bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒05‒03
twelve papers selected by
Joanna Zawacka-Pankau
  1. Cumulative risk of skin cancer in patients with Li-Fraumeni syndrome.
  2. CAR T-cell therapy for a relapsed/refractory acute B-cell lymphoblastic lymphoma patient in the context of Li-Fraumeni syndrome.
  3. Frequency of pathogenic/likely pathogenic germline variants in cancer-related genes among children with acute leukemia in Saudi Arabia.
  4. Detection of germline variants using expanded multigene panels in patients with localized pancreatic cancer.
  5. Spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next-generation sequencing.
  6. Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes.
  7. Genetic testing for hereditary cancer syndromes: patient recommendations for improved risk communication.
  8. Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei.
  9. Hereditary Syndromes in Neuroendocrine Tumors.
  10. Rare germline genetic variants and risk of aggressive prostate cancer.
  11. Characterization of a germline splice site variant MLH1 c.678-3T>A in a Lynch syndrome family.
  12. Germline variant in REXO2 is a novel candidate gene in familial pheochromocytoma.
  1. Fam Cancer. 2020 Apr 30.
    Cumulative risk of skin cancer in patients with Li-Fraumeni syndrome.
    Nieuwenburg SA, Adan F, Ruijs MWG, Sonke GS, van Leerdam ME, Crijns MB.
      Li-Fraumeni syndrome (LFS) is an inherited cancer syndrome, characterized by an early onset of various types of cancers. LFS is associated with a germline mutation in the TP53 gene. The risk of developing skin cancer in patients with LFS is unknown. To evaluate the cumulative risk of skin cancer in patients with LFS and to compare this risk to the general Dutch population. In this retrospective cohort study, all proven TP53 mutation carriers in the Netherlands Cancer Institute were included from their first visit to the Institute until June 2017. Medical charts and pathology reviews cross-referenced with PALGA, the nationwide network and registry of histo- and cytopathology were used to identify incident skin cancers. Cumulative risks were calculated by Kaplan-Meier analysis. Seventy-one patients (59% female) from 33 families were included. Ten patients (14%) developed a total of 19 skin cancers at a median age of 41 (25-65) years. The cumulative risk of skin cancer is 10.4% (95% CI 4.4-23.5%) at age 40, 25.2% (95% CI 12.3-47.6%) at age 60, and a at age 70 this risk is 44.6% (95% CI 22.9-73.9%). The cumulative risks of melanoma and basal cell carcinoma at age 70 are increased compared to the general Dutch population, namely 12.6% (95% CI 3.6-38.4%) and 34.6% (95% CI 15.4-66.2%), respectively. Patients with LFS have an increased risk of developing skin cancer. A dermatological consultation may be considered at least once in individuals with LFS to raise awareness for skin cancer and inform about risk factors.
    Keywords:  Li-fraumeni syndrome; Skin cancer; TP53
    DOI:  https://doi.org/10.1007/s10689-020-00178-1
  2. J Immunother Cancer. 2020 Apr;pii: e000364. [Epub ahead of print]8(1):
    CAR T-cell therapy for a relapsed/refractory acute B-cell lymphoblastic lymphoma patient in the context of Li-Fraumeni syndrome.
    Chen L, Xu B, Long X, Gu J, Lou Y, Wang D, Cao Y, Wang N, Li C, Wang G, Wang Y, Zhu L, Wang J, An H, Xiao M, Xiao Y, Zhou J.
      BACKGROUND: Li-Fraumeni syndrome (LFS) is characterized as an autosomal dominant cancer predisposition disorder caused by germline TP53 gene mutations. Both primary and therapy-related hematopoietic malignancies with LFS are associated with dismal outcomes with standard therapies and even allogenic stem cell transplantation (SCT).CASE PRESENTATION: We reported a relapsed/refractory acute B-cell lymphoblastic lymphoma (B-LBL) patient in the context of LFS. He was identified to harbor a TP53 c.818G>A (p.R273H) germline mutation, and his family history was significant for rectal carcinoma in his father, an unknown cancer in his sister and acute lymphoblastic leukemia in his brother and one of his sons. The patient received murine monoclonal anti-CD19 and anti-CD22 chimeric antigen receptor (CAR) T-cell "cocktail" therapy and achieved complete remission with negative minimal residual disease (MRD), as assessed by morphology and multiparameter flow cytometry. Fifteen months after murine monoclonal CAR T-cell "cocktail" therapy, the patient's B-LBL recurred. Fortunately, a round of fully human monoclonal anti-CD22 CAR T-cell therapy was still effective in this patient, and he achieved CR again and continued to be followed. Each time after infusion, the CAR T-cells underwent extremely rapid exponential expansion, which may be due to the disruption of TP53, a gene that can functionally control cell cycle arrest. Grade 4 and grade 1 cytokine release syndrome occurred after the first and second rounds of CAR T-cell therapy, respectively.
    CONCLUSIONS: This case provides the first report of the use of CAR T-cell therapy in a hematologic malignancy patient with LFS. As traditional chemotherapy and allogenic SCT are not effective therapy strategies for patients with hematologic malignancies and LFS, CAR T-cell therapy may be an alternate choice.ChiCTR-OPN-16008526 and ChiCTR1900023922.
    Keywords:  haematology; immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2019-000364
  3. Pediatr Blood Cancer. 2020 May 02. e28340
    Frequency of pathogenic/likely pathogenic germline variants in cancer-related genes among children with acute leukemia in Saudi Arabia.
    Alsultan A, Essa M, Aljefri A, Ayas M, Alharbi M, Alkhayat N, Al-Anzi F, Yassin F, Alkasim F, Alharbi Q, Abdullah S, Jastaniah W.
      BACKGROUND: The frequency of pathogenic/likely pathogenic (P/LP) germline mutations in cancer-related genes among children with cancer in highly consanguineous populations is not well studied.METHODS: Whole-exome sequencing of germline DNA was performed in 60 children with acute leukemia. We used the St. Jude Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE) data portal for the classification of germline variants by the St. Jude Medal Ceremony pipeline.
    RESULTS: Fifty-seven patients had acute lymphoblastic leukemia (ALL) and three patients had acute myeloid leukemia. Parental consanguinity was present in 27 (45%) patients. All patients were of Arab ancestry. Three patients (5%) had a history of cancer in their siblings. Five patients (8.3%) had P/LP germline mutations in cancer-related genes. Three patients with B-ALL had heterozygous pathogenic mutations in TP53, BRCA1, and BRCA2; one patient with B-ALL had homozygous pathogenic mutation in PMS2; and one patient with T-ALL had LP homozygous mutation in AK2 that was associated with reticular dysgenesis. Among patients who had history of parental consanguinity, three (11%) had P/LP germline mutations compared with two (8%) in the absence of parental consanguinity. Fourteen (23%) patients had gold medal variants in cancer-related genes, 13 were heterozygous, and one was homozygous. Silver medal variants were present in 35 (58%) patients; all were heterozygous except one homozygous.
    CONCLUSIONS: Children with acute leukemia in Saudi Arabia had low frequency of P/LP mutations in cancer-related genes despite the high rate of consanguinity. Larger studies using whole-genome sequencing are needed to further explore the heritability of childhood leukemia.
    Keywords:  acute leukemia; cancer-related genes; children; germline variants
    DOI:  https://doi.org/10.1002/pbc.28340
  4. HPB (Oxford). 2020 Apr 27. pii: S1365-182X(20)30109-X. [Epub ahead of print]
    Detection of germline variants using expanded multigene panels in patients with localized pancreatic cancer.
    Krepline AN, Geurts JL, Akinola I, Christians KK, Clarke CN, George B, Ritch PS, Khan AH, Hall WA, Erickson BA, Griffin MO, Evans DB, Tsai S.
      BACKGROUND: Current guidelines recommend genetic testing for all patients with pancreatic cancer (PC).METHODS: Patients with localized PC who received neoadjuvant therapy between 2009 and 2018 were identified. Genetic consultation (including personal and family history of cancer), genetic testing, and variant data were abstracted.
    RESULTS: Of 510 patients identified, 163 (32%) underwent genetic counseling and genetic testing was performed in 127 (25%). Patients who underwent genetic testing were younger (median age: 63 vs. 67, p = 0.01). Multi-gene testing was performed in 114 (90%) of 127 patients, targeted gene testing was performed in 8 (6%), and not specified in 5 (4%). Of 127 patients who underwent genetic testing, 20 (16%) had pathogenic (P)/likely pathogenic (LP) variants, observed in ATM (n = 7/105,7%), CHEK2 (n = 3/98, 3%), BRCA1 (n = 2/117, 2%), BRCA2 (n = 2/122, 2%), PALB2 (n = 1/115, 1%), MUTYH (n = 1/98, 1%), CDKN2A (n = 1/94, 1%), STK11 (n = 1/97, 1%), NBN (n = 1/98, 1%), and MSH6 (n = 1/97, 1%). Of 20 patients with either a P/LP variant, nine (45%) had a prior cancer, three (15%) had a first-degree relative with PC, and six (30%) had an any-degree relative with PC.
    CONCLUSION: Pathogenic/likely pathogenic variants were identified in 16% of patients who underwent genetic testing, 60% of which occurred in the homologous recombination pathway.
    DOI:  https://doi.org/10.1016/j.hpb.2020.03.022
  5. Cancer. 2020 Apr 27.
    Spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next-generation sequencing.
    Zhou J, Wang H, Fu F, Li Z, Feng Q, Wu W, Liu Y, Wang C, Chen Y.
      BACKGROUND: Partner and localizer BRCA2 (PALB2) is a breast cancer predisposition gene, but the clinical relevance of PALB2 germline mutations in Chinese patients with breast cancer remains unknown. This study attempted to investigate the full prevalence and spectrum of PALB2 germline mutations in China and the associations between PALB2 germline mutations and breast cancer risk.METHODS: A total of 21,216 unselected patients with breast cancer were enrolled from 10 provinces in China, and 5890 Chinese women without cancer were enrolled as healthy controls. PALB2 screening was based on next-generation sequencing.
    RESULTS: A total of 16,501 BRCA1/2-negative patients with breast cancer were analyzed. Deleterious PALB2 mutation carriers accounted for 0.97% (n = 160) in the breast cancer cohort and for 0.19% (n = 11) in the healthy control cohort. Forty-one novel PALB2 germline mutations were identified. A high frequency of PALB2 c.751C>T was detected, and it accounted for 10.63% of the PALB2 germline mutations detected (17 of 160). PALB2 mutations were significantly associated with increased breast cancer risk (odds ratio [OR], 5.23; 95% confidence interval [CI], 2.84-9.65; P < .0001), especially among women 30 years old or younger (OR, 10.09; 95% CI, 3.95-25.79; P < .0001). Clinical characteristics, including a family history, bigger tumor size, triple-negative breast cancer, positive lymph nodes, and bilateral breast cancer, were closely related to PALB2 mutations.
    CONCLUSIONS: This study revealed a comprehensive spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer in China. PALB2 germline mutations confer a moderately increased risk for breast cancer but profoundly increase breast cancer risk for those 30 years old or younger in the Chinese population.
    Keywords:  breast cancer risk; clinical characteristics; germline mutation; next-generation sequencing; partner and localizer BRCA2 (PALB2)
    DOI:  https://doi.org/10.1002/cncr.32905
  6. Sci Rep. 2020 Apr 27. 10(1): 7073
    Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes.
    Talhouet S, Peron J, Vuilleumier A, Friedlaender A, Viassolo V, Ayme A, Bodmer A, Treilleux I, Lang N, Tille JC, Chappuis PO, Buisson A, Giraud S, Lasset C, Bonadona V, Trédan O, Labidi-Galy SI.
      BRCA1/BRCA2 genes play a central role in DNA repair and their mutations increase sensitivity to DNA-damaging agents. There are conflicting data regarding the prognostic value of BRCA germline mutations in breast cancer (BC) patients. We collected clinical, pathological and genetic data of a cohort 925 BC patients preselected for genetic screening and treated with neoadjuvant or adjuvant chemotherapy, of whom 266 were BRCA carriers. Overall, 171 women carried a BRCA1 mutation, 95 carried a BRCA2 mutation, and 659 were non-carriers. In the entire cohort, there was a prolonged disease-free survival (DFS) for BRCA carriers (hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.44-0.90 for BRCA1; HR = 0.72; 95%CI, 0.47-1.1 for BRCA2; p = 0.020) and a trend toward prolonged disease-specific survival (DSS; HR = 0.65; 95%CI, 0.40-1.1 for BRCA1; HR = 0.78; 95%CI, 0.44-1.38 for BRCA2; p = 0.19) though not statistically significant. In the TNBC group, BRCA carriers had prolonged DFS (adjusted HR = 0.50; 95%CI, 0.28-0.89 for BRCA1; adjusted HR = 0.37; 95%CI, 0.11-1.25, for BRCA2; p = 0.034) and DSS (adjusted HR = 0.42; 95%CI, 0.21-0.82 for BRCA1; adjusted HR = 0.45; 95%CI, 0.11-1.9 for BRCA2; p = 0.023). In the non-TNBC group, the BRCA1 or BRCA2 mutations did not have any impact on survival. These results suggest that BRCA1/BRCA2 germline mutations are associated with prolonged survival only if women were diagnosed with TNBC.
    DOI:  https://doi.org/10.1038/s41598-020-63759-1
  7. Health Expect. 2020 Apr 27.
    Genetic testing for hereditary cancer syndromes: patient recommendations for improved risk communication.
    Pollard S, Kalloger S, Weymann D, Sun S, Nuk J, Schrader KA, Regier DA.
      BACKGROUND: Multi-gene panel testing is replacing single-gene testing for patients with suspected hereditary cancer syndromes. The detection of a hereditary cancer syndrome allows tested individuals to initiate enhanced primary and secondary prevention efforts-where available-with a view to reduce disease burden. Current policy prevents testing programmes from communicating genetic test results with potentially affected family members, yet it is well documented that tested individuals face multiple challenges in initiating such discussions with relatives.OBJECTIVE: In response to this challenge, we sought patient recommendations about how to improve genetic risk communication to enhance interfamilial discussions about primary and secondary disease prevention.
    DESIGN: We conducted 25 semi-structured interviews with individuals who received genetic testing through British Columbia's Hereditary Cancer Program between 2017 and 2018. Interviews were professionally transcribed and analysed using a constant comparative approach.
    RESULTS: Participants described difficulty engaging in conversations with relatives who were resistant to receiving genetic risk information, when communicating with younger relatives and where participants reported strained familial relationships. Participants recommended that testing facilities provide a summary of results and implications and that resources be made available to prepare patients for challenging discussions with family members.
    DISCUSSION: Our study demonstrates that individuals undergoing genetic testing for suspected hereditary cancer syndromes would benefit from additional supportive resources alongside genetic counselling. Providing this on-going support will enhance the accurate and transparent communication of risk to facilitate the uptake of cascade testing and enhanced prevention strategies.
    Keywords:  family communication; genetic counselling; genetic testing; hereditary cancer syndromes; medical decision making; risk communication
    DOI:  https://doi.org/10.1111/hex.13062
  8. BMC Cancer. 2020 May 01. 20(1): 369
    Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei.
    Lung MS, Mitchell CA, Doyle MA, Lynch AC, Gorringe KL, Bowtell DDL, , Campbell IG, Trainer AH.
      BACKGROUND: Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours.METHODS: Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ≥10. Genome-wide copy number analysis was performed on tumour tissue from both individuals to identify regions of LOH.
    RESULTS: Fifteen novel variants in 15 genes were shared by the father and daughter, including a nonsense mutation in REEP5. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes (EXOG, RANBP2, RANBP6 and TNFRSF1B) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 individuals with presumed sporadic AMTs or PMP; no LoF or rare missense germline variants were identified.
    CONCLUSION: Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.
    Keywords:  Appendiceal tumour; Exome sequencing; Familial; Germline predisposition; Pseudomyxoma peritonei
    DOI:  https://doi.org/10.1186/s12885-020-6705-y
  9. Curr Treat Options Oncol. 2020 Apr 30. 21(6): 50
    Hereditary Syndromes in Neuroendocrine Tumors.
    Lewis MA.
      OPINION STATEMENT: Oncologists should be able to discern the salient clinical features of the most common germline mutations that give rise to neuroendocrine tumors. Astute recognition of an index patient affected by a hereditary syndrome can lead to a "tip-of-the-iceberg" phenomenon whereby their entire kindred can then be proactively monitored and managed potentially with substantial reduction of morbidity and mortality. Through careful history-taking, as well as thoughtful assimilation of findings from the physical exam, biochemical laboratories, scans, and pathology reports, the clinician can spot phenotypic clues that distinguish these familial patterns from sporadic cases of tumorigenesis.
    Keywords:  Carcinoid tumor; Germline mutation; Multiple endocrine neoplasia; Neuroendocrine tumors; Neurofibromatosis 1; Paraganglioma; Pheochromocytoma; Tuberous sclerosis; Von Hippel-Lindau disease
    DOI:  https://doi.org/10.1007/s11864-020-00749-5
  10. Int J Cancer. 2020 Apr 27.
    Rare germline genetic variants and risk of aggressive prostate cancer.
    Nguyen-Dumont T, MacInnis RJ, Steen JA, Theys D, Tsimiklis H, Hammet F, Mahmoodi M, Pope BJ, Park DJ, Mahmood K, Severi G, Bolton D, Milne RL, Giles GG, Southey MC.
      Few genetic risk factors have been demonstrated to be specifically associated with aggressive prostate cancer (PrCa). Here, we report a case-case study of PrCa comparing the prevalence of germline pathogenic/likely pathogenic (P/LP) genetic variants in 787 men with aggressive disease and 769 with non-aggressive disease. Overall, we observed P/LP variants in 11.4% of men with aggressive PrCa and 9.8% of men with non-aggressive PrCa (two-tailed Fisher's exact tests, P = 0.28). The proportion of BRCA2 and ATM P/LP variant carriers in men with aggressive PrCa exceeded that observed in men with non-aggressive PrCa; 18/787 carriers (2.3%) and 4/769 carriers (0.5%), P = 0.004, and 14/787 carriers (0.02%) and 5/769 carriers (0.01%), P = 0.06, respectively. Our findings contribute to the extensive international effort to interpret the genetic variation identified in genes included on gene-panel tests, for which there is currently an insufficient evidence-base for clinical translation in the context of PrCa risk.
    Keywords:  aggressive prostate cancer; gene panel testing; germline genetic variants
    DOI:  https://doi.org/10.1002/ijc.33024
  11. Fam Cancer. 2020 Apr 30.
    Characterization of a germline splice site variant MLH1 c.678-3T>A in a Lynch syndrome family.
    Yang C, Sheehan M, Borras E, Cadoo K, Offit K, Zhang L.
      Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome. Classification and interpretation of intronic variants, especially those outside the consensus ± 1 ~ 2 splice sites are challenging as it is uncertain whether such variants would affect splicing accuracy and efficiency. The assessment of the pathogenicity of splice site variants in MLH1 is further complicated by the various isoforms due to alternative splicing. In this report, we describe a 42-year-old female with Lynch syndrome who carries a germline variant, MLH1 c.678-3T>A, in the splice acceptor site of intron 8. Functional studies and semiquantitative analysis demonstrated that this variant causes a significant increase in the transcripts with exon 9 or exon 9 and 10 deletions, which presumably leads to premature protein truncation or abnormal protein. In addition, we also observed MSI-H and loss of MLH1 by IHC in patient's tumor tissue. This variant also segregated with Lynch Syndrome related cancers in three affected family members. Based on these evidence, the MLH1 c.678-3T>A variant is considered pathogenic.
    Keywords:  Germline; Lynch syndrome; MLH1; Splice site variant; c.678-3T>A
    DOI:  https://doi.org/10.1007/s10689-020-00180-7
  12. Genet Res (Camb). 2020 May 01. 102 e3
    Germline variant in REXO2 is a novel candidate gene in familial pheochromocytoma.
    Laitman Y, Tzur S, Attai R, Tirosh A, Friedman E.
      Pheochromocytoma (PCC) is a rare, mostly benign tumour of the adrenal medulla. Hereditary PCC accounts for ~35% of cases and has been associated with germline mutations in several cancer susceptibility genes (e.g., KIF1B, SDHB, VHL, SDHD, RET). We performed whole-exome sequencing in a family with four PCC-affected patients in two consecutive generations and identified a potential novel candidate pathogenic variant in the REXO2 gene that affects splicing (c.531-1G>T (NM 015523.3)), which co-segregated with the phenotype in the family. REXO2 encodes for RNA exonuclease 2 protein and localizes to 11q23, a chromosomal region displaying allelic imbalance in PCC. REXO2 protein has been associated with DNA repair, replication and recombination processes and thus its inactivation may contribute to tumorigenesis. While the study suggests that this novel REXO2 gene variant underlies PCC in this family, additional functional studies are required in order to establish the putative role of the REXO2 gene in PCC predisposition.
    Keywords:  REXO2 gene; inherited predisposition; pheochromocytoma; whole-exome sequencing
    DOI:  https://doi.org/10.1017/S0016672320000038
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