bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒05‒23
twenty papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet


  1. J Pediatr Hematol Oncol. 2021 May 18.
      Germline adenomatous polyposis coli (APC) gene mutation is a cancer-predisposing condition commonly presenting as familial adenomatous polyposis. We describe a patient first diagnosed at the age of 3 years with metastatic hepatoblastoma. With a positive family history, germline testing confirmed maternally inherited APC mutation (p.Thr899Ansfs*13). The patient was subsequently diagnosed at 8 years with colonic adenocarcinoma in the absence of macroscopic polyposis. Total colectomy with adjuvant chemotherapy was delivered and the patient remained disease-free for 5 years since the second diagnosis. This report demonstrates the importance of considering germline APC mutation in children with hepatoblastoma, who may benefit from the early institution of colonoscopic surveillance.
    DOI:  https://doi.org/10.1097/MPH.0000000000002209
  2. Nat Rev Gastroenterol Hepatol. 2021 May 17.
      Pancreatic cancer is a leading cause of cancer death worldwide and its global burden has more than doubled over the past 25 years. The highest incidence regions for pancreatic cancer include North America, Europe and Australia, and although much of this increase is due to ageing worldwide populations, there are key modifiable risk factors for pancreatic cancer such as cigarette smoking, obesity, diabetes and alcohol intake. The prevalence of these risk factors is increasing in many global regions, resulting in increasing age-adjusted incidence rates for pancreatic cancer, but the relative contribution from these risk factors varies globally due to variation in the underlying prevalence and prevention strategies. Inherited genetic factors, although not directly modifiable, are an important component of pancreatic cancer risk, and include pathogenic variants in hereditary cancer genes, genes associated with hereditary pancreatitis, as well as common variants identified in genome-wide association studies. Identification of the genetic changes that underlie pancreatic cancer not only provides insight into the aetiology of this cancer but also provides an opportunity to guide early detection strategies. The goal of this Review is to provide an up-to-date overview of the established modifiable and inherited risk factors for pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41575-021-00457-x
  3. Clin J Gastroenterol. 2021 May 21.
      Multiple primary malignant neoplasm (MPMN) is a rare disease with two or more malignant neoplasms in one patient. In less than 0.1% of cancer patients, four or more occur. MPMN is frequently associated with hereditary cancer syndrome, although in rare cases, it is not. A female patient developed 17 MPMNs. Although they were successfully treated with surgery, radiation, and adjuvant chemotherapy, the patient died from the recurrence of ovarian cancer. To explore genetic susceptibility to MPMN, immunohistochemical analysis, microsatellite instability analysis, germ line exome sequencing, and unscheduled DNA synthesis assays were performed. However, the results of immunohistochemical analysis and microsatellite instability indicated that there were no known hereditary cancer syndromes, and exome sequencing with 88 representative genes associated with hereditary cancer syndrome revealed no variants. An unscheduled DNA synthesis assay to rule out xeroderma pigmentosum was also performed, but the result was negative. While the presence of multiple neoplasms is rare, the present case represents 17 primary neoplasms with no associations with hereditary cancer syndrome. Although the cause of MPMN was not detected in this patient, careful follow-up and deliberate cancer screening enabled successful disease management over 17 years from the appearance of the first neoplasm.
    Keywords:  Genetics–cancer genetics; Genodermatosis; Hereditary cancer syndrome; Multiple primary cancer; Surgery
    DOI:  https://doi.org/10.1007/s12328-021-01444-0
  4. Am J Clin Oncol. 2021 May 19.
      OBJECTIVES: Endometrial cancer (EC) risk in BRCA1/2 mutation carriers has been uncertain. EC risk in women with germline BRCA1 or BRCA2 mutations was recently assessed in a multicenter cohort study. BRCA1/2 mutation carriers had a 2- to 3-fold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers. To further evaluate risk, we looked at EC and BRCA1/2 in the UK Biobank cohort.METHODS: EC diagnosis was ascertained using the 10th Revision of the International Classification of Diseases. We analyzed the single nucleotide polymorphisms (SNPs) rs799917 (BRCA1) and rs144848 (BRCA2). A case-control study found a possible association of rs799917 but not rs144848 with EC. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai.
    RESULTS: Percentage ECs within genotypes for SNPs rs799917 and rs144848 was 0.6%. The variability within SNP genotypes was insignificant (P=0.288 for rs799917, 2-tailed Fisher exact test; P=0.931 for rs144848). In comparison, an estimated 70,200 women who had been diagnosed with uterine cancer between 1991 and 2010 were alive in the UK at the end of 2010. A total of 21,892,000 UK residents were ages 50 to 92; approximately half were women. Therefore, prevalence of EC in these UK women was 0.6%, identical to percentage EC within 6 genotypes for SNPs rs799917 and rs144848.
    CONCLUSION: Although we cannot rule out an increase in several rare types of EC, our analysis suggests that the overall incidence or risk of EC does not appear to be increased by the presence of BRCA1 or BRCA2 mutations.
    DOI:  https://doi.org/10.1097/COC.0000000000000833
  5. Br J Cancer. 2021 May 18.
      BACKGROUND: The objective of this study was to establish the contribution of PALB2 mutations to prostate cancer risk and to estimate survival among PALB2 carriers.METHODS: We genotyped 5472 unselected men with prostate cancer and 8016 controls for two Polish founder variants of PALB2 (c.509_510delGA and c.172_175delTTGT). In patients with prostate cancer, the survival of carriers of a PALB2 mutation was compared to that of non-carriers.
    RESULTS: A PALB2 mutation was found in 0.29% of cases and 0.21% of controls (odds ratio (OR) = 1.38; 95% confidence interval (CI) 0.70-2.73; p = 0.45). PALB2 mutation carriers were more commonly diagnosed with aggressive cancers of high (8-10) Gleason score than non-carriers (64.3 vs 18.1%, p < 0.0001). The OR for high-grade prostate cancer was 8.05 (95% CI 3.57-18.15, p < 0.0001). After a median follow-up of 102 months, the age-adjusted hazard ratio for all-cause mortality associated with a PALB2 mutation was 2.52 (95% CI 1.40-4.54; p = 0.0023). The actuarial 5-year survival was 42% for PALB2 carriers and was 72% for non-carriers (p = 0.006).
    CONCLUSION: In Poland, PALB2 mutations predispose to an aggressive and lethal form of prostate cancer.
    DOI:  https://doi.org/10.1038/s41416-021-01410-0
  6. Hum Genome Var. 2021 May 19. 8(1): 19
      We identified a Japanese patient with Lynch syndrome with a novel large germline deletion of chromosome 2p16-21, including the EPCAM, MSH2, and KCNK12 genes. The proband was a 46-year-old man with ascending colon cancer. The clinical significance of germline KCNK12 gene deletion, which encodes one of the subfamilies of two-pore-domain potassium channels, is still unknown.
    DOI:  https://doi.org/10.1038/s41439-021-00152-y
  7. J Gastrointest Oncol. 2021 Apr;12(2): 216-225
      Background: Hereditary diffuse gastric cancer syndrome, attributed to inactivating germline CDH1 variants, is associated with an elevated lifetime risk of gastric cancer. We sought to evaluate cancer detection using probe-based confocal laser endomicroscopy (pCLE) during endoscopic surveillance.Methods: A prospective, single-institution study was conducted in asymptomatic adults with pathogenic or likely pathogenic (P/LP) CDH1 variants. Subjects received endoscopic gastric surveillance using pCLE in conjunction with the Cambridge method (CM). Abnormalities visualized by pCLE were biopsied, followed by non-targeted mucosal biopsies according to the CM. Primary endpoint was to determine pCLE sensitivity for detection of occult SRC carcinoma compared to CM.
    Results: Thirty-six patients with P/LP CDH1 variants underwent endoscopy using pCLE and CM. Majority were female (75%) with median age 47 years. Targeted biopsies of focal abnormalities on WLE were negative for carcinoma. Overall, 19.4% (7/36) patients had SRC detected on ≥1 biopsy. Non-targeted CM biopsies revealed SRC in 11.1% (4/36), whereas pCLE revealed SRC in 16.7% (6/36). Fifteen patients underwent total gastrectomy; all 15 explants contained occult carcinoma. In those 15 patients, the false-negative SRC detection rates for pCLE and CM were 67% and 87%, respectively.
    Conclusions: Confocal endomicroscopy alone has low sensitivity for occult cancer detection in CDH1 variant carriers, although it appeared no worse than the current recommended method and required fewer biopsies per patient. A more reliable endoscopic surveillance is needed as a viable alternative to surgery in this high-risk population (ClinicalTrials.gov, Number: NCT03648879).
    Keywords:  Hereditary gastric cancer; endoscopy; stomach; surveillance
    DOI:  https://doi.org/10.21037/jgo-20-430
  8. Clin Exp Dermatol. 2021 May 19.
      Li-Fraumeni Syndrome (LFS) is a recognised cancer predisposition syndrome associated with early onset of multiple cancer types. It was first described in 1969 following the identification of two soft tissue sarcomas in five families with the index case presenting with rhabdomyosarcoma in childhood.1 The tumour spectrum classically includes a range of soft tissue sarcomas, bone tumours, haematological malignancies, breast cancer and adrenal cortical cancer.
    DOI:  https://doi.org/10.1111/ced.14748
  9. Stem Cell Reports. 2021 May 04. pii: S2213-6711(21)00208-3. [Epub ahead of print]
      Inherited thrombocytopenia results in low platelet counts and increased bleeding. Subsets of these patients have monoallelic germline mutations in ETV6 or RUNX1 and a heightened risk of developing hematologic malignancies. Utilizing CRISPR-Cas9, we compared the in vitro phenotype of hematopoietic progenitor cells and megakaryocytes derived from induced pluripotent stem cell (iPSC) lines harboring mutations in either ETV6 or RUNX1. Both mutant lines display phenotypes consistent with a platelet-bleeding disorder. Surprisingly, these cellular phenotypes were largely distinct. The ETV6-mutant iPSCs yield more hematopoietic progenitor cells and megakaryocytes, but the megakaryocytes are immature and less responsive to agonist stimulation. On the contrary, RUNX1-mutant iPSCs yield fewer hematopoietic progenitor cells and megakaryocytes, but the megakaryocytes are more responsive to agonist stimulation. However, both mutant iPSC lines display defects in proplatelet formation. Our work highlights that, while patients harboring germline ETV6 or RUNX1 mutations have similar clinical phenotypes, the molecular mechanisms may be distinct.
    Keywords:  ETV6; Runx1; embryonic stem cells; hematopoiesis; iPSCs; megakaryocyte
    DOI:  https://doi.org/10.1016/j.stemcr.2021.04.013
  10. J Med Genet. 2021 May 18. pii: jmedgenet-2020-107615. [Epub ahead of print]
      BACKGROUND: Identifying at-risk relatives of individuals with genetic conditions facilitates 'cascade' genetic testing and cancer prevention. Although current standards of care give mutation-positive (index) patients the responsibility of sharing genetic risk information with relatives, the communication is suboptimal, limited largely to close relatives. We developed FamilyCONNECT, a provider-mediated, patient-navigated online tool to facilitate family outreach, and assessed its feasibility, usability and acceptability.METHODS: (1) Development of the FamilyCONNECT prototype; (2) testing using online surveys of: (a) members of Lynch Syndrome (LS) International (LSI); (b) genetics service providers; and (3) hands-on testing with patients with LS.
    RESULTS: (1) FamilyCONNECT's features include introductory email to elicit participation, informational website/video, identity authentication/account creation, informed consent, sharing of genetic test results, pedigree expansion and process to invite at-risk relatives. (2a) 33% of the 170 LSI participants completed the survey. FamilyCONNECT's features received favourable responses from at least 79% of respondents. Unfavourable responses were for length of the consent document and mistrust of opening emailed links. (2b) Thirty-five genetics professionals responded to the providers' survey. Key perceived barriers to FamilyCONNECT's usage were privacy/confidentiality (83%), a lack of institutional resources (76%), a defined process (66%) and time (69%). (3) Ten patients navigated data collection fields and provided feedback for improvements.
    CONCLUSION: FamilyCONNECT tool's content and features were well received among patients with LS as well as providers. The tool could be a viable alternative to increase family outreach among patients with LS. Future efforts will focus on refining FamilyCONNECT and assessing its uptake and utilisation by patients with LS.
    Keywords:  genetic research; information science
    DOI:  https://doi.org/10.1136/jmedgenet-2020-107615
  11. BMC Cancer. 2021 May 19. 21(1): 572
      BACKGROUND: Pregnancy-associated breast cancer (PABC) defined as breast cancer diagnosed during gestation, lactation or within 1 year after delivery, represents a truly challenging situation with significantly increasing incidence rate. The genomic background of PABC has only recently been addressed while the underlying mechanisms of the disease still remain unknown. This analysis aims to further elucidate the frequency of PABC cases attributable to genetic predisposition and identify specific cancer susceptibility genes characterizing PABC.METHODS: A comprehensive 94-cancer gene panel was implemented in a cohort of 20 PABC patients treated in our clinic and descriptive correlation was performed among the results and the patients' clinicopathological data.
    RESULTS: In the present study, 35% of PABC patients tested carried pathogenic mutations in two known cancer predisposition genes (BRCA1 and CHEK2). In total, 30% of the patients carried BRCA1 pathogenic variants. An additional 5% carried pathogenic variants in the CHEK2 gene. Variants of unknown/uncertain significance (VUS) in breast cancer susceptibility genes BRCA2, CHEK2 and BRIP1 were also identified in three different PABC patients (15%). Not all patients carrying germline mutations reported known family history of cancer.
    CONCLUSIONS: Genetic testing should be considered as an option for PABC patients since the disease is highly associated with genetic susceptibility among other predisposing factors. Germline mutation identification may further modify PABC management approach and improve the prognostic outcome.
    Keywords:  BRCA1; BRCA2; BRIP1; Breast cancer; CHEK2; Germline mutation; Pregnancy
    DOI:  https://doi.org/10.1186/s12885-021-08310-9
  12. Development. 2021 May 15. pii: dev199166. [Epub ahead of print]148(10):
      In mammals, the pre-gastrula proximal epiblast gives rise to primordial germ cells (PGCs) or somatic precursors in response to BMP4 and WNT signaling. Entry into the germline requires activation of a naïve-like pluripotency gene regulatory network (GRN). Recent work has shown that suppression of OTX2 expression in the epiblast by BMP4 allows cells to develop a PGC fate in a precise temporal window. However, the mechanisms by which OTX2 suppresses PGC fate are unknown. Here, we show that, in mice, OTX2 prevents epiblast cells from activating the pluripotency GRN by direct repression of Oct4 and Nanog. Loss of this control during PGC differentiation in vitro causes widespread activation of the pluripotency GRN and a deregulated response to LIF, BMP4 and WNT signaling. These abnormalities, in specific cell culture conditions, result in massive germline entry at the expense of somatic mesoderm differentiation. Increased generation of PGCs also occurs in mutant embryos. We propose that the OTX2-mediated repressive control of Oct4 and Nanog is the basis of the mechanism that determines epiblast contribution to germline and somatic lineage.
    Keywords:   Otx2 ; Pluripotency Gene Regulatory Network; Primordial germ cells
    DOI:  https://doi.org/10.1242/dev.199166
  13. J Med Case Rep. 2021 May 22. 15(1): 282
      BACKGROUND: Pheochromocytoma and paraganglioma caused by succinate dehydrogenase gene mutations is called hereditary pheochromocytoma/paraganglioma syndrome. In particular, succinate dehydrogenase subunit B mutations are important because they are strongly associated with the malignant behavior of pheochromocytoma and paraganglioma . This is a case report of a family of hereditary pheochromocytoma/paraganglioma syndrome carrying a novel mutation in succinate dehydrogenase subunit B.CASE PRESENTATION: A 19-year-old Japanese woman, whose father died of metastatic paraganglioma, was diagnosed with abdominal paraganglioma, and underwent total resection. Succinate dehydrogenase subunit B genetic testing detected a splice-site mutation, c.424-2delA, in her germline and paraganglioma tissue. Afterwards, the same succinate dehydrogenase subunit B mutation was detected in her father's paraganglioma tissues. In silico analysis predicted the mutation as "disease causing." She is under close follow-up, and no recurrence or metastasis has been observed for 4 years since surgery.
    CONCLUSIONS: We detected a novel succinate dehydrogenase subunit B mutation, c.424-2delA, in a Japanese family afflicted with hereditary pheochromocytoma/paraganglioma syndrome and found the mutation to be responsible for hereditary pheochromocytoma/paraganglioma syndrome. This case emphasizes the importance of performing genetic testing for patients with pheochromocytoma and paraganglioma suspected of harboring the succinate dehydrogenase subunit B mutation (that is, metastatic, extra-adrenal, multiple, early onset, and family history of pheochromocytoma and paraganglioma) and offer surveillance screening to mutation carriers.
    Keywords:  Hereditary pheochromocytoma/paraganglioma syndrome; Metastatic paraganglioma; Succinate dehydrogenase subunit B; Surveillance
    DOI:  https://doi.org/10.1186/s13256-021-02852-z
  14. World J Gastroenterol. 2021 May 07. 27(17): 1943-1958
      Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease. Recently, patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors. Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8% of patients with sporadic pancreatic cancer. In patients with germline BRCA mutations, platinum-based chemotherapies and poly (ADP-ribose) polymerase inhibitors are effective treatment options which may offer survival benefits. This review will focus on the molecular biology, epidemiology, and management of BRCA-mutated pancreatic cancer. Furthermore, we will discuss future directions for this area of research and promising active areas of research.
    Keywords:  BRCA; Deoxyribonucleic acid repair; Pancreatic cancer; Platinum chemotherapy; Poly (ADP-ribose) polymerase inhibitors; Systemic therapy
    DOI:  https://doi.org/10.3748/wjg.v27.i17.1943
  15. Br J Cancer. 2021 May 20.
      BACKGROUND: p53 plays a key role in the DNA repair process and response to ionising radiation. We sought to determine the clinical phenotype of TP53 mutations and p53 pathway alterations in patients with rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) treated with radiation.METHODS: Of patients with available genomic sequencing, we identified 109 patients with RMS and ES treated to a total of 286 radiation sites. We compared irradiated tumour control among tumours with TP53 mutations (n = 40) to those that were TP53 wild-type (n = 246). We additionally compared irradiated tumour control among tumours with any p53 pathway alteration (defined as tumours with TP53 mutations or TP53 wild-type tumours identified to have MDM2/4 amplification and/or CDKN2A/B deletion, n = 78) to those without such alterations (n = 208).
    RESULTS: The median follow-up was 26 months from radiation. TP53 mutations were associated with worse irradiated tumour control among the entire cohort (hazard ratio, HR = 2.8, P < 0.0001). Tumours with any p53 pathway alteration also had inferior irradiated tumour control (HR = 2.0, P = 0.003). On multivariable analysis, after controlling for tumour histology, intent of radiation, presence of gross disease, and biologically effective dose, TP53 mutations continued to be associated with a radioresistant phenotype (HR = 7.1, P < 0.0001).
    CONCLUSIONS: Our results show that TP53 mutations are associated with increased radioresistance in RMS and ES. Novel strategies to overcome this radioresistance are important for improved outcomes in p53 disruptive RMS and ES.
    DOI:  https://doi.org/10.1038/s41416-021-01438-2
  16. Oncologist. 2021 May 20.
      BACKGROUND: Pembrolizumab, a PD-L1 checkpoint inhibitor, has elicited responses in mismatch repair (MMR) deficient advanced solid tumors, leading to its agnostic approval by the U.S Food and Drug Administration in 2017 when no other therapeutic options are available. However, there is still insufficient data on the response to checkpoint inhibitors in advanced endometrial cancer related to Lynch syndrome (LS) and specifically, in uterine serous carcinoma which is uncommon in LS.KEY POINTS: Even though checkpoint inhibitors are effective in mismatch repair-deficient endometrial cancer, it is unknown whether the response to them differs between women with endometrial cancer due to germline mutations in a mismatch repair gene (Lynch syndrome) and women with sporadic endometrial cancer. In our case, a patient with a Lynch syndrome and recurrent mismatch repair-deficient serous endometrial cancer achieved a durable remission on the first-line therapy with a checkpoint inhibitor pembrolizumab and remains progression-free after more than two years. Based on our observation and the data, suggesting the stronger immune activation in women with Lynch syndrome-associated endometrial cancer, we propose to use checkpoint inhibitor monotherapy early in the course of their treatment and stratify patients for the presence of Lynch syndrome in clinical trials.
    PATIENT STORY: Here we report a case of metastatic uterine serous carcinoma due to a germline MSH6 mutation (Lynch syndrome) which was discovered because of her tumor MMR deficiency. The patient was started on first-line pembrolizumab in 2018 and sustained a partial response. She remains asymptomatic and progression-free for more than two years. Tumor sequencing showed a high mutational burden and an upstream somatic mutation in the same gene, p.F1088fs. Immunohistochemical staining was negative for PD-L1 expression. We discuss clinical characteristics of the patient, molecular features of her tumor, and the mechanism of her tumor response. We also discuss the duration of immunotherapy in her case.
    CONCLUSION: Our case demonstrated a partial response and a long-term remission from the front-line single-agent pembrolizumab in a woman with metastatic uterine serous carcinoma and Lynch syndrome due to a germline MSH6 gene mutation. Our experience suggests a potential significant clinical benefit of checkpoint inhibitors used as single agents early on in the treatment of MMR-deficient/MSI-H/hypermutated uterine cancers in women with Lynch Syndrome.
    Keywords:  Lynch Syndrome; checkpoint inhibitors; endometrial cancer; immunotherapy; molecular biology; uterine serous carcinoma
    DOI:  https://doi.org/10.1002/onco.13832