bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021–06–06
twelve papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Utility of interim blood tests for cancer screening in Li-Fraumeni syndrome.
  2. Oncological Follow-up with 2-[18F]-FDG PET/CT in Li-Fraumeni Syndrome
  3. Inherited Predisposition to Gastric Cancer.
  4. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.
  5. Frequency of CDH1 Germline Mutations in Non-Gastric Cancers.
  6. Double heterozygotes of BRCA1/BRCA2 and mismatch repair gene pathogenic variants: case series and clinical implications.
  7. Prostate cancer risk variants of the HOXB genetic locus.
  8. A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants.
  9. Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility.
  10. Identification of a Splice Variant (c.5074+3A>C) of BRCA1 by RNA Sequencing and TOPO Cloning.
  11. CDH1 Gene Mutation Hereditary Diffuse Gastric Cancer Outcomes: Analysis of a Large Cohort, Systematic Review of Endoscopic Surveillance, and Secondary Cancer Risk Postulation.
  12. Pediatric Rhabdomyosarcoma: Epidemiology and Genetic Susceptibility.
  1. Fam Cancer. 2021 Jun 02.
    Utility of interim blood tests for cancer screening in Li-Fraumeni syndrome.
    Leatrisse Oba, Ana F Best, Phuong L Mai, Maria Isabel Achatz, Paul S Albert, Sharon A Savage, Payal P Khincha.
      Comprehensive annual screening reduces cancer-related mortality in Li-Fraumeni syndrome (LFS), a cancer-prone disorder caused by pathogenic germline TP53 variants. Blood tests at months 4 and 8 between annual screening are recommended but their effectiveness in early cancer detection has not been established. Interim blood counts and inflammatory biomarkers were evaluated in 132 individuals with LFS (112 adults, 87 female, median age 36 years [range 3-68], median follow-up 37 months [range 2-70]) and test abnormalities were observed in 225 (35%). Thirteen cancers in 12 individuals were diagnosed between annual screenings but only one cancer (colorectal adenocarcinoma) was diagnosed due to an abnormal interim blood test. Fisher's exact test and generalized estimating equation models found no statistical associations between cancer diagnoses and any test abnormality. Four- and 8-monthly interim screening blood tests may not be of independent benefit for cancer detection in LFS, but annual cancer screening and personalized follow-up remain essential.
    Keywords:  Blood tests; Cancer screening; Li-fraumeni syndrome; Surveillance; TP53
    DOI:  https://doi.org/10.1007/s10689-021-00265-x
  2. Mol Imaging Radionucl Ther. 2021 06 03. 30(2): 110-112
    Oncological Follow-up with 2-[18F]-FDG PET/CT in Li-Fraumeni Syndrome
    Marylin Acuña Hernandez, Iván Fabricio Vega Gonzalez, Lina López Vélez, Catalina Melo Arango.
      Li-Fraumeni syndrome is a rare disorder caused by abnormalities of the tumor-suppressor protein P53 gene. We present the case of a 26-years-old female diagnosed with bilateral ductal carcinoma. The genetic panel for breast cancer gene 1 (BRCA1) and BRCA2 mutations was negative and positive heterozygous germline tumor protein P53 gene mutations, considering Li-Fraumeni syndrome. A 2-[18F]-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) was used for postsurgical staging to show the right lung hypermetabolic nodule. A lobectomy was accomplished, and histopathology reported pulmonary adenocarcinoma. A year later, oncological follow-up was conducted with 2-[18F]-FDG PET/CT without evidence of abnormalities.
    Keywords:  Li-Fraumeni syndrome; fluorodeoxyglucose 18F; positron emission tomography
    DOI:  https://doi.org/10.4274/mirt.galenos.2020.33255
  3. Gastrointest Endosc Clin N Am. 2021 Jul;pii: S1052-5157(21)00033-7. [Epub ahead of print]31(3): 467-487
    Inherited Predisposition to Gastric Cancer.
    Sheila D Rustgi, Charlotte K Ching, Fay Kastrinos.
      Approximately 10% of patients with gastric cancer show familial aggregation and up to 3% are related to an inherited cancer syndrome. There are multiple germline pathogenic variants and cancer syndromes associated with an increased risk of gastric cancer. Appropriate assessment of familial and genetic risk may allow a personalized approach to gastric cancer prevention through screening and risk-reducing surgeries. The ability to better identify carriers with pathogenic genetic variants associated with gastric cancer before a diagnosis of cancer requires effective genetic risk assessment and testing, followed by optimal screening and surveillance recommendations to further reduce the morbidity and mortality.
    Keywords:  Gastric cancer; Genetic testing; Hereditary diffuse gastric cancer; Lynch syndrome
    DOI:  https://doi.org/10.1016/j.giec.2021.03.010
  4. N Engl J Med. 2021 Jun 03.
    Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.
    OlympiA Clinical Trial Steering Committee and Investigators
       BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer.
    METHODS: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival.
    RESULTS: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest.
    CONCLUSIONS: Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).
    DOI:  https://doi.org/10.1056/NEJMoa2105215
  5. Cancers (Basel). 2021 May 12. pii: 2321. [Epub ahead of print]13(10):
    Frequency of CDH1 Germline Mutations in Non-Gastric Cancers.
    Giulia Massari, Francesca Magnoni, Giorgio Favia, Nickolas Peradze, Paolo Veronesi, Carlo La Vecchia, Giovanni Corso.
      Hereditary Diffuse Gastric Cancer (HDGC) is a complex inherited syndrome caused by CDH1 germline mutations. DGC is the hallmark cancer of this genetic predisposition, but several other cancers are associated with these CDH1 mutations. In this review, we revised all studies reporting CDH1 mutations in non-GC patients. The selected studies included: (a) families aggregating with GC and other cancers, both, and (b) families presenting only non-gastric tumors association. Among non-gastric tumors, our results show that CDH1 mutations are most frequently identified in breast cancer. The frequency of missense mutations is higher in the non-GC group, as the age at diagnosis in this group. Moreover, the predominant CDH1 mutation affects the extracellular domain. Our data suggest that CDH1 genetic testing should be considered also in other cancers, especially breast tumors.
    Keywords:  CDH1 mutation; Lobular breast cancer; diffuse gastric cancer; hereditary cancer
    DOI:  https://doi.org/10.3390/cancers13102321
  6. Breast Cancer Res Treat. 2021 Jun 04.
    Double heterozygotes of BRCA1/BRCA2 and mismatch repair gene pathogenic variants: case series and clinical implications.
    Ido Laish, Eitan Friedman, Gili Levi-Reznick, Inbal Kedar, Lior Katz, Zohar Levi, Naama Halpern, Shani Parnasa, Aasem Abu-Shatya, Elizabeth Half, Yael Goldberg.
       BACKGROUND: Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes.
    METHODS: Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed.
    RESULTS: Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984_3987dupGTCA founder PV; 3 patients had the MSH6 c.3956_3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1-2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36-76 years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines.
    CONCLUSIONS: This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies.
    Keywords:  Ashkenazi Jews; Founder mutations; Hereditary breast and ovarian cancer syndrome; Lynch syndrome; Pathogenic sequence variants
    DOI:  https://doi.org/10.1007/s10549-021-06258-9
  7. Sci Rep. 2021 May 31. 11(1): 11385
    Prostate cancer risk variants of the HOXB genetic locus.
    William D Dupont, Joan P Breyer, Spenser H Johnson, W Dale Plummer, Jeffrey R Smith.
      The G84E germline mutation of HOXB13 predisposes to prostate cancer and is clinically tested for familial cancer care. We investigated the HOXB locus to define a potentially broader contribution to prostate cancer heritability. We sought HOXB locus germline variants altering prostate cancer risk in three European-ancestry case-control study populations (combined 7812 cases and 5047 controls): the International Consortium for Prostate Cancer Genetics Study; the Nashville Familial Prostate Cancer Study; and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Multiple rare genetic variants had concordant and strong risk effects in these study populations and exceeded genome-wide significance. Independent risk signals were best detected by sentinel variants rs559612720 within SKAP1 (OR = 8.1, P = 2E-9) and rs138213197 (G84E) within HOXB13 (OR = 5.6, P = 2E-11), separated by 567 kb. Half of carriers inherited both risk alleles, while others inherited either alone. Under mutual adjustment, the variants separately carried 3.6- and 3.1-fold risk, respectively, while joint inheritance carried 11.3-fold risk. These risks were further accentuated among men meeting criteria for hereditary prostate cancer, and further still for those with early-onset or aggressive disease. Among hereditary prostate cancer cases diagnosed under age 60 and with aggressive disease, joint inheritance carried a risk of OR = 27.7 relative to controls, P = 2E-8. The HOXB sentinel variant pair more fully captured genetic risk for prostate cancer within the study populations than either variant alone.
    DOI:  https://doi.org/10.1038/s41598-021-89399-7
  8. Sci Rep. 2021 May 31. 11(1): 11401
    A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants.
    Mariann Unhjem Wiik, Tiffany-Jane Evans, Sami Belhadj, Katherine A Bolton, Dagmara Dymerska, Shantie Jagmohan-Changur, Gabriel Capellá, Grzegorz Kurzawski, Juul T Wijnen, Laura Valle, Hans F A Vasen, Jan Lubinski, Rodney J Scott, Bente A Talseth-Palmer.
      Individuals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of cancers, including colorectal cancer (CRC) in LS. We combined genotype data from 1881 LS patients, carrying pathogenic variants in MLH1, MSH2 or MSH6, for rs2075786 (G>A, intronic variant), 1207 LS patients for rs2736108 (C>T, upstream variant) and 1201 LS patients for rs7705526 (C>A, intronic variant). The risk of cancer was estimated by heterozygous/homozygous odds ratio (OR) with mixed-effects logistic regression to adjust for gene/gender/country of sample origin considering family identity. The AA genotype of SNP rs2075786 is associated with 85% higher odds at developing cancer compared to GG genotype in MSH2 pathogenic variant carriers (p = 0.0160). Kaplan-Meier analysis also shows an association for rs2075786; the AA allele for MSH2 variant carriers confers risk for earlier diagnosis of LS cancer (log-rank p = 0.0011). We report a polymorphism in TERT to be a possible modifier of disease risk in MSH2 pathogenic variant carriers. The rs2075786 SNP in TERT is associated with a differential risk of developing cancer for MSH2 pathogenic variant carriers. Use of this information has the potential to personalise screening protocols for LS patients.
    DOI:  https://doi.org/10.1038/s41598-021-90501-2
  9. Cancers (Basel). 2021 May 30. pii: 2704. [Epub ahead of print]13(11):
    Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility.
    Sally Yepes, Nirav N Shah, Jiwei Bai, Hela Koka, Chuzhong Li, Songbai Gui, Mary Lou McMaster, Yanzi Xiao, Kristine Jones, Mingyi Wang, Aurelie Vogt, Bin Zhu, Bin Zhu, Amy Hutchinson, Meredith Yeager, Belynda Hicks, Brian Carter, Neal D Freedman, Laura Beane-Freeman, Stephen J Chanock, Yazhuo Zhang, Dilys M Parry, Xiaohong R Yang, Alisa M Goldstein.
       BACKGROUND: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China.
    METHODS: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma.
    RESULTS: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients.
    CONCLUSION: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.
    Keywords:  WES; WGS; cancer susceptibility; chordoma; germline variants; notochord development
    DOI:  https://doi.org/10.3390/cancers13112704
  10. Genes (Basel). 2021 May 26. pii: 810. [Epub ahead of print]12(6):
    Identification of a Splice Variant (c.5074+3A>C) of BRCA1 by RNA Sequencing and TOPO Cloning.
    Jinyoung Hong, Ji Hyun Kim, Se Hee Ahn, Hyunjung Gu, Suhwan Chang, Woochang Lee, Dae-Yeon Kim, Sail Chun, Won-Ki Min.
      Grading the pathogenicity of BRCA1/2 variants has great clinical importance in patient treatment as well as in the prevention and screening of hereditary breast and ovarian cancer (HBOC). For accurate evaluation, confirming the splicing effect of a possible splice site variant is crucial. We report a significant splicing variant (c.5074+3A>C) in BRCA1 in a patient with recurrent ovarian cancer. Next-generation sequencing (NGS) of BRCA1/2 from patient's peripheral blood identified the variant, which was strongly suspected of being a splicing mutation based on in silico predictions. Direct RNA analysis yielded multiple transcripts, and TOPO cloning of the complementary DNA (cDNA) and Sanger sequencing revealed an aberrant transcript with an insertion of the first 153 bp of intron 17, and another transcript with the 153 bp insertion along with an exon 18 deletion. A premature termination codon was presumed to be formed by the 153 bp partial intron retention common to the two transcripts. Therefore, BRCA1 c.5074+3A>C was classified as a likely pathogenic variant. Our findings show that active use of functional studies of variants suspected of altered splicing are of great help in classifying them.
    Keywords:  BRCA1 gene; RNA sequence analysis; cloning; hereditary breast and ovarian cancer syndrome
    DOI:  https://doi.org/10.3390/genes12060810
  11. Cancers (Basel). 2021 May 26. pii: 2622. [Epub ahead of print]13(11):
    CDH1 Gene Mutation Hereditary Diffuse Gastric Cancer Outcomes: Analysis of a Large Cohort, Systematic Review of Endoscopic Surveillance, and Secondary Cancer Risk Postulation.
    Matthew G K Benesch, Stuart R Bursey, Andrew C O'Connell, Morag G Ryan, Carrie L Howard, Cecily C Stockley, Alexander Mathieson.
      Hereditary diffuse gastric cancer (HDGC) is a rare signet-ring cell adenocarcinoma (SRCC) linked to CDH1 (E-cadherin) inactivating germline mutations, and increasingly other gene mutations. Female CDH1 mutation carriers have additional risk of lobular breast cancer. Risk management includes prophylactic total gastrectomy (PTG). The utility of endoscopic surveillance is unclear, as early disease lacks macroscopic lesions. The current systematic biopsy protocols have unknown efficacy, and other secondary cancer risks are postulated. We conducted a retrospective study of consecutive asymptomatic HDGC patients undergoing PTG, detailing endoscopic, pathologic, and outcome results. A systematic review compared endoscopic biopsy foci detection via random sampling versus Cambridge Protocol against PTG findings. A population-level secondary-cancer-risk postulation among sporadic gastric SRCC patients was completed using the Surveillance, Epidemiology, and End Results database. Of 97 patients, 67 underwent PTG, with 25% having foci detection on random endoscopic biopsy despite 75% having foci on final pathology. There was no improvement in the endoscopic detection rate by Cambridge Protocol. The postulated hazard ratio among sporadic gastric SRCC patients for a secondary colorectal SRCC was three-fold higher, relative to conventional adenocarcinoma patients. Overall, HDGC patients should not rely on endoscopic surveillance to delay PTG, and may have secondary SRCC risks. A definitive determination of actual risk requires collaborative patient outcome data banking.
    Keywords:  CDH1; Cambridge Protocol; E-cadherin; cancer risk; gastric cancer; lobular breast cancer; mutation
    DOI:  https://doi.org/10.3390/cancers13112622
  12. J Clin Med. 2021 May 09. pii: 2028. [Epub ahead of print]10(9):
    Pediatric Rhabdomyosarcoma: Epidemiology and Genetic Susceptibility.
    Bailey A Martin-Giacalone, P Adam Weinstein, Sharon E Plon, Philip J Lupo.
      Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet little is known about its etiology. Studies that examine either environmental exposures or germline genetic predisposition in RMS have begun to identify factors that contribute to this malignancy. Here, we summarize epidemiological reports of RMS incidence in terms of several factors, including age at diagnosis, biological sex, and geographic location. We then describe findings from association studies, which explore the role of parental exposures, birth and perinatal characteristics, and childhood exposures in RMS. Further, we discuss RMS predisposition syndromes and large-scale sequencing studies that have further identified RMS-associated genes. Finally, we propose future directions of study, which aim to advance our understanding of the origin of RMS and can provide knowledge for novel RMS therapies.
    Keywords:  cancer predisposition; epidemiology; genetic susceptibility; pediatric cancer
    DOI:  https://doi.org/10.3390/jcm10092028
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