bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022‒06‒05
eleven papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. Clonal hematopoiesis and mosaicism revealed by a multi-tissue analysis of constitutional TP53 Status.
  2. Diagnosis of pleomorphic myxoid liposarcoma: Does it provoke germline testing for Li-Fraumeni syndrome?
  3. Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for all GI Cancers?
  4. Germline Abnormalities in DNA Methylation and Histone Modification and Associated Cancer Risk.
  5. Germline genetics of prostate cancer.
  6. DNA damage repair gene germline profiling for metastatic prostate cancer patients of different ancestries.
  7. Lynch syndrome pre-screening and comprehensive characterization in a multi-center large cohort of Chinese patients with colorectal cancer.
  8. Prevalence and risk factors of barrett's esophagus in lynch syndrome.
  9. Significance of prostate/pancreatic/skin cancer family history for detecting BRCA2 pathogenic variant careers among patients with breast cancer.
  10. Biallelic mismatch repair deficiency - A rare and trouble genetic syndrome.
  11. Homozygous ATM mutation due to germline uniparental isodisomy in patient with T acute lymphoblastic leukemia and hepatosplenic T-cell lymphoma.
  1. Cancer Epidemiol Biomarkers Prev. 2022 Jun 02. pii: cebp.EPI-21-1296-A.2021. [Epub ahead of print]
    Clonal hematopoiesis and mosaicism revealed by a multi-tissue analysis of constitutional TP53 Status.
    Danielle Castillo, Tze-An Yuan, Bita Nehoray, Aleck Cervantes, Kevin K Tsang, Kai Yang, Sharon R Sand, Janet Mokhnatkin, Josef Herzog, Thomas P Slavin, Sophie Hyman, Alison Schwartz, Benjamin L Ebert, Christopher I Amos, Judy E Garber, Jeffrey N Weitzel.
      BACKGROUND: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li-Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and post-zygotic mosaicism (PZM) is critically needed for risk assessment and management.METHODS: Participants in the Li Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible. Demographics, personal/family cancer history and clinical laboratory test reports were obtained. DNA from multiple tissues was analyzed using a custom QIAseq® assay (ACE panel) that included TP53 and other CH-associated genes; the ACE panel and eyebrow follicles were assessed in a workflow to discern TP53 PV clinical categories.
    RESULTS: Among 134 participants there was a significant difference for the age at diagnosis (p=<0.001), component cancers (p=0.007), and clinical testing criteria (p=<0.001), comparing germline vs PZM or ACE. ACE panel analysis of DNA from 55 sets of eyebrow follicles (mean 1.4 ug) and 36 formalin-fixed paraffin imbedded tissues demonstrated low variance (standard error 3%; p = 0.993) for TP53 variant allele fraction, with no significant difference (p=0.965) between tissue types, and detected CH gene PVs. Of 55 multi-tissue cases, germline status was confirmed for 20, PZM in 7, ACE for 25 and 3 were indeterminate. Additional CH variants were detected in 6 ACE and 2 germline cases.
    CONCLUSIONS: We demonstrated an effective approach and tools for discerning germline TP53 status.
    IMPACT: Discernment of PZM and TP53-driven CH increases diagnostic accuracy and enables risk-appropriate care.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-21-1296
  2. Pediatr Blood Cancer. 2022 Jun 02. e29766
    Diagnosis of pleomorphic myxoid liposarcoma: Does it provoke germline testing for Li-Fraumeni syndrome?
    Sindhura Chitikela, Vivek Bhagel, Adarsh Barwad, Shamim Ahmed, Sameer Rastogi.
      
    DOI:  https://doi.org/10.1002/pbc.29766
  3. J Clin Oncol. 2022 Jun 01. JCO2102764
    Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for all GI Cancers?
    Heather Hampel, Matthew B Yurgelun.
      Use of germline genetic testing among patients with cancer is increasing because of (1) the availability of multigene panel tests that include multiple cancer susceptibility genes in a single test, (2) decreased costs of these tests and improvements in insurance coverage, and (3) US Food and Drug Administration-approval of genotype-directed therapies such as poly(ADP-ribose) polymerase inhibitors for individuals with certain cancers and pathogenic germline variants in BRCA1 and BRCA2 (with possible benefits with other genes in the homologous repair deficiency pathway). In addition, National Comprehensive Cancer Network guidelines have already endorsed germline genetic testing for all patients with certain cancer types (epithelial ovarian cancer, exocrine pancreatic cancer, and high-grade/metastatic prostate cancer), regardless of age or personal/family history of cancer. Herein, we debate the pros and cons of offering germline multigene panel testing to all patients diagnosed with any GI cancer. The authors agree that it may just be a matter of time before germline multigene panel testing is offered to all patients with cancer; however, this article will highlight some of the benefits, risks, and limitations of this approach so that research can help fill some of the gaps to ensure that genetic medicine continues to be implemented in ways that improve real-world patient care and outcomes.
    DOI:  https://doi.org/10.1200/JCO.21.02764
  4. Curr Hematol Malig Rep. 2022 Jun 02.
    Germline Abnormalities in DNA Methylation and Histone Modification and Associated Cancer Risk.
    Jenna A Fernandez, Mrinal M Patnaik.
      PURPOSE OF REVIEW: Somatic mutations in DNA methyltransferases and other DNA methylation associated genes have been found in a wide variety of cancers. Germline mutations in these genes have been associated with several rare hereditary disorders. Among the described germline/congenital disorders, neurological dysfunction and/or growth abnormalities appear to be a common phenotype. Here, we outline known germline abnormalities and examine the cancer risks associated with these mutations.RECENT FINDINGS: The increased use and availability of sequencing techniques in the clinical setting has expanded the identification of germline abnormalities involving DNA methylation machinery. This has provided additional cases to study these rare hereditary disorders and their predisposition to cancer. Studying these syndromes may offer an opportunity to better understand the contribution of these genes in cancer development.
    Keywords:  Cancer predisposition; DNA methylation; Epigenetics; Germline mutation; Hereditary disorders; Histone tail modifications
    DOI:  https://doi.org/10.1007/s11899-022-00665-5
  5. Prostate. 2022 Aug;82 Suppl 1 S3-S12
    Germline genetics of prostate cancer.
    Hiba M Khan, Heather H Cheng.
      BACKGROUND: An important fraction (>/~10%) of men with high-risk, localized prostate cancer and metastatic prostate cancer carry germline (heritable) pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes. These can represent known or suspected autosomal dominant cancer predisposition syndromes. Growing evidence suggests that pathogenic variants in key genes involved in homologous recombination and mismatch DNA repair are important in prostate cancer initiation and/or the development of metastases.AIMS: Here we provide a comprehensive review regarding individual genes and available literature regarding risks for developing prostate cancer, and discuss current national guidelines for germline genetic testing in the prostate cancer population and treatment implications.
    RESULTS: The association with prostate cancer risk and treatment implications is best understood for those with germline mutations of BRCA2, with emerging data supporting associations with ATM, CHEK2, BRCA1, HOXB13, MSH2, MSH6, PALB2, TP53 and NBN. Treatment implications in the metastatic castration resistant prostate cancer setting include rucaparib and olaparib, and pembrolizumab with potential clinical trial opportunities in earlier disease settings.
    DISCUSSION: The data summarized in this review has led to the expansion of national guidelines for germline genetic testing in prostate cancer. We review these guidelines, and discuss the importance of cascade genetic testing of relatives, diverse populations with attention to inclusion, as well as prostate cancer screening updates and clinical trial opportunities for men who carry genetic risk factors for prostate cancer.
    Keywords:  BRCA1; BRCA2; DNA damage repair; Lynch syndrome; germline mutations; prostate cancer
    DOI:  https://doi.org/10.1002/pros.24340
  6. Prostate. 2022 Jun 02.
    DNA damage repair gene germline profiling for metastatic prostate cancer patients of different ancestries.
    Bilal Abdi, Noemie Basset, Emmanuel Perrot, Marc-Antoine Benderra, Ahmed Khalil, Stephane Oudard, Pascal Blanchet, Laurent Brureau, Florence Coulet, Olivier Cussenot, Geraldine Cancel-Tassin.
      BACKGROUND: Germline and somatic mutations in DNA damage repair genes (DDRg) are now recognized as new biomarkers for the management of metastatic prostate cancers (mPC). We evaluate the frequency of germline DDRg mutations among French mPC patients of European and African ancestries.METHODS: Targeted next-generation sequencing of 21 DDRg was performed on germline DNA from 557 mPC patients, including 15.1% of cases with an African origin.
    RESULTS: Forty-seven germline mutations in 11 DDR genes were identified in 46 patients of the total cohort (8.3%). BRCA2 (4.1%) and ATM (2.0%) were the most frequently mutated genes. There was no difference in DDRg mutation frequency between mPC patients of European ancestry and those of African origin. Germline mutations of BRCA2 were associated with a positive family history of breast cancer (p = 0.02). The mean age at metastatic stage (59.7 vs. 67.0; p = 0.0003) and the mean age at death (65.2 vs. 73.9; p = 0.0003) were significantly earlier for carriers of BRCA2 mutation than for non-carriers. Moreover, the Cox model showed that BRCA2 positive status was statistically associated with poorer survival (hazard ratio: 0.29; 95% confidence interval 0.18-0.48; p < 0.0001).
    CONCLUSION: We showed that, in France, BRCA2 and ATM are the main predisposing DDR genes in mPC patients, with a particular aggressiveness for BRCA2 leading to early metastatic stage and death.
    Keywords:  DNA damage repair gene; germline; metastatic; mutation; prostate cancer
    DOI:  https://doi.org/10.1002/pros.24374
  7. Cancer Biol Med. 2022 Jun 01. pii: j.issn.2095-3941.2021.0585. [Epub ahead of print]
    Lynch syndrome pre-screening and comprehensive characterization in a multi-center large cohort of Chinese patients with colorectal cancer.
    Yan Li, Lihong Fan, Jianming Zheng, Xiu Nie, Yu Sun, Qin Feng, Shenyi Lian, Wenqi Bai, Weijing Cai, Yanan Yang, Bo Su, Yanfeng Xi, Dongmei Lin.
      OBJECTIVE: Lynch syndrome (LS) pre-screening methods remain under-investigated in colorectal cancers (CRCs) in Asia. Here, we aimed to systematically investigate LS pre-screening and comprehensively characterize LS CRCs.METHODS: Microsatellite instability (MSI) and germline variants of DNA mismatch repair (MMR) genes were examined in 406 deficient MMR (dMMR) and 250 proficient MMR CRCs. The genetic differences between LS and sporadic CRCs were studied with whole exome sequencing analysis.
    RESULTS: The incidence of dMMR in Chinese patients with CRCs was 13.8%. Consistency analysis between MMR immunohistochemistry (IHC) and MSI testing showed the kappa value was 0.758. With next-generation sequencing (NGS), germline variants were detected in 154 CRCs. Finally, 88 patients with CRC were identified as having LS by Sanger sequencing. Among them, we discovered 21 previously unreported pathogenic germline variants of MMR genes. Chinese patients with LS, compared with sporadic CRCs, tended to be early-onset, right-sided, early-stage and mucinous. Overall, the performance of MMR IHC and MSI testing for LS pre-screening was comparable: the area under the ROC curve for dMMR, MSI-H, and MSI-H/L was 0.725, 0.750, and 0.745, respectively. dMMR_MSI-H LS and sporadic CRCs showed substantial differences in somatic genetic characteristics, including different variant frequencies of APC, CREBBP, and KRAS, as well as different enriched pathways of VEGF, Notch, TGFβR, mTOR, ErbB, and Rac protein signal transduction.
    CONCLUSIONS: MMR IHC and MSI testing were effective methods for LS pre-screening. The revealed clinical and somatic genetic characteristics in LS CRCs may have the potential to improve the performance of LS pre-screening in combination with dMMR/MSI.
    Keywords:  Lynch syndrome; Microsatellite instability; mismatch repair; sequencing; somatic genetic characteristics
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2021.0585
  8. Fam Cancer. 2022 Jun 02.
    Prevalence and risk factors of barrett's esophagus in lynch syndrome.
    Natalie Farha, Ruishen Lyu, David Liska, Amit Bhatt, Carole Macaron, Carol A Burke.
      Lynch syndrome (LS), the most common hereditary cause of colorectal cancer, predisposes to upper gastrointestinal neoplasia. The prevalence of Barrett's esophagus (BE) is elevated in some hereditary gastrointestinal cancer syndromes but has not been systematically evaluated in LS. We assessed the prevalence of BE, BE-related dysplasia, esophageal adenocarcinoma (EAC), and factors associated with BE in LS. Asymptomatic patients with a germline pathogenic variant (PV) in the DNA mismatch repair (MMR) genes undergoing EGD for LS surveillance were identified from a hereditary colorectal cancer registry. We assessed the prevalence of BE and compared demographic, clinical, and endoscopic factors in LS patients with and without BE by logistic regression analysis. 323 patients were included. 21 patients (6.5%) were diagnosed with BE including 38% of females and 33% without gastroesophageal reflux disease (GERD). Dysplasia was diagnosed in two patients (9.5%) and EAC in one (4.8%) patient. Factors associated with BE included male gender (OR 3.00, 1.21-7.46), age at last LS EGD (OR 1.04, 1.01-1.08), presence of hiatal hernia (OR 20.09, 4.57-88.23), hiatal hernia > 3 cm (OR 11.25, 2.41-51.94), and GERD (OR 3.39, 1.32-8.67). No MMR PV was associated with BE. BE was diagnosed in 1 of 15 patients undergoing EGD surveillance for LS and nearly 10% had dysplasia including one EAC. Risk factors associated with BE in LS are similar to those established for BE in the general population. More studies are needed to evaluate if an association between BE and LS exists.
    Keywords:  Barrett’s esophagus; Esophageal adenocarcinoma; Lynch Syndrome; MMR
    DOI:  https://doi.org/10.1007/s10689-022-00298-w
  9. Breast Cancer. 2022 May 31.
    Significance of prostate/pancreatic/skin cancer family history for detecting BRCA2 pathogenic variant careers among patients with breast cancer.
    Yuko Minoura, Masato Takahashi, Hideki Maeda, Sayuri Kuwahara, Hanae Tachikawa, Mitsugu Yamamoto, Nobumoto Tomioka, Kenichi Watanabe, Akihiro Sakurai.
      BACKGROUND: When considering BRCA1/2 genetic testing for diagnosis of hereditary breast and ovarian cancer (HBOC), family history (FH) of breast and ovarian cancer is commonly considered. However, FH of other HBOC-related cancers, such as prostate, pancreatic, and skin cancer (malignant melanoma), is often overlooked.METHODS: Among 945 patients who received genetic testing of BRCA1/2 at our hospital between October 2010 and September 2021, we compared the FH of 123 patients diagnosed with HBOC and 669 other patients who had breast cancer and had a documented FH. This study focused on the FH of HBOC-related cancers such as breast, ovarian, prostate, pancreatic, and skin cancer, as well as colorectal, gastric, liver, lung, and uterine cancers, which are common among Japanese, and other cancers.
    RESULTS: FH of prostate, pancreatic, and skin cancer was significantly higher in the BRCA2 pathogenic variant (PV) cases than in the wild-type (WT) cases. The mean number of family members are as follows: BRCA1 PV/ BRCA2 PV/ WT; prostate cancer: 0.05/ 0.34/ 0.09 (P < 0.0001, Kruskal-Wallis multiple comparisons test), pancreatic cancer: 0.13/ 0.21/ 0.10 (P = 0.01637), and skin cancer: 0.03/ 0.07/ 0.01 (P = 0.00129), respectively.
    CONCLUSIONS: When considering BRCA1/2 genetic testing, FH of prostate, pancreatic, and skin cancers may also be examined as HBOC-related cancers to provide testing for patients who would benefit from it. However, further studies for the association between skin cancer and HBOC will be required because it has not been reported in Japan.
    Keywords:  Family history; Hereditary breast and ovarian cancer (HBOC); Skin cancer (malignant melanoma)
    DOI:  https://doi.org/10.1007/s12282-022-01360-2
  10. Rev Esp Enferm Dig. 2022 May 31.
    Biallelic mismatch repair deficiency - A rare and trouble genetic syndrome.
    Diana Ramos, Catarina Brandão, Cátia Sousa, Mário Dinis-Ribeiro.
      Biallelic mismatch repair deficiency (BMMRD) is a rare autosomal recessive disorder characterized by numerous early-onset cancers, especially gastrointestinal tumors. Biallelic germline mutations in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) cause this devastating disease. Given the rarity of the syndrome, often-asymptomatic tumors, diagnosis is frequently unrecognized or delayed. A high degree of clinical awareness is needed to identify new cases. Immunohistochemical assessment of MMR protein expression and analysis of microsatellite instability are the first tools with which to initiate the study of this syndrome in solid malignancies. MMR immunohistochemical shows a hallmark pattern with absence of staining in both neoplastic and non-neoplastic cells for the biallelic mutated gene. We present a unique case of a young boy diagnosed with invasive colon adenocarcinoma and brain tumor, with classical BMMRD features, found to have biallelic pathogenic PMS2 mutations.
    DOI:  https://doi.org/10.17235/reed.2022.8928/2022
  11. Cancer Genet. 2022 May 21. pii: S2210-7762(22)00083-7. [Epub ahead of print]266-267 15-18
    Homozygous ATM mutation due to germline uniparental isodisomy in patient with T acute lymphoblastic leukemia and hepatosplenic T-cell lymphoma.
    Michelle F Jacobs, Dan Robinson, Yi-Mi Wu, Valerie P Opipari, Rajen Mody.
      Uniparental disomy has long been recognized as a significant cause of genetic disease in imprinting-associated conditions. More recently, it has increasingly been implicated as a potentially significant cause of autosomal recessive disease. Here we report a case of a patient with a history of leukemia and αβ hepatosplenic T-cell lymphoma who was diagnosed with ataxia telangiectasia via paired tumor-germline testing at age 20. Germline testing detected a homozygous pathogenic variant in the ATM gene. Parental testing identified this variant only in the mother, leading to suspicion for non-paternity or an atypical cause of autosomal recessive disease. Additional analysis of the proband's sample identified a 54 megabase region at chr11q13.4-q25 with alleles all derived from a single parent, consistent with uniparental isodisomy as causative of autosomal recessive ataxia telangiectasia in this case. This report provides further evidence that uniparental isodisomy should be considered in the potential etiology of autosomal recessive conditions, including in the setting of paired tumor-germline testing. Confirming the method of inheritance is particularly important in cases such as this one where being a heterozygous carrier has medical management implications for cancer screening for relatives as well as for cascade testing and family planning for relatives.
    Keywords:  ATM; Ataxia telangiectasia; Cancer predisposition; Genetic counseling; Uniparental disomy
    DOI:  https://doi.org/10.1016/j.cancergen.2022.05.039
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