bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020–09–27
thirteen papers selected by
Joanna Zawacka-Pankau, University of Warsaw
  1. Upper Gastrointestinal Cancer Risk and Surveillance Outcomes in Li-Fraumeni Syndrome.
  2. Reducing fatty acid oxidation improves cancer-free survival in a mouse model of Li-Fraumeni syndrome.
  3. Comparison of Molecular, Clinicopathological, and Pedigree Differences Between Lynch-Like and Lynch Syndromes.
  4. Constitutional variants in POT1, TERF2IP, and ACD genes in patients with melanoma in the Polish population.
  5. Analysis of genomic pathogenesis according to the revised Bethesda guidelines and additional criteria.
  6. Genotype-phenotype correlations among TP53 carriers: Literature review and analysis of probands undergoing multi-gene panel testing and single-gene testing.
  7. RB1 Germline Variant Predisposing to a Rare Ovarian Germ Cell Tumor: A Case Report.
  8. Mutation Rates in Cancer Susceptibility Genes in Patients With Breast Cancer With Multiple Primary Cancers.
  9. Human GATA2 mutations and hematologic disease: how many paths to pathogenesis?
  10. A novel germline EGFR variant p.R831H causes predisposition to familial CDK12-mutant prostate cancer with tandem duplicator phenotype.
  11. Lymph node metastasis in hereditary medullary thyroid cancer is independent of the underlying RET germline mutation.
  12. Germline ancestry influences the evolutionary disease course in lung adenocarcinomas.
  13. Context Determines Effects of TP53 Mutations.
  1. Am J Gastroenterol. 2020 Sep 22.
    Upper Gastrointestinal Cancer Risk and Surveillance Outcomes in Li-Fraumeni Syndrome.
    Bryson W Katona, Jacquelyn Powers, Danielle B McKenna, Jessica M Long, Anh N Le, Ryan Hausler, Kristin Zelley, Sarah Jennings, Susan M Domchek, Katherine L Nathanson, Suzanne P MacFarland, Kara N Maxwell.
       INTRODUCTION: To assess the upper gastrointestinal (UGI) cancer risk and surveillance outcomes in Li-Fraumeni syndrome (LFS).
    METHODS: Analysis of the International Agency for Research on Cancer database and a single-center adult LFS cohort.
    RESULTS: UGI cancer was present in 7.2% of families and 3.9% of individuals with a pathogenic/likely pathogenic TP53 mutation in International Agency for Research on Cancer; 29% occurred before age 30. Our institutional cohort had 35 individuals (31% of the LFS cohort) with 48 cumulative upper endoscopies; 3 (8.5%) individuals had concerning UGI findings.
    DISCUSSION: UGI cancer is observed in LFS. Upper endoscopy should be part of a comprehensive LFS surveillance program.
    DOI:  https://doi.org/10.14309/ajg.0000000000000935
  2. Cancer Prev Res (Phila). 2020 Sep 21. pii: canprevres.0368.2020. [Epub ahead of print]
    Reducing fatty acid oxidation improves cancer-free survival in a mouse model of Li-Fraumeni syndrome.
    Ping-Yuan Wang, Jin Ma, Jie Li, Matthew F Starost, Michael J Wolfgang, Komudi Singh, Mehdi Pirooznia, Ju-Gyeong Kang, Paul M Hwang.
      Germline mutations of TP53, which cause the cancer predisposition disorder Li-Fraumeni syndrome (LFS), can increase mitochondrial activity as well as fatty acid β-oxidation (FAO) in mice. Increased fatty acid metabolism can promote cancer malignancy, but its specific contribution to tumorigenesis in LFS remains unclear. To investigate this, we crossed LFS mice carrying the p53 R172H knockin mutation (p53172H/H, homolog of the human TP53 R175H LFS mutation) with Myoglobin knockout (MB-/-) mice known to have decreased FAO. MB-/- p53172H/H double mutant mice also showed mildly reduced FAO in thymus, a common site of T lymphoma development in LFS mice, in association with a ~40% improvement in cancer-free survival time. RNA-Seq profiling revealed that the p53 R172H mutation promotes mitochondrial metabolism and ribosome biogenesis, both of which are suppressed by the disruption of MB. The activation of ribosomal protein S6, involved in protein translation and implicated in cancer promotion, was also inhibited in the absence of MB. To further confirm the role of FAO in lymphomagenesis, mitochondrial FAO enzyme Carnitine Palmitoyltransferase 2 (CPT2) was specifically disrupted in T cells of p53172H/H mice using a Cre-loxP-mediated strategy. The heterozygous knockout of CPT2 resulted in thymus FAO haploinsufficiency and a ~30% improvement in survival time, paralleling the anti-proliferative signaling observed with MB disruption. Thus, our current study demonstrates that moderating FAO in LFS can suppress tumorigenesis and improve cancer-free survival with potential implications for cancer prevention.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-20-0368
  3. Front Genet. 2020 ;11 991
    Comparison of Molecular, Clinicopathological, and Pedigree Differences Between Lynch-Like and Lynch Syndromes.
    Yun Xu, Zonghao Huang, Cong Li, Congcong Zhu, Yuqin Zhang, Tian'an Guo, Fangqi Liu, Ye Xu.
      In this study, we compared the molecular, clinical, and pathological characteristics, as well as pedigrees, between patients with Lynch-like syndrome (LLS) and confirmed Lynch syndrome (LS) to develop appropriate management strategies for patients with LLS and their affected family members. Between June 2008 and September 2018, 81 patients with LLS and 47 patients with LS who developed colorectal cancer (CRC) were enrolled in this study. Multigene panel testing included 139 genes and was performed for all patients. The variants identified in each group were described, and clinicopathological characteristics and pedigrees were compared between the two groups. In the LLS group, a total of 52 variants were detected in 44 (54.3%) patients. Among the 52 variants, 17 were variants of unknown significance in mismatch repair genes, and the other most frequently mutated genes were MUYTH, POLE, BRCA2, and GJB2. The proportion of early-onset patients was significantly higher among the LS probands than among the LLS probands (74.5 and 53.1%, respectively; χ2 = 5.712, P = 0.017). On the other hand, the proportion of primary CRC developed in the rectum was higher in the LLS group than in the LS group (25.9 and 10.6%, respectively; χ2 = 2.358, P = 0.046). There were no significant differences in the occurrence of metachronous CRC (P = 0.632) and extra-colorectal cancer (extra-CRC) (P = 0.145) between the two groups. However, analysis of pedigrees showed that more patients developed CRC in the LS families (P = 0.013), whereas more patients with extra-CRC were observed in the LLS families (P = 0.045). A higher prevalence of male patients was observed in the LLS families (P = 0.036). In conclusion, LLS should be classified as a mixed entity, containing cases of LS, other hereditary cancer syndromes, and sporadic CRC. The high risks of CRC and extra-CRCs, which were found in this study, suggest tailored management policy and surveillance should be formulated based on individual and family risk. The surveillance regimen can be based on the presence of confirmed pathogenic/likely pathogenic germline variant(s) and family history.
    Keywords:  DNA mismatch repair; Lynch syndrome; Lynch-like syndrome; colorectal cancer; pedigree
    DOI:  https://doi.org/10.3389/fgene.2020.00991
  4. Eur J Cancer Prev. 2020 Sep 24.
    Constitutional variants in POT1, TERF2IP, and ACD genes in patients with melanoma in the Polish population.
    Karolina Malińska, Jakub Deptuła, Emilia Rogoża-Janiszewska, Bohdan Górski, Rodney Scott, Helena Rudnicka, Aniruddh Kashyap, Paweł Domagała, Jolanta Hybiak, Bartłomiej Masojć, Cezary Cybulski, Andrzej Kram, Magdalena Boer, Magdalena Kiedrowicz, Jan Lubiński, Tadeusz Dębniak.
      Evaluation of the prevalence of POT1, ACD, and TERF2IP mutations among Polish melanoma patients. A cohort of 60 patients from melanoma-prone families, 1500 unselected cases and 1500 controls were genotyped. Methodology included Sanger sequencing, in-silico software predilection, and TaqMan assays. We identified three nonsynonymous variants: POT1 c.903 G>T; TERF2IP c.970 A>G; and ACD c.1544 T>C and a splice site variant ACD c.645 G>A. The c.903 G>T was predicted to be pathogenic according to PolyPhen-2, benign according to Mutation Taster, PROVEAN, AGVGD, and SIFT. The c.645 G>A was defined as disease caused by Mutation Taster and Human Splicing Finder and as variant of unknown significance by ClinVar. The other detected variants were described as benign. The c.903 G>T variant was present in two unselected cases and one control [P = 0.57, odds ratio (OR) = 2.00]; the c.645 G>A variant was not detected among the unselected cases and the controls; the c.970 A>G variant was present in 110 cases and 133 controls (P = 0.14, OR = 0.81); the c.1544 T>C variant was present in 687 cases and 642 controls (P = 0.11, OR = 1.07). We found no loss of heterozygosity of the c.903 G>T, c.970 A>G, and c.645 G>A variants. C.645 G>A variant had no effect on splicing or expression. The changes in POT1 c.903 G>T and ACD c.645 G>A can be classified as rare variants of unknown significance, the other variants appear to be polymorphisms. Germline mutations in POT1, ACD, and TERF2IP are infrequent among Polish melanoma patients.
    DOI:  https://doi.org/10.1097/CEJ.0000000000000633
  5. J Cancer Res Clin Oncol. 2020 Sep 22.
    Analysis of genomic pathogenesis according to the revised Bethesda guidelines and additional criteria.
    Jin Cheon Kim, Jong Hwan Kim, Ye Jin Ha, Chan Wook Kim, Ka Hee Tak, Yong Sik Yoon, Yi Hong Kwon, Seon Ae Roh, Dong-Hyung Cho, Seon-Kyu Kim, Seon-Young Kim, Yong Sung Kim.
       PURPOSE: As few genotype-phenotype correlations are available for nonsyndromic hereditary colorectal cancer (CRC), we implemented genomic analysis on the basis of the revised Bethesda guideline (RBG) and extended (12 items) to verify possible subtypes.
    METHODS: Patients with sporadic CRC (n = 249) were enrolled, stratified according to the revised Bethesda guidelines (RBG+ and RBG- groups) plus additional criteria. Exome/transcriptome analyses (n = 98) and cell-based functional assays were conducted.
    RESULTS: We detected 469 somatic and 830 germline gene mutations differing significantly between the positive and negative groups, associated with 12 RBG items/additional criteria. Twenty-one genes had significantly higher mutation rates in left, relative to right, colon cancer, while USP40, HCFC1, and HSPG2 mutation rates were higher in rectal than colon cancer. FAT4 mutation rates were lower in early-onset CRC, in contrast to increased rates in microsatellite instability (MSI)-positive tumors, potentially defining an early-onset microsatellite-stable subtype. The mutation rates of COL6A5 and MGAM2 were significantly and SETD5 was assumably, associated CRC pedigree with concurrent gastric cancer (GC). The predicted deleterious/damaging germline variants, SH2D4A rs35647122, was associated with synchronous/metachronous CRC with related tumors, while NUP160 rs381660 and KRTAP27-1 rs2244485 were potentially associated with a GC pedigree and less strictly defined hereditary CRC, respectively. SH2D4A and NUP160 acted as oncogenic facilitators.
    CONCLUSION: Our limited genomic analysis for RBG and additional items suggested that specific somatic alterations in the respective items may enlighten relevant pathogenesis along with the knowledge of germline mutations. Further validation is needed to indicate appropriate surveillance in suspected individuals.
    Keywords:  Hereditary colorectal cancer; NGS; Nonsyndromic; Revised Bethesda guideline; SNP
    DOI:  https://doi.org/10.1007/s00432-020-03391-8
  6. Cancer Genet. 2020 Sep 11. pii: S2210-7762(20)30271-4. [Epub ahead of print]248-249 11-17
    Genotype-phenotype correlations among TP53 carriers: Literature review and analysis of probands undergoing multi-gene panel testing and single-gene testing.
    Cristina Fortuno, Tina Pesaran, Jessica Mester, Jill Dolinsky, Amal Yussuf, Kelly McGoldrick, Paul A James, Amanda B Spurdle.
      Pathogenic germline variants in the TP53 gene predispose to a wide range of cancers, known collectively as Li-Fraumeni syndrome (LFS). There has been much research aimed to identify genotype-phenotype correlations, that is, differences between variant location and/or effect and cancer spectrum. These correlations, should they exist, have potential to impact clinical management of carriers. Review of previously published studies showed a variety of study designs and inconsistency in reported findings. Here, we used pooled data from 427 TP53 carriers who had undergone multigene panel testing and 154 TP53 carriers identified by single-gene testing to investigate correlations between TP53 genotype (truncating variants, hotspot variants, other missense variants with dominant-negative effect, missense variants without dominant-negative effect) and a number of LFS-selected malignancies. Our results suggest that carriers of truncating and hotspot variants might be more likely to present with LFS cancers and have shorter time to first cancer diagnosis compared to carriers of other variant types. However, the differences observed were minor, and we conclude that there is currently insufficient evidence to consider location and/or molecular effect of pathogenic variants to assist with clinical management of TP53 carriers. Larger studies are necessary to confirm the correlations suggested by our analysis.
    DOI:  https://doi.org/10.1016/j.cancergen.2020.09.002
  7. Front Oncol. 2020 ;10 1467
    RB1 Germline Variant Predisposing to a Rare Ovarian Germ Cell Tumor: A Case Report.
    Elisa Gelli, Chiara Fallerini, Floriana Valentino, Annarita Giliberti, Francesca Castiglione, Lucrezia Laschi, Maria Palmieri, Alessandra Fabbiani, Rossella Tita, Maria Antonietta Mencarelli, Alessandra Renieri, Francesca Ariani.
      Malignant ovarian germ cell tumors (MOGCTs) are neoplasms of the ovary, of which, due to their rarity and heterogeneity, few is reported about genetic background and development. Here, we report a 18-years old patient diagnosed with an ovarian mixed germ cell tumor, without any previous history of malignancies, who has been treated with surgery and chemotherapy and died 4 years later due to peritoneal metastasis complications. Patient's blood DNA was screened for a panel of 52 cancer-related genes in order to identify predisposing aberrations to this rare cancer. The analysis discovered the uncharacterized c.2393G>A variant in RB1, the retinoblastoma gene, leading both to a missense change and a splicing perturbation of the RB1 transcript. The variant was found to be hypomorphic, damaging the C-terminal domain with a partially impaired protein function. The variant is inherited from the unaffected mother. Due to an imprinting mechanism, the maternal allele is ~3-fold more expressed than the paternal one. The parent-of-origin effect combined with the hypomorphic impact of the variant determines a rescue of sufficient tumor-suppressor activity to prevent retinoblastoma development but can predispose to other cancers in the adult age. In order to understand the somatic events acting on the germline predisposition we used the NGS-liquid biopsy covering 77 cancer driver genes. Using this approach, we detected deleterious mutations in TP53, SMAD4, FGFR3, and MSH2, indicative of a dis-regulation of cell cycle and DNA repair mechanisms pathways. In conclusion, we have pinpointed for the first time that an RB1 leaky variant, not leading to retinoblastoma because of its maternal origin, can predispose in adults to a very rare form of ovarian cancer and that the somatic disruption of few genes contributes to the tumor progression and aggressiveness.
    Keywords:  RB1; hypomorphic variant; ovarian cancer; tumor predisposition; yolk sac tumor
    DOI:  https://doi.org/10.3389/fonc.2020.01467
  8. JCO Precis Oncol. 2020 ;pii: PO.19.00301. [Epub ahead of print]4
    Mutation Rates in Cancer Susceptibility Genes in Patients With Breast Cancer With Multiple Primary Cancers.
    Kara N Maxwell, Brandon M Wenz, Abha Kulkarni, Bradley Wubbenhorst, Kurt D'Andrea, Benita Weathers, Noah Goodman, Joseph Vijai, Jenna Lilyquist, Steven N Hart, Thomas P Slavin, Kasmintan A Schrader, Vignesh Ravichandran, Tinu Thomas, Chunling Hu, Mark E Robson, Paolo Peterlongo, Bernardo Bonanni, James M Ford, Judy E Garber, Susan L Neuhausen, Payal D Shah, Angela R Bradbury, Angela M DeMichele, Kenneth Offit, Jeffrey N Weitzel, Fergus J Couch, Susan M Domchek, Katherine L Nathanson.
       PURPOSE: Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown.
    PATIENTS AND METHODS: We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]).
    RESULTS: Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% v 4.9% [P = .02] and 7.1% v 4.2% [P = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non-breast cancers was unrelated to mutation rate. TP53 and MSH6 mutations were significantly enriched in patients with MP-BC but not S-BC, whereas ATM and PALB2 mutations were significantly enriched in both groups compared with ExAC.
    CONCLUSION: Mutation rates are at least 7% in all patients with BRCA1/2 mutation-negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age < 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.
    DOI:  https://doi.org/10.1200/PO.19.00301
  9. Blood Adv. 2020 Sep 22. 4(18): 4584-4592
    Human GATA2 mutations and hematologic disease: how many paths to pathogenesis?
    Emery H Bresnick, Mabel M Jung, Koichi R Katsumura.
      The surge of human genetic information, enabled by increasingly facile and economically feasible genomic technologies, has accelerated discoveries on the relationship of germline genetic variation to hematologic diseases. For example, germline variation in GATA2, encoding a vital transcriptional regulator of multilineage hematopoiesis, creates a predisposition to bone marrow failure and acute myeloid leukemia termed GATA2 deficiency syndrome. More than 300 GATA2 variants representing missense, truncating, and noncoding enhancer mutations have been documented. Although these variants can diminish GATA2 expression and/or function, the functional ramifications of many variants are unknown. Studies using genetic rescue and knockin mouse systems have established that GATA2 mutations differentially affect molecular processes in distinct target genes and within a single target cell. Considering that target genes for a transcription factor can differ in sensitivity to altered levels of the factor, and transcriptional mechanisms are often cell type specific, the context-dependent consequences of GATA2 mutations in experimental systems portend the complex phenotypes and interindividual variation of GATA2 deficiency syndrome. This review documents GATA2 human genetics and the state of efforts to traverse from physiological insights to pathogenic mechanisms.
    DOI:  https://doi.org/10.1182/bloodadvances.2020002953
  10. Oncogene. 2020 Sep 25.
    A novel germline EGFR variant p.R831H causes predisposition to familial CDK12-mutant prostate cancer with tandem duplicator phenotype.
    Kaiyu Qian, Gang Wang, Lingao Ju, Jiyan Liu, Yongwen Luo, Yejinpeng Wang, Tianchen Peng, Fangjin Chen, Yi Zhang, Yu Xiao, Xinghuan Wang.
      5-10% of total prostate cancer (PCa) cases are hereditary. Particularly, immune checkpoint inhibitor-sensitive tandem duplicator phenotype (TDP) accounts for 6.9% of PCa cases, whereas genetic susceptibility genes remain completely unknown. We identified a Chinese family with two PCa patients, in which the PCa phenotype co-segregated with a rare germline variant EGFRR831H. Patient-derived conditionally reprogrammed cells (CRC) exhibited increased EGFR and AKT phosphorylation, and a sensitivity to EGFR antagonist Afatinib in migration assays, suggesting the EGFR allele was constitutively active. Both EGFRR831H-mutant tumours contained biallelic CDK12 inactivation, together with prominent tandem duplication across the genome. These somatic mutations could be detected in urine before surgery. Analysis of public databases showed a significant correlation between the mutation status of EGFR and CDK12. Taken together, our genetic and functional analyses identified a previously undescribed link between EGFR and PCa.
    DOI:  https://doi.org/10.1038/s41388-020-01476-9
  11. Eur J Surg Oncol. 2020 Sep 08. pii: S0748-7983(20)30746-0. [Epub ahead of print]
    Lymph node metastasis in hereditary medullary thyroid cancer is independent of the underlying RET germline mutation.
    Andreas Machens, Kerstin Lorenz, Frank Weber, Henning Dralle.
      Although the onset of hereditary medullary thyroid cancer (MTC) depends on mutational risk, the impact of that risk on lymph node metastasis is unclear. Included in this investigation were 387 carriers of RET germline mutations with node-negative MTC (201 carriers) or node-positive MTC (186 carriers). Age at thyroidectomy increased significantly from highest (p.Met918Thr; 45 carriers), high (p.Cys634Arg/Gly/Phe/Ser/Trp/Tyr; 138 carriers) and moderate-high risk (p.Cys609/611/618/620Arg/Gly/Phe/Ser/Trp/Tyr; 93 carriers) to low-moderate risk (p.Glu768Asp, p. Leu790Phe, p. Val804Leu/Met, p. Ser891Ala; 111 carriers). In contrast, tumor progression to lymph node metastasis was similar, taking 8.6-9.1 years with moderate risk mutations and 13.6-14.5 years with high and highest risk mutations. Primary tumor size across the mutational risk spectrum changed little, measuring 18.1-22.1 mm with and 2.7-7.3 mm without lymph node metastasis. Because the biological behavior of hereditary MTC is similar after disease onset, equal treatment of comparable tumors is warranted regardless of the underlying RET mutation.
    Keywords:  Age-dependent tumor progression; Genetic risk; Germline mutation; Lymph node metastasis; Medullary thyroid carcinoma; RET Proto-oncogene
    DOI:  https://doi.org/10.1016/j.ejso.2020.09.004
  12. Evol Appl. 2020 Aug;13(7): 1550-1557
    Germline ancestry influences the evolutionary disease course in lung adenocarcinomas.
    Alina Schenk, Saioa López, Maik Kschischo, Nicholas McGranahan.
      Precision medicine relies on targeting specific somatic alterations present in a patient's tumor. However, the extent to which germline ancestry may influence the somatic burden of disease has received little attention. We estimated the genetic ancestry of non-small-cell lung cancer (NSCLC) patients and performed an in-depth analysis of the influence of genetic ancestry on the evolutionary disease course. Compared with European Americans (EA), African Americans (AA) with lung adenocarcinoma (LUAD) were found to be significantly younger and smoke significantly less. However, LUADs from AAs exhibited a significantly higher somatic mutation burden, with a more pronounced tobacco carcinogen footprint and increased frequencies of alterations affecting cancer genes. Conversely, no significant differences were observed between lung squamous cell carcinomas (LUSC) from EAs and AAs. Our results suggest germline ancestry influences the somatic evolution of LUAD but not LUSC.
    Keywords:  cancer; genomics; germline ancestry; somatic evolution
    DOI:  https://doi.org/10.1111/eva.12964
  13. Cancer Discov. 2020 Sep 25.
    Context Determines Effects of TP53 Mutations.
      Mutations in TP53-the most commonly mutated gene in cancer-remain poorly understood. Recent work shows that the effects of mutations in this p53-encoding gene are dependent on context, including allelic state and the presence of microbial metabolites.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NB2020-088
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