bims-lifras 2022-02-06 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022–02–06
ten papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Establishment and characterization of NCC-UPS4-C1: a novel cell line of undifferentiated pleomorphic sarcoma from a patient with Li-Fraumeni syndrome.
Germline Variants in DNA Damage Repair Genes: An Emerging Role in the Era of Precision Medicine in Pancreatic Adenocarcinoma.
When to use germline genetic testing in prostate cancer.
Germline Cancer Testing in Unselected Patients with Gastric and Esophageal Cancers: A Multi-center Prospective Study.
BAP1 germline variants in Finnish patients with malignant mesothelioma.
Ovarian toxicity of carboplatin and paclitaxel in mouse carriers of mutation in BRIP1 tumor suppressor gene.
Automated Clinical Practice Guideline Recommendations for Hereditary Cancer Risk Using Chatbots and Ontologies: System Description.
Pancreatic cancer patients with germline BRCA mutations can benefit from olaparib treatment.
Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A).
Association of cancer with comorbid inflammatory conditions and treatment in patients with Lynch syndrome.

Hum Cell. 2022 Feb 03.

Establishment and characterization of NCC-UPS4-C1: a novel cell line of undifferentiated pleomorphic sarcoma from a patient with Li-Fraumeni syndrome.

Takuya Ono, Yuki Yoshimatsu, Rei Noguchi, Yooksil Sin, Ryuto Tsuchiya, Taro Akiyama, Jun Sugaya, Suguru Fukushima, Naoki Kojima, Akihiko Yoshida, Akira Kawai, Tadashi Kondo.

  Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by a germline mutation of the TP53. The lifetime risk of cancer in individuals with LFS is ≥ 70% for men and ≥ 90% for women. Undifferentiated pleomorphic sarcoma (UPS) is one of the core cancers associated with LFS. UPS is a subtype of undifferentiated soft tissue sarcoma that shows no identifiable line of differentiation. The standard curative treatment for UPS is complete surgical resection. However, local recurrence and distant metastasis to the lung can usually be found after resection of the UPS. Therefore, a novel treatment strategy for patients with UPS is required. Although well characterized, patient-derived tumor cell lines facilitate the high-throughput screening of a large number of drugs, and no sarcoma cell lines derived from a patient with LFS have been registered in public cell banks. Thus, this study aimed to establish a novel, well-characterized UPS cell line from a patient with LFS. From surgically resected UPS tumor tissues, we established the first UPS cell line from a patient with LFS and named it NCC-UPS4-C1. NCC-UPS4-C1 harbored copy number alterations and had the TP53 tumor suppressor gene mutation. The cells exhibited constant cell growth and invasive ability. This well-characterized NCC-UPS4-C1 cell line was then utilized for high-throughput screening of 214 anti-cancer drugs, and two effective drugs were identified. One of the two drugs, romidepsin, was commonly effective for the NCC-UPS1-C1, NCC-UPS2-C1, and NCC-UPS3-C1 cell lines that we previously reported; a potential drug for the treatment of UPS was suggested using well-characterized UPS cell lines. These data indicate that NCC-UPS4-C1, which is the first sarcoma cell line established from a patient with LFS, enables researchers to conduct vigorous preclinical research on UPS.

Keywords:  Anti-cancer drug screening; Li–Fraumeni syndrome; Patient-derived cell line; Soft tissue sarcoma; Undifferentiated pleomorphic sarcoma

DOI:  https://doi.org/10.1007/s13577-022-00671-y
Ann Gastroenterol Surg. 2022 Jan;6(1): 7-16

Germline Variants in DNA Damage Repair Genes: An Emerging Role in the Era of Precision Medicine in Pancreatic Adenocarcinoma.

Sami Shoucair, Andrew R Baker, Jun Yu.

  Pancreatic adenocarcinoma is a lethal disease that is projected to become the second most common cause of cancer deaths by 2030. The role of adjuvant therapy after surgical resection has been established by several clinical trials to prolong survival and improve outcomes. Multiagent chemotherapy seems to be the most promising approach to counteract early recurrence and improve survival; however, in the era of precision medicine, patient selection and individualized therapy seems to hold the key to desirable superior outcomes. Several cancer susceptibility genes have been proven to be associated with an increased risk of pancreatic cancer, both familial and sporadic cases. The role of genomic profiling for germline variants has been extensive and of limited clinical value, considering their low prevalence in pancreatic ductal adenocarcinoma (PDAC). However, an accumulating body of evidence from several studies in the past decade have successfully shown a recognizable value of germline variants in risk assessment and patient stratification. Recently, anti-PD-1 therapy (pembrolizumab) has been FDA-approved for use in solid malignancies with a Mismatch repair deficiency or high Microsatellite instability. Several trials have evaluated the role of poly (ADP-ribose) polymerase (PARP) inhibitors in patients harboring germline BRCA1/2 mutations. Finally, germline variants in DNA damage response genes and particularly deleterious ones have the potential to guide therapy after surgical resection and serve as biomarkers to predict survival. The dire need to address challenges for applying precision medicine in real-life clinical settings for PDAC patients lies in further characterizing the genetic and molecular processes through translational research.

Keywords:  DDR genes; germline variants; pancreatic cancer; precision medicine

DOI:  https://doi.org/10.1002/ags3.12514
Clin Adv Hematol Oncol. 2022 Feb;20(2): 78-81

When to use germline genetic testing in prostate cancer.

Veda N Giri.
Dig Dis Sci. 2022 Feb 05.

Germline Cancer Testing in Unselected Patients with Gastric and Esophageal Cancers: A Multi-center Prospective Study.

P L S Uson, K L Kunze, M A Golafshar, G Botrus, D Riegert-Johnson, L Boardman, M J Borad, D Ahn, M B Sonbol, A Kahn, M Klint, E D Esplin, R L Nussbaum, A K Stewart, T Bekaii-Saab, N J Samadder.

   BACKGROUND AND AIMS: To determine prevalence and clinical utility of pathogenic germline variants (PGV) in gastric and esophageal cancer patients using universal genetic testing approach.
METHODS: We undertook a prospective study of germline sequencing using an > 80 gene next-generation sequencing platform among patients with gastric and esophageal cancers receiving care at Mayo Clinic Cancer Center between April 1, 2018, and March 31, 2020. Patients were not selected based on cancer stage, family history of cancer, ethnicity, or age. Family cascade testing was offered at no cost.
RESULTS: A total of 96 patients were evaluated. Median age was 66 years, 80.2% were male, 89.6% were white. Nearly 39% of the cohort had esophageal cancer, 35.4% gastric cancer and 26% gastroesophageal junction cancers. Approximately half (52%) of the patients had metastatic disease. Pathogenic germline variants (PGV) were detected in 15.6% (n = 15) patients. The prevalence of PGV was 10.8% in esophageal cancer, 17.6% in gastric cancer and 20% in gastroesophageal cancer. Eighty percent of patients with a positive result would not have been detected by screening with standard guidelines for genetic testing. Most PGV detected included genes with high and moderate penetrance related to DNA damage response including BRCA1, BRCA2, PALB2 and ATM.
CONCLUSIONS: Universal multi-gene panel testing in gastric and esophageal cancers was associated with detection of heritable mutations in 15% of patients. The majority of PGV would not be detected with current screening guidelines and are related to DNA damage response.

Keywords:  BRCA; Esophageal cancer; Gastric cancer; Germline testing

DOI:  https://doi.org/10.1007/s10620-022-07387-x
Lung Cancer. 2022 Jan 24. pii: S0169-5002(22)00029-0. [Epub ahead of print]165 102-107

BAP1 germline variants in Finnish patients with malignant mesothelioma.

Pauliina Repo, Aleksandra Staskiewicz, Eva Sutinen, Mikko Rönty, Tero T Kivelä, Marjukka Myllärniemi, Joni A Turunen.

   OBJECTIVES: Although asbestos exposure is the most common cause of malignant mesothelioma (MM), an aggressive cancer of the pleura or peritoneum, up to 7% of patients harbor a genetic predisposition to MM. Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause a dominantly inherited tumor predisposition syndrome, BAP1-TPDS, in which MM is the second most common associated cancer. Other frequent cancers in BAP1-TPDS are uveal melanoma (UM), cutaneous melanoma and renal cell carcinoma. Additionally patients can exhibit benign skin lesions, BAP1-inactivated nevi (BIN). Most BINs arise sporadically, but patients with BAP1-TPDS may harbor multiple BINs before other tumors or as the only indication of the syndrome. Our objective was to establish the frequency of pathogenic germline BAP1 variants in Finnish patients with MM.
MATERIALS AND METHODS: 56 DNA samples archived in the Helsinki Biobank from Finnish patients with MM were sequenced for germline BAP1 variations. Formalin fixed paraffin embedded nevi from a pathogenic variant carrier were subjected to immunohistochemistry and exome sequencing.
RESULTS: Sanger sequencing identified one patient with Finnish founder mutation c.1780_1781insT, p.(G549Vfs*49) in BAP1. The carrier was diagnosed with MM over fifteen years before the cohorts mean onset age (mean 68, range 27 to 82) although the patient had no asbestos exposure or family history of BAP1-TPDS. However, the patient had three BINs removed prior to the MM. The c.1780_1781insT is now found from five Finnish BAP1-TPDS families with unknown common ancestor.
CONCLUSION: The frequency of pathogenic germline BAP1 variants in Finnish patients with MM is 1.8 % (95 % CI, 0.04 to 9.2), comparable to the frequency in Finnish patients with UM (1.9 %). The frequency of recurring BINs in patients with BAP1-TPDS should be studied further and genetic testing for BAP1 variants considered if the patient has ≥ 2 BAP1-TPDS core tumors, including BINs.

Keywords:  BAP1; BAP1-TPDS; BAP1-inactivated nevus; Malignant mesothelioma; Tumor predisposition

DOI:  https://doi.org/10.1016/j.lungcan.2022.01.017
Sci Rep. 2022 Feb 01. 12(1): 1658

Ovarian toxicity of carboplatin and paclitaxel in mouse carriers of mutation in BRIP1 tumor suppressor gene.

E Ntemou, P Diaz Vidal, C Alexandri, G Van den Steen, M Lambertini, I Demeestere.

More than 10% of women diagnosed with breast cancer during reproductive age carry hereditary germline pathogenic variants in high-penetrance BRCA genes or in others genes involved in DNA repair mechanisms such as PALB2, BRIP or ATM. Anticancer treatments may have an additional negative impact on the ovarian reserve and subsequently on the fertility of young patients carrying such mutations. Recently, the combination of carboplatin and paclitaxel is being recommended to these BRCA-mutated patients as neoadjuvant therapy. However, the impact on the ovary is unknown. Here, we investigated their effect of on the ovarian reserve using mice carriers of BRCA1-interacting protein C-terminal helicase-1 (BRIP1) mutation that plays an important role in BRCA1-dependent DNA repair. Results revealed that the administration of carboplatin or paclitaxel did not affect the ovarian reserve although increased DNA double-strand breaks were observed with carboplatin alone. Co-administration of carboplatin and paclitaxel resulted in a significant reduction of the ovarian reserve leading to a lower IVF performance, and an activation of the PI3K-Pten pathway, irrespective of the genetic background. This study suggests that co-administration of carboplatin and paclitaxel induces cumulative ovarian damage and infertility but a heterozygote genetic predisposition for DNA damage related to BRCA1 gene function does not increase this risk.

DOI: https://doi.org/10.1038/s41598-022-05357-x
JMIR Cancer. 2022 Jan 31. 8(1): e29289

Automated Clinical Practice Guideline Recommendations for Hereditary Cancer Risk Using Chatbots and Ontologies: System Description.

Jordon B Ritchie, Lewis J Frey, Jean-Baptiste Lamy, Cecelia Bellcross, Heath Morrison, Joshua D Schiffman, Brandon M Welch.

   BACKGROUND: Identifying patients at risk of hereditary cancer based on their family health history is a highly nuanced task. Frequently, patients at risk are not referred for genetic counseling as providers lack the time and training to collect and assess their family health history. Consequently, patients at risk do not receive genetic counseling and testing that they need to determine the preventive steps they should take to mitigate their risk.
OBJECTIVE: This study aims to automate clinical practice guideline recommendations for hereditary cancer risk based on patient family health history.
METHODS: We combined chatbots, web application programming interfaces, clinical practice guidelines, and ontologies into a web service-oriented system that can automate family health history collection and assessment. We used Owlready2 and Protégé to develop a lightweight, patient-centric clinical practice guideline domain ontology using hereditary cancer criteria from the American College of Medical Genetics and Genomics and the National Cancer Comprehensive Network.
RESULTS: The domain ontology has 758 classes, 20 object properties, 23 datatype properties, and 42 individuals and encompasses 44 cancers, 144 genes, and 113 clinical practice guideline criteria. So far, it has been used to assess >5000 family health history cases. We created 192 test cases to ensure concordance with clinical practice guidelines. The average test case completes in 4.5 (SD 1.9) seconds, the longest in 19.6 seconds, and the shortest in 2.9 seconds.
CONCLUSIONS: Web service-enabled, chatbot-oriented family health history collection and ontology-driven clinical practice guideline criteria risk assessment is a simple and effective method for automating hereditary cancer risk screening.

Keywords:  clinical practice guidelines; consumer health informatics; hereditary cancer; restful API; risk assessment; service-oriented architecture

DOI:  https://doi.org/10.2196/29289
Transl Cancer Res. 2020 Apr;9(4): 2154-2156

Pancreatic cancer patients with germline BRCA mutations can benefit from olaparib treatment.

Shibani Mukherjee, Aroumougame Asaithamby.

DOI: https://doi.org/10.21037/tcr.2020.03.07
Front Genet. 2021 ;12 799807

Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A).

Quanli Han, Si Liu, Zhi Cui, Qi Wang, Tonghui Ma, Liwen Jiang, Xiaomo Li, Guanghai Dai.

  Lynch syndrome (LS) is a cancer-predisposing genetic disease mediated by pathogenic mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Accumulating evidence demonstrates that there is significant biological heterogeneity across MMR genes. Compared to MLH1 and MSH2, PMS2 variant carriers have a much lower risk for LS-related cancers. Tumors in MLH1 and MSH2 variant carriers often display MMR deficiency (dMMR) and/or high microsatellite instability (MSI-H), two predictive biomarkers for immunotherapy efficacy. However, tumors in PMS2 variant carriers are largely microsatellite stable (MSS) instead of MSI. Therefore, the optimal management of cancer patients with LS requires the integration of disease stage, MMR gene penetrance, dMMR/MSI status, and tumor mutational burden (TMB). In this work, we presented a locally advanced lung cancer patient with dMMR/MSI-H/TMB-H tumor and selective loss of PMS2 by immunohistochemistry. Germline testing revealed a rare PMS2 splicing variant (c.1144+1G>A) in the proband and his healthy daughter. The diagnosis of LS was made based on genetic analysis of this variant and literature review. Given the incomplete penetrance of PMS2, the proband and the carrier received tailored genetic counseling. To reduce cancer risk, the proband received four cycles of nivolumab plus chemotherapy and achieved a disease-free survival of sixteen months.

Keywords:  Lynch syndrome; PMS2; incomplete penetrance; lung cancer; splicing variant

DOI:  https://doi.org/10.3389/fgene.2021.799807
World J Clin Oncol. 2022 Jan 24. 13(1): 49-61

Association of cancer with comorbid inflammatory conditions and treatment in patients with Lynch syndrome.

Muhammad S Faisal, Carol A Burke, David Liska, Amy L Lightner, Brandie Leach, Margaret O'Malley, Lisa LaGuardia, Benjamin Click, J P Achkar, Matthew Kalady, J M Church, Gautam Mankaney.

   BACKGROUND: Individuals with Lynch syndrome (LS) and hereditary non-polyposis colorectal cancer (HNPCC) are at increased risk of both colorectal cancer and other cancers. The interplay between immunosuppression, a comorbid inflammatory condition (CID), and HNPCC on cancer risk is unclear.
AIM: To evaluate the impact of CIDs, and exposure to monoclonal antibodies and immunomodulators, on cancer risk in individuals with HNPCC.
METHODS: Individuals prospectively followed in a hereditary cancer registry with LS/HNPCC with the diagnosis of inflammatory bowel disease or rheumatic disease were identified. We compared the proportion of patients with cancer in LS/HNPCC group with and without a CID. We also compared the proportion of patients who developed cancer following a CID diagnosis based upon exposure to immunosuppressive medications.
RESULTS: A total of 21 patients with LS/HNPCC and a CID were compared to 43 patients with LS/HNPCC but no CID. Cancer occurred in 84.2% with a CID compared to 76.7% without a CID (P = 0.74) with no difference in age at first cancer diagnosis 45.5 ± 14.6 vs 43.8 ± 7.1 years (P = 0.67). LS specific cancers were diagnosed in 52.4% with a CID vs 44.2% without a CID (P = 0.54). Nine of 21 (42.9%) patients were exposed to biologics or immunomodulators for the treatment of their CID. Cancer after diagnosis of CID was seen in 7 (77.8%) of exposed individuals vs 5 (41.7%) individuals unexposed to biologics/immunomodulators (P = 0.18). All 7 exposed compared to 3/5 unexposed developed a LS specific cancer. The exposed and unexposed groups were followed for a median 10 years and 8.5 years, respectively. The hazard ratio for cancer with medication exposure was 1.59 (P = 0.43, 95%CI: 0.5-5.1).
CONCLUSION: In patients with LS/HNPCC, the presence of a concurrent inflammatory condition, or use of immunosuppressive medication to treat the inflammatory condition, might not increase the rate of cancer occurrence in this limited study.

Keywords:  Biologics; Hereditary non-polyposis colorectal cancer; Immunosuppression; Inflammatory bowel disease; Lynch syndrome

DOI:  https://doi.org/10.5306/wjco.v13.i1.49