bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–11–27
seven papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. The prevalence of germline pathogenic variants in Estonian colorectal cancer patients: results from routine clinical setting 2016-2021.
  2. Germline mutations in prostate cancer: a systematic review of the evidence for personalized medicine.
  3. Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in CDKN2A and Pancreatic Cancer.
  4. Whole-exome sequencing of BRCA-negative breast cancer patients and case-control analyses identify variants associated with breast cancer susceptibility.
  5. The Role of Radiation Therapy in Locally Advanced Breast Cancer in a Patient With Li-Fraumeni Syndrome.
  6. Likelihood of germline mutation with solitary retinoblastoma based on tumour location at presentation.
  7. Lynch syndrome, molecular mechanisms and variant classification.
  1. Front Genet. 2022 ;13 1020543
    The prevalence of germline pathogenic variants in Estonian colorectal cancer patients: results from routine clinical setting 2016-2021.
    Laura Roht, Mikk Tooming, Kadri Rekker, Hanno Roomere, Kadri Toome, Ülle Murumets, Ustina Šamarina, Katrin Õunap, Tiina Kahre.
      Background: Colorectal cancer (CRC) is the third most common cancer in Estonia in both women and men. According to the Estonian National Institute for Health Development, in 2017, there were 357 new colon cancer only cases in women and 282 in men. For colorectal cancer, the number for men and women altogether was 1040 in the same year. In 2018, there were over 1.8 million new cases worldwide. The Mayo Clinic found in a prospective, two-year multi-site study of CRC patients that 15.5% of patients carried pathogenic germline variants (PGV), using an >80 gene Next Generation Sequencing (NGS) panel. Material and methods: This retrospective study aimed to analyse the estimated prevalence of pathogenic/likely pathogenic germline variants in Estonian colorectal cancer patients using NGS in a routine clinical setting. We gathered five-year data (July 2016-July 2021) of colorectal cancer patients (mostly not selected for age or family history) tested with either Illumina TruSight Cancer (94 genes) or TruSight Hereditary Cancer (113 genes) NGS panels. Results: Three hundred and fourteen NGS analyses were performed due to either CRC or polyposis in anamnesis and/or family anamnesis, including 126 CRC cases and 44 colorectal polyposis cases, while 144 were either healthy family members or had other types of cancers. While a known disease-causing variant was identified in 16.4% of all cancer patients tested, we found that 21.4% of CRC patients had such a variant. Among the 44 colorectal polyps cases MLH1, gene was the most affected one (25%), the second and third most affected genes were MSH2 and CHEK2. Other genes with disease-causing variants found in CRC patients included APC, BLM, BMPR1A, BRCA1, FANCM, MSH6, MUTYH, PMS2, SMAD4, SPINK1 and VHL. Conclusion: Our result give an overview of genetic testing of CRC patients, the prevalence of disease-causing variants and their landscape in Estonia. According to Estonian data, only 2.7-6.1% of CRC patients are genetically tested, which is around ten times less frequently than breast cancer patients and their family members. The diagnostic yield of CRC patients is 21.4%, suggesting that genetic testing will likely improve timely diagnosis and outcomes.
    Keywords:  NGS; colorectal cancer; hereditary cancer syndromes; molecular genetics of CRC; routine clinical setting diagnostics
    DOI:  https://doi.org/10.3389/fgene.2022.1020543
  2. Prostate Cancer Prostatic Dis. 2022 Nov 24.
    Germline mutations in prostate cancer: a systematic review of the evidence for personalized medicine.
    Filippo Marino, Angelo Totaro, Carlo Gandi, Riccardo Bientinesi, Stefano Moretto, Filippo Gavi, Francesco Pierconti, Roberto Iacovelli, PierFrancesco Bassi, Emilio Sacco.
       BACKGROUND: The goal of precision medicine in prostate cancer (PCa) is to individualize the treatment according to the patient's germline mutation status. PCa has a very high rate of genetic predisposition compared with other cancers in men, with an estimated rate of cancers ascribable to hereditary factors of 5-15%.
    METHODS: A systematic search (PubMed, Web of Science, and ClinicalTrials.gov) of English literature from 2000 to 2022, using the keywords "prostate cancer", "germline mutations", "family history", and "inheritance" was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
    RESULTS: The search identified 980 publications. Of these, 200 papers were removed before screening (duplicates, non-English literature, and publication year before 2000) and 245 records were excluded after title/abstract screening. Finally, 50 articles were included in the final analysis. We analyze the latest evidence on the genetic basis of PCa predisposition and clinical implications for more personalized screening protocols and therapeutic management of this high-prevalent cancer.
    DISCUSSION: Emerging data show that germline mutations in homologous recombination genes (BRCA1/2, ATM, CHECK2), in mismatch repair genes (MLH1, MLH2, MSH6), and other additional genes are associated with the development and aggressiveness of PCa. Germline testing and genetic counseling have increasingly important implications in cancer screening and therapeutic decisions making for patients affected by PCa. Patients with localized PCa and some gene mutations are more likely to develop aggressive cancer, so active treatment may be preferable to active surveillance for these patients. Moreover, in patients with metastatic PCa, these gene alterations may be useful biomarkers for predicting response to specific therapy such as PARP inhibitors, recently approved for the treatment of metastatic castration-resistant PCa. The evidence supports recent guidelines and recommendations considering germline genetic testing for patients with a positive family history of PCa or men with high risk or metastatic disease.
    DOI:  https://doi.org/10.1038/s41391-022-00609-3
  3. JCO Precis Oncol. 2022 Nov;6 e2200145
    Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in CDKN2A and Pancreatic Cancer.
    Esteban Astiazaran-Symonds, Cole Graham, Jung Kim, Margaret A Tucker, Christian Ingvar, Hildur Helgadottir, Lorenza Pastorino, Remco van Doorn, Joshua N Sampson, Bin Zhu, William Bruno, Paola Queirolo, Giuseppe Fornarini, Stefania Sciallero, Brian Carter, Belynda Hicks, Amy Hutchinson, Kristine Jones, Douglas R Stewart, Stephen J Chanock, Neal D Freedman, Maria Teresa Landi, Veronica Höiom, Susana Puig, Nelleke Gruis, Xiaohong R Yang, Paola Ghiorzo, Alisa M Goldstein.
       PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in CDKN2A. However, it is unclear what role this gene or other genes play in its etiology.
    MATERIALS AND METHODS: We analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with (CDKN2A+) and without (CDKN2A-) GPV. Exome sequencing was performed on 84 patients with PDAC, 47 CDKN2A+ and 37 CDKN2A-. After variant filtering, various RVA tests and permutation tests were run separately by CDKN2A status. Genes with the strongest nominal associations were evaluated in patients with PDAC from The Cancer Genome Atlas and the UK Biobank (UKB). A secondary analysis including only GPV from UKB was also performed.
    RESULTS: In RVA tests, ERCC4 and RET showed the most compelling evidence as plausible PDAC candidate genes for CDKN2A+ patients. In contrast, the findings in CDKN2A- patients provided evidence for HMBS, EPCAM, and MRE11 as potential new candidate genes and confirmed ATM, BRCA2, and PALB2 as PDAC genes, consistent with findings in The Cancer Genome Atlas and the UKB. As expected, CDKN2A- patients were more likely to harbor GPVs from the 189 genes investigated. When including only GPVs from UKB, significant associations with PDAC were seen for ATM, BRCA2, and CDKN2A.
    CONCLUSION: These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in CDKN2A+ patients has a distinct etiology from PDAC in CDKN2A- patients.
    DOI:  https://doi.org/10.1200/PO.22.00145
  4. Hum Genomics. 2022 Nov 23. 16(1): 61
    Whole-exome sequencing of BRCA-negative breast cancer patients and case-control analyses identify variants associated with breast cancer susceptibility.
    Ning Yuan Lee, Melissa Hum, Aseervatham Anusha Amali, Wei Kiat Lim, Matthew Wong, Matthew Khine Myint, Ru Jin Tay, Pei-Yi Ong, Jens Samol, Chia Wei Lim, Peter Ang, Min-Han Tan, Soo-Chin Lee, Ann S G Lee.
       BACKGROUND: For the majority of individuals with early-onset or familial breast cancer referred for genetic testing, the genetic basis of their familial breast cancer remains unexplained. To identify novel germline variants associated with breast cancer predisposition, whole-exome sequencing (WES) was performed.
    METHODS: WES on 290 BRCA1/BRCA2-negative Singaporeans with early-onset breast cancer and/or a family history of breast cancer was done. Case-control analysis against the East-Asian subpopulation (EAS) from the Genome Aggregation Database (gnomAD) identified variants enriched in cases, which were further selected by occurrence in cancer gene databases. Variants were further evaluated in repeated case-control analyses using a second case cohort from the database of Genotypes and Phenotypes (dbGaP) comprising 466 early-onset breast cancer patients from the United States, and a Singapore SG10K_Health control cohort.
    RESULTS: Forty-nine breast cancer-associated germline pathogenic variants in 37 genes were identified in Singapore cases versus gnomAD (EAS). Compared against SG10K_Health controls, 13 of 49 variants remain significantly enriched (False Discovery Rate (FDR)-adjusted p < 0.05). Comparing these 49 variants in dbGaP cases against gnomAD (EAS) and SG10K_Health controls revealed 23 concordant variants that were significantly enriched (FDR-adjusted p < 0.05). Fourteen variants were consistently enriched in breast cancer cases across all comparisons (FDR-adjusted p < 0.05). Seven variants in GPRIN2, NRG1, MYO5A, CLIP1, CUX1, GNAS and MGA were confirmed by Sanger sequencing.
    CONCLUSIONS: In conclusion, we have identified pathogenic variants in genes associated with breast cancer predisposition. Importantly, many of these variants were significant in a second case cohort from dbGaP, suggesting that the strategy of using case-control analysis to select variants could potentially be utilized for identifying variants associated with cancer susceptibility.
    Keywords:  BRCA1/2 negative; Breast cancer; Case–control analysis; Germline variants; Whole-exome sequencing
    DOI:  https://doi.org/10.1186/s40246-022-00435-7
  5. Am Surg. 2022 Nov 24. 31348221135780
    The Role of Radiation Therapy in Locally Advanced Breast Cancer in a Patient With Li-Fraumeni Syndrome.
    Ashley C Roberts, Lilia G Lunt, Alison C Coogan, Andrea Madrigrano.
      Li-Fraumeni syndrome (LFS) is associated with many different cancers, including early onset breast cancer. Due to an increased risk of radiation-induced malignancy, radiation therapy is often avoided in this patient population. This case study evaluates a 38-year-old female with a history of juvenile granulosa cell tumor of the ovary and malignant phyllodes tumor of right breast, who subsequently developed bilateral invasive ductal carcinoma and was treated with bilateral mastectomies. Studies show that in a high-risk patient, post-mastectomy radiation therapy (PMRT) should not be ruled out due to a history of LFS, as the benefit of PMRT may outweigh the risk of a radiation-induced malignancy.
    Keywords:  Breast; general surgery; surgical oncology
    DOI:  https://doi.org/10.1177/00031348221135780
  6. Br J Ophthalmol. 2022 Nov 22. pii: bjophthalmol-2022-321757. [Epub ahead of print]
    Likelihood of germline mutation with solitary retinoblastoma based on tumour location at presentation.
    Philip W Dockery, Megan Ruben, Emily R Duffner, Hannah J Levin, Sara E Lally, Jerry A Shields, Carol L Shields.
       BACKGROUND/AIMS: To evaluate the likelihood of germline mutation in patients presenting with solitary retinoblastoma based on tumour location at first examination.
    METHODS: Retrospective analysis of solitary unilateral retinoblastoma for likelihood of germline mutation (family history of retinoblastoma and/or genetic testing indicating germline RB1 mutation and/or development of additional new or bilateral tumours) based on tumur location at presentation (macular vs extramacular).
    RESULTS: Of 480 consecutive patients with solitary retinoblastoma, 85 were in the macula (18%) and 395 were extramacular (82%). By comparison (macular vs extramacular tumours), macular tumours had smaller basal diameter (12.7 mm vs 18.9 mm, p<0.001) and smaller tumour thickness (6.1 mm vs 10.7 mm, p<0.001). Patients with macular tumours demonstrated greater likelihood for germline mutation (23% vs 12%, OR=2.18, p=0.011), specifically based on family history of retinoblastoma (13% vs 2%, OR=4.64, p=0.004), genetic testing showing germline RB1 mutation (27% vs 15%, OR=2.04 (95% CI 1.04 to 4.01), p=0.039), development of new tumours (13% vs 3%, OR=5.16 (95% CI 2.06 to 12.87), p=0.001) and/or development of bilateral disease (9% vs 2%, OR=4.98 (95% CI 1.70 to 14.65), p=0.004).
    CONCLUSIONS: Among patients with solitary unilateral retinoblastoma, those presenting with macular tumour (compared with extramacular tumour) show 2.18 times greater likelihood for germline mutation and an even higher likelihood of development of subsequent tumours. Solitary macular retinoblastoma should raise an index of suspicion for likely germline mutation and multifocal disease.
    Keywords:  Genetics; Macula; Neoplasia; Retina
    DOI:  https://doi.org/10.1136/bjo-2022-321757
  7. Br J Cancer. 2022 Nov 24.
    Lynch syndrome, molecular mechanisms and variant classification.
    Amanda B Abildgaard, Sofie V Nielsen, Inge Bernstein, Amelie Stein, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen.
      Patients with the heritable cancer disease, Lynch syndrome, carry germline variants in the MLH1, MSH2, MSH6 and PMS2 genes, encoding the central components of the DNA mismatch repair system. Loss-of-function variants disrupt the DNA mismatch repair system and give rise to a detrimental increase in the cellular mutational burden and cancer development. The treatment prospects for Lynch syndrome rely heavily on early diagnosis; however, accurate diagnosis is inextricably linked to correct clinical interpretation of individual variants. Protein variant classification traditionally relies on cumulative information from occurrence in patients, as well as experimental testing of the individual variants. The complexity of variant classification is due to (1) that variants of unknown significance are rare in the population and phenotypic information on the specific variants is missing, and (2) that individual variant testing is challenging, costly and slow. Here, we summarise recent developments in high-throughput technologies and computational prediction tools for the assessment of variants of unknown significance in Lynch syndrome. These approaches may vastly increase the number of interpretable variants and could also provide important mechanistic insights into the disease. These insights may in turn pave the road towards developing personalised treatment approaches for Lynch syndrome.
    DOI:  https://doi.org/10.1038/s41416-022-02059-z
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