyzed patients in our cohort.
    CONCLUSION: Work like the present has an important implication on public health and science. It is critical that molecular profiling studies are performed on underserved and understudied population like Morocco.
    Keywords:  BRCA 2; BRCA1; Hereditary breast and ovarian cancer
    DOI:  https://doi.org/10.1186/s12885-020-07250-0
  8. Sci Rep. 2020 Aug 11. 10(1): 13518
    Hartman TR, Demidova EV, Lesh RW, Hoang L, Richardson M, Forman A, Kessler L, Speare V, Golemis EA, Hall MJ, Daly MB, Arora S.
      Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. Retrospective review of de-identified results from 844 eoRC patients, undergoing testing with a multi-gene panel, for a variety of indications, by Ambry Genetics. PVs in cancer-risk genes were identified in 12.8% of patients-with 3.7% in RC-specific, and 8.55% in DDRR genes. DDRR gene PVs were most commonly identified in CHEK2, BRCA1, BRCA2, and ATM. Among the 2.1% of patients with a BRCA1 or BRCA2 PV, < 50% reported a personal history of hereditary breast or ovarian-associated cancer. No association between age of RC diagnosis and prevalence of PVs in RC-specific or DDRR genes was observed. Additionally, 57.9% patients reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). Multi-gene testing including DDRR genes may provide a more comprehensive risk assessment in eoRC patients. Further validation is needed to characterize the association with eoRC.
    DOI:  https://doi.org/10.1038/s41598-020-70449-5