bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022‒06‒19
eleven papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. TP53 Variant in the Blood of a Patient with Gastric Cancer Undergoing Tumor Profiling Tests Diagnosed as Clonal Hematopoiesis.
  2. Hereditary diffuse gastric cancer and E-cadherin germline mutations.
  3. Unexpected actionable genetic variants revealed by multigene panel testing of patients with uterine cancer.
  4. Technology-enhanced AcceleRation of Germline Evaluation for Therapy (TARGET): A randomized controlled trial of a pretest patient-driven webtool vs. genetic counseling for prostate cancer germline testing.
  5. The Additional Diagnostic Benefit of Pancreatic Cancer Molecular Profiling After Germline Testing.
  6. Compliance with the Current NCCN Guidelines and Its Critical Role in Pancreatic Adenocarcinoma.
  7. Impact of germline mutations in cancer-predisposing genes on long-term survival in patients with epithelial ovarian cancer.
  8. Is Biannual Surveillance for Pancreatic Cancer Sufficient in Individuals With Genetic Syndromes or Familial Pancreatic Cancer?
  9. A Germline Mutation in ATR Is Associated With Lung Adenocarcinoma in Asian Patients.
  10. Association between germline variants and somatic mutations in colorectal cancer.
  11. Genomic profiling reveals non-small cell lung cancer with common mutations of EGFR exon 20 and exon 21: a case report.
  1. Am J Case Rep. 2022 Jun 14. 23 e936455
    TP53 Variant in the Blood of a Patient with Gastric Cancer Undergoing Tumor Profiling Tests Diagnosed as Clonal Hematopoiesis.
    Miki Kawai, Yuka Iijima-Yamashita, Iku Taguchi, Masato Kataoka, Masashi Sanada, Yoshiko Murakami, Chiyoe Kitagawa, Hiroyoshi Hattori.
      BACKGROUND Clonal hematopoiesis is the production of a specific single clonal type of cell in the blood and is often found in cancer genomic profiling tests. When the clone carries a pathogenic variant, it may be important to differentiate between somatic or germline origin. The variant in the blood that has a lower minor allele frequency could reflect heterozygous germline origin, somatic mosaicism, and clonal hematopoiesis. It is important to evaluate suspected variants to determine the course of treatment and follow-up of the patient, depending on the patient's medical condition and family situation. CASE REPORT We report a 53-year-old Japanese man with gastric cancer who underwent a cancer genomic profiling test searching for therapeutic agents. The profiling test detected a variant, TP53 c.559+2T>G minor allele frequencies of 9% (168/1865) in tumor tissue and 29.1% (58/199) in paired blood. Since the TP53 variant has the possibility of Li-Fraumeni syndrome, ancillary testing was performed using fingernails, buccal swab, and blood specimens. The genomic analysis revealed no TP53 variant in his fingernails. The patient had previously received platinum-based chemotherapies, suggesting that the variant reflected treatment-induced clonal hematopoiesis. CONCLUSIONS Identifying clonal hematopoiesis when performing genomic profiling tests for patients with cancer is important. Examining multiple tissues to determine whether a variant arises from clonal hematopoiesis or is of germline origin can provide more accurate genetic information and improve patient follow-up care.
    DOI:  https://doi.org/10.12659/AJCR.936455
  2. Eur J Cancer Prev. 2021 Dec 01. 31(Suppl 1): S12
    Hereditary diffuse gastric cancer and E-cadherin germline mutations.
    Giovanni Corso.
      
    DOI:  https://doi.org/10.1097/01.cej.0000816708.33618.ee
  3. Gynecol Oncol. 2022 Jun 09. pii: S0090-8258(22)00334-1. [Epub ahead of print]
    Unexpected actionable genetic variants revealed by multigene panel testing of patients with uterine cancer.
    Brandie Heald, Sara Mokhtary, Sarah M Nielsen, Susan Rojahn, Shan Yang, Scott T Michalski, Edward D Esplin.
      OBJECTIVE: Hereditary uterine cancer (UC) is traditionally associated with pathogenic/likely pathogenic germline variants (PGVs) in Lynch syndrome genes or PTEN; however, growing evidence supports a role for other genes that may reveal new clinical management options. In this study we assessed the prevalence and potential clinical impact of PGVs identified in UC patients referred for comprehensive germline genetic testing that combined testing for Lynch syndrome, PTEN, and other cancer predisposition genes.METHODS: Prevalence of PGVs in patients referred to a single clinical lab for germline genetic testing with an indication of uterine or endometrial cancer were retrospectively assessed and compared by syndrome type, patient age at testing, and self-reported ancestry. Potential clinical actionability of PGVs was based on established guidelines for clinical management, targeted therapies, and clinical trial eligibility.
    RESULTS: PGVs were detected in 13.6% of the cohort (880/6490). PGVs were most frequently observed in Lynch syndrome genes (60.4%) and PTEN (1.5%), with 38.1% in another cancer predisposition gene (i.e., CHEK2, BRCA1/BRCA2). PGV prevalence was similar for patients <50 years and those ≥50 years (15.1% vs 13.2%). Nearly all PGVs (97.2%) were associated with guideline-recommended management, including cascade testing; 60.5% were associated with FDA-approved therapies; and 35.2% were associated with clinical trials.
    CONCLUSIONS: Focusing germline testing on Lynch syndrome genes and PTEN and limiting testing to patients <50 years of age at diagnosis may overlook a substantial proportion of UC patients who harbor actionable PGVs. Universal comprehensive genetic testing of UC patients could benefit many patients and at-risk family members.
    Keywords:  Endometrial cancer; Genetic testing; Inherited; Lynch syndrome; PTEN-hamartoma tumor syndrome; Pathogenic germline variants
    DOI:  https://doi.org/10.1016/j.ygyno.2022.05.023
  4. Contemp Clin Trials. 2022 Jun 13. pii: S1551-7144(22)00147-1. [Epub ahead of print] 106821
    Technology-enhanced AcceleRation of Germline Evaluation for Therapy (TARGET): A randomized controlled trial of a pretest patient-driven webtool vs. genetic counseling for prostate cancer germline testing.
    Stacy Loeb, Heather H Cheng, Amy Leader, Laura Gross, Tatiana Sanchez Nolasco, Nataliya Byrne, David R Wise, Lucas Hollifield, Lauren H Brown, Elias Slater, Christopher Pieczonka, Leonard G Gomella, William K Kelly, Edouard J Trabulsi, Nathan Handley, Costas D Lallas, Thenappan Chandrasekar, Patrick Mille, Mark Mann, James Ryan Mark, Gordon Brown, Sameer Chopra, Jenna Wasserman, Jade Phillips, Patrick Somers, Veda N Giri.
      BACKGROUND: Germline testing has an increasingly important role in prostate cancer care. However, a relative shortage of genetic counselors necessitates alternate strategies for delivery of pre-test education for germline testing. This study, funded by the Prostate Cancer Foundation, seeks to address the need for novel methods of delivery of pre-test germline education beyond traditional germline counseling to facilitate informed patient decision-making for germline testing.METHODS: This is a two-armed randomized controlled trial (RCT) with a target enrollment of 173 participants with prostate cancer per study arm (total anticipated n = 346). Patients who meet criteria for germline testing based on tumor features, family history or Ashkenazi Jewish ancestry are being recruited from 5 US sites including academic, private practice and Veterans healthcare settings. Consenting participants are randomized to the interactive pretest webtool or germline counseling with assessment of key patient-reported outcomes involved in informed decision-making for germline germline testing.
    RESULTS: Participants complete surveys at baseline, after pretest education/counseling, and following disclosure of germline germline results. The primary outcome of the study is decisional conflict for germline testing. Secondary outcomes include germline knowledge, satisfaction, uptake of germline testing, and understanding of results.
    CONCLUSION: Our hypothesis is that the web-based germline education tool is non-inferior to traditional germline counseling regarding key patient-reported outcomes involved in informed decision-making for germline testing. If proven, the results would support deploying the webtool across various practice settings to facilitate pre-test germlines education for individuals with prostate cancer and developing collaborative care strategies with germline counseling.
    CLINICALTRIALS: gov Identifier: NCT04447703.
    Keywords:  DNA repair; Germline counseling; Germline testing; Prostate cancer; Technology
    DOI:  https://doi.org/10.1016/j.cct.2022.106821
  5. Pancreas. 2022 Jun 11.
    The Additional Diagnostic Benefit of Pancreatic Cancer Molecular Profiling After Germline Testing.
    Evan J Walker, Amie M Blanco, Julia Carnevale, Pelin Cinar, Eric A Collisson, Margaret A Tempero, Andrew H Ko.
      OBJECTIVES: Germline genetic testing is universally recommended for patients with pancreatic cancer to guide therapeutic selection, but tumor molecular profiling (TMP) is not. We aimed to determine the real-world additional diagnostic benefit of TMP after germline testing for detecting therapeutically actionable alterations.METHODS: Medical records and genetic test reports were reviewed for all patients who underwent germline testing and TMP at the University of California San Francisco during January 2016-January 2020. The detection rate of actionable alterations with germline testing alone was compared to that with both germline testing and TMP.
    RESULTS: Among 738 eligible patients, 144 (20%) met study criteria. Germline testing detected 10 actionable alterations in 10 patients. Tumor molecular profiling identified 3 new therapeutic targets among these 10 patients and 45 targets in 41 additional patients, increasing the number of patients with actionable findings from 10 (7%) to 51 (35%). Most actionable alterations (35/58, 60%) involved genes associated with the Homologous Recombination DNA Damage Repair pathway.
    CONCLUSIONS: Tumor molecular profiling after germline testing increased the detection of actionable alterations by 5-fold. Tumor molecular profiling is a necessary complement to germline genetic testing to fully inform therapeutic decision making for all patients with pancreatic cancer.
    DOI:  https://doi.org/10.1097/MPA.0000000000002021
  6. Lab Med. 2022 Jun 16. pii: lmac046. [Epub ahead of print]
    Compliance with the Current NCCN Guidelines and Its Critical Role in Pancreatic Adenocarcinoma.
    Jeffrey M Petersen, Darshana N Jhala.
      OBJECTIVES: Since 2019, the National Comprehensive Cancer Network (NCCN) has recommended genetic testing for patients diagnosed with pancreatic adenocarcinoma that includes universal germline testing and tumor gene profiling for metastatic, locally advanced, or recurrent disease. However, testing compliance with this guideline has not yet been published in the English literature.METHODS: A quality assurance/quality improvement retrospective review was done to identify patients diagnosed with pancreatic adenocarcinoma from January 2019 to February 2021 to include the patient's clinical status and genetic test results.
    RESULTS: There were 20 patient cases identified with pancreatic adenocarcinoma. A total of 11 cases had molecular tumor gene profiling and microsatellite instability/mismatch repair (MSI/MMR) testing performed and 1 case had only MSI/MMR testing by immunohistochemistry performed. Only 3 patients of the 20 in total received germline testing.
    CONCLUSION: There was a significant number of patients for whom tumor gene profiling or germline testing had never been attempted as per recommended NCCN guidelines.
    Keywords:  NCCN guidelines; cancer; endoscopic ultrasound guided fine needle aspiration (EUS-FNA); germline profiling; molecular tumor profiling; pancreas; quality assurance
    DOI:  https://doi.org/10.1093/labmed/lmac046
  7. Br J Cancer. 2022 Jun 16.
    Impact of germline mutations in cancer-predisposing genes on long-term survival in patients with epithelial ovarian cancer.
    Joanne Kotsopoulos, Neda Zamani, Barry Rosen, John R McLaughlin, Harvey A Risch, Shana J Kim, Ping Sun, Mohammad Reza Akbari, Steven A Narod.
      BACKGROUND: Several clinical and tumour factors impact on ovarian cancer survival. It is important to evaluate if germline mutations impact long-term outcomes among patients with epithelial ovarian cancer.METHODS: We followed 1422 Ontario women with ovarian cancer. Clinical information was obtained from medical records and vital status was determined by registry linkage. Germline genetic testing was performed for 12 susceptibility genes. We estimated 20-year cancer-specific survival according to various factors.
    RESULTS: Twenty-year survival was inferior for women with serous cancers vs. other types (22.3% vs. 68.6%; P < 0.0001). Of the 1422 patients, 248 (17.4%) carried a germline mutation; 119 BRCA1; 75 BRCA2; 7 in a mismatch repair (MMR) gene and 47 in one of seven other genes. Among serous patients, 20-year survival was 28.9% for similar for women with a BRCA1 (28.9%), BRCA2 (21.2%) or no mutation (21.6%). Among endometrioid patients, 20-year survival was poor for women with a BRCA vs. no mutation (47.3% vs. 70.4%; P = 0.004). Six of the seven MMR mutation carriers are currently alive, while all three PALB2 mutation carriers died within 3 years of diagnosis. Among women with Stage III/IV serous cancers, 20-year survival was 9.4% for those with vs. 46.5% for those with no residual disease (HR = 2.91; 95% CI 2.12-4.09, P < 0.0001).
    CONCLUSIONS: The most important predictor of long-term survival was no residual disease post surgery. BRCA mutation status was not predictive of long-term survival while those with MMR mutations had excellent survival. Larger studies on PALB2 carriers are needed.
    DOI:  https://doi.org/10.1038/s41416-022-01840-4
  8. J Natl Compr Canc Netw. 2022 Jun;pii: jnccn21249. [Epub ahead of print]20(6): 663-673.e12
    Is Biannual Surveillance for Pancreatic Cancer Sufficient in Individuals With Genetic Syndromes or Familial Pancreatic Cancer?
    Yifan Wang, Adeline Cuggia, Yen-I Chen, Josée Parent, Agatha Stanek, Robert E Denroche, Amy Zhang, Robert C Grant, Céline Domecq, Bryn Golesworthy, Chaya Shwaartz, Ayelet Borgida, Spring Holter, Julie M Wilson, George Chong, Grainne M O'Kane, Jennifer J Knox, Sandra E Fischer, Steven Gallinger, Zu-Hua Gao, William D Foulkes, Kevin A Waschke, George Zogopoulos.
      BACKGROUND: Individuals with a family history of pancreatic adenocarcinoma (PC) or with a germline mutation in a PC susceptibility gene are at increased risk of developing PC. These high-risk individuals (HRIs) may benefit from PC surveillance.METHODS: A PC surveillance program was developed to evaluate the detection of premalignant lesions and early-stage PCs using biannual imaging and to determine whether locally advanced or metastatic PCs develop despite biannual surveillance. From January 2013 to April 2020, asymptomatic HRIs were enrolled and followed with alternating MRI and endoscopic ultrasound every 6 months.
    RESULTS: Of 75 HRIs, 43 (57.3%) had a germline mutation in a PC susceptibility gene and 32 (42.7%) had a familial pancreatic cancer (FPC) pedigree. Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) were identified in 26 individuals (34.7%), but only 2 developed progressive lesions. One patient with Peutz-Jeghers syndrome (PJS) developed locally advanced PC arising from a BD-IPMN. Whole-genome sequencing of this patient's PC and of a second patient with PJS-associated PC from the same kindred revealed biallelic inactivation of STK11 in a KRAS-independent manner. A review of 3,853 patients from 2 PC registries identified an additional patient with PJS-associated PC. All 3 patients with PJS developed advanced PC consistent with the malignant transformation of an underlying BD-IPMN in <6 months. The other surveillance patient with a progressive lesion had FPC and underwent resection of a mixed-type IPMN that harbored polyclonal KRAS mutations.
    CONCLUSIONS: PC surveillance identifies a high prevalence of BD-IPMNs in HRIs. Patients with PJS with BD-IPMNs may be at risk for accelerated malignant transformation.
    DOI:  https://doi.org/10.6004/jnccn.2021.7107
  9. Front Oncol. 2022 ;12 855305
    A Germline Mutation in ATR Is Associated With Lung Adenocarcinoma in Asian Patients.
    Guangyao Bao, Xiaojiao Guan, Jie Liang, Yao Yao, Yifan Xiang, Tian Li, Xinwen Zhong.
      Background: Familial lung cancer (FLC) accounts for 8% of lung adenocarcinoma. It is known that a few germline mutations are associated with risk increasing and may provide new screening and treatment option. The goal of this study is to identify an FLC gene among three members of an FLC family.Methods: To uncover somatic and embryonic mutations linked with familial lung cancer, whole exome sequencing was done on surgical tissues and peripheral blood from three sisters in a family diagnosed with pulmonary lung adenocarcinoma (LUAD). At the same time, single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data in public databases were enrolled to identify specific gene expression level.
    Results: Ataxia Telangiectasia and Rad3-Related Protein (ATR) gene C.7667C >G (p.T2556S) mutation were found in 3 patients with familial lung cancer. Whole-genome sequencing revealed that the three sisters exhibited similar somatic mutation patterns. Besides ATR mutations, common mutated genes (BRCA1, EGFR, and ROS1) that characterize LUAD were also found in 5 tumor samples. Analysis for the ATR expression in LUAD patients by single-cell sequencing data, we found ATR expression of tumor patients at high level in immune cells when compared with normal patients, but the expression of ATR in stromal cells has the opposite result.
    Conclusion: We found a germline mutation in the ATR gene in three sisters of a Chinese family affected by familial lung cancer, which may be a genetic factor for lung cancer susceptibility.
    Keywords:  ATR; familiar lung cancer; germline mutation; lung adenocarcinoma; sequencing
    DOI:  https://doi.org/10.3389/fonc.2022.855305
  10. Sci Rep. 2022 Jun 17. 12(1): 10207
    Association between germline variants and somatic mutations in colorectal cancer.
    Richard Barfield, Conghui Qu, Robert S Steinfelder, Chenjie Zeng, Tabitha A Harrison, Stefanie Brezina, Daniel D Buchanan, Peter T Campbell, Graham Casey, Steven Gallinger, Marios Giannakis, Stephen B Gruber, Andrea Gsur, Li Hsu, Jeroen R Huyghe, Victor Moreno, Polly A Newcomb, Shuji Ogino, Amanda I Phipps, Martha L Slattery, Stephen N Thibodeau, Quang M Trinh, Amanda E Toland, Thomas J Hudson, Wei Sun, Syed H Zaidi, Ulrike Peters.
      Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.
    DOI:  https://doi.org/10.1038/s41598-022-14408-2
  11. Transl Cancer Res. 2022 May;11(5): 1423-1428
    Genomic profiling reveals non-small cell lung cancer with common mutations of EGFR exon 20 and exon 21: a case report.
    Xiaojun Bi, Pengyu Song, Chengye Wang, Xuefei Zhang, Changhong Liu.
      Background: Epidermal growth factor receptor (EGFR) gene is one of the most common driver genes for non-small cell lung cancer (NSCLC). The PIONEER study showed that 51.4% of unselected Asian patients with advanced lung adenocarcinoma have EGFR-sensitive mutations. EGFR mutations mainly occur in the first four [18-21] exons of the intracellular tyrosine kinase (TK) region. At present, there are more than 30 types of mutations in the TK region, including exon 19 deletion mutation (19Del) and exon 21 L858R mutation (L858R) which are the most common types of sensitive mutations, accounting for more than 90% of all EGFR mutations. About 10% of NSCLC patients with EGFR mutations are rare mutation types, including exon 18 point mutation (G719X), exon 20 point mutation (S768I), exon 19 point mutation (L747S), exon 21 point mutation (L833V), etc. About 1% of NSCLC patients have primary double mutations of EGFR.Case Description: In this present study, we identified a 59-year-old female patient with no smoking history had double mutations in EGFR exon 20 R776S mutation and exon 21 L858R mutation by next-generation sequencing (NGS).
    Conclusions: This observation may explore a new mechanism study for EGFR-TKIs and provide a new direction for clinical treatment of NSCLC.
    Keywords:  Case report; epidermal growth factor receptor (EGFR); lung adenocarcinoma; next-generation sequencing (NGS)
    DOI:  https://doi.org/10.21037/tcr-21-2604
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