bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023–01–15
seventeen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Profiling of the genetic features of Chinese patients with gastric cancer with HRD germline mutations in a large-scale retrospective study.
  2. Internet-Based Germline Genetic Testing for Men With Metastatic Prostate Cancer.
  3. Is it a prime time for germline genetic testing for hepatocellular carcinoma?
  4. Molecular characteristics of Asian male BRCA-related cancers.
  5. Pilot study of the prevalence of autoimmune disorders in Li-Fraumeni syndrome.
  6. Hereditary platelet disorders associated with germline variants in RUNX1, ETV6 and ANKRD26.
  7. Low Frequency of Cancer-Predisposition Gene Mutations in Liver Transplant Candidates with Hepatocellular Carcinoma.
  8. Surveillance imaging and early surgical intervention for improved CNS tumor outcomes in children with Li-Fraumeni syndrome: Children's National Hospital experience and literature review.
  9. Unexplained mismatch repair deficiency: Case closed.
  10. Cancer Risk Associated With PTEN Pathogenic Variants Identified Using Multigene Hereditary Cancer Panel Testing.
  11. Evidence Grows for Universal Germline Genetic Testing for Patients with Breast Cancer.
  12. Advances of aneuploidy research in the maternal germline.
  13. Inherited mutations in Chinese patients with upper tract urothelial carcinoma.
  14. Prevalence of Germline BRCA1/2 Variants in Ashkenazi and Non-Ashkenazi Prostate Cancer Populations: A Systematic Review and Meta-Analysis.
  15. Missed opportunities in the real-world genetic testing in BRCA gene variant carriers with cancers meeting NCCN criteria.
  16. Rates and outcomes of testing for lynch syndrome in a national colorectal cancer screening programme.
  17. Hereditary gist syndrome secondary to germline mutation in kit.
  1. J Med Genet. 2023 Jan 10. pii: jmg-2022-108816. [Epub ahead of print]
    Profiling of the genetic features of Chinese patients with gastric cancer with HRD germline mutations in a large-scale retrospective study.
    Chenghai Zhang, Dandan Zhu, Yurong Qu, Min Shi, Jingjiao Ma, Yebo Peng, Bowen Zhu, Houquan Tao, Tonghui Ma, TieYing Hou.
       BACKGROUND: Approximately 10% of gastric cancers (GCs) are associated with strong familial clustering and can be attributed to genetic predisposition. Homologous recombination deficiency (HRD) leads to genomic instability and accumulation of genetic variations, playing an important role in the development and progression of cancer. We aimed to delineate the germline mutation characteristics of patients with HRD-mut GC in Chinese.
    METHODS: We retrospectively reviewed the genomic sequencing data of 1135 patients with Chinese GC. Patients harbouring at least one loss of function (LoF) germline mutations in BRCA1, BRCA2, ATM, PALB2, BRIP1, CHEK1, CHEK2, FANCA and FANCL were selected for analysis.
    RESULTS: 89 patients were identified with LoF germline mutations of HRD gene. Germline mutations occurred most commonly in ATM (30.33%), followed by BRIP1 (17.98%), BRCA2 (14.61%), BRCA1 (12.36%), FANCA (10.11%), PALB2 (10.11%), FANCL (6.74%), CHEK1 (3.37%) and CHEK2 (3.37%). 14 out of 89 patients with HRD-mut harboured double mutations in HRD and MMR genes, with the median age of 51.5 years. The decreasing median age would be attributed to five patients with HRD+MMR double-muts harbouring mutations in both HRD and MMR genes. The median age of onset of patients with HRD+MMR double-muts is 47, which is significantly earlier than that of Chinese patients with GC (p=0.0235).
    CONCLUSION: Our data suggest that carrying both HRD and MMR gene LoF germline mutations may cause early-onset GC. Germline mutations in the HRD gene should be of concern in the study of hereditary GC.
    Keywords:  Genetic Variation; Germ-Line Mutation; Loss of Function Mutation
    DOI:  https://doi.org/10.1136/jmg-2022-108816
  2. JCO Precis Oncol. 2023 Jan;7 e2200104
    Internet-Based Germline Genetic Testing for Men With Metastatic Prostate Cancer.
    Heather H Cheng, Alexandra O Sokolova, Roman Gulati, Deborah Bowen, Sarah A Knerr, Nola Klemfuss, Petros Grivas, Andrew Hsieh, John K Lee, Michael T Schweizer, Todd Yezefski, Alicia Zhou, Evan Y Yu, Peter S Nelson, Bruce Montgomery.
       PURPOSE: Germline mutations in DNA repair genes are present in approximately 10% of men with metastatic prostate cancer (mPC), and guidelines recommend genetic germline testing. Notable barriers exist, including access to genetic counseling, insurance coverage, and out-of-pocket costs. The GENTleMEN study was designed to determine the feasibility of an Internet-based, patient-driven germline genetic testing approach for men with mPC.
    PATIENTS AND METHODS: In this prospective cohort study, men with mPC provided informed consent via an Internet-based platform and completed a questionnaire including demographics and family cancer history. Supporting medical data were also collected. Genetic testing was performed using the Color Genomics 30-gene targeted panel of cancer predisposition genes on a mailed saliva sample. Men whose test results identified a germline pathogenic or likely pathogenic variant received results by phone or telehealth genetic counseling; other participants received results by email with an option for phone-based or telehealth genetic counseling.
    RESULTS: As of August 18, 2021, 816 eligible men were consented, of whom 68% (551) completed genetic testing, and 8.7% (48 of 551) were found to carry a pathogenic or likely pathogenic variant in a germline DNA repair gene: CHEK2 (17), BRCA2 (15), ATM (6), NBN1 (3), BRCA1 (2), PALB2 (2), PMS2 (2), and MSH6 (1). Participants were more likely to complete the testing process if they were non-Hispanic White, married, highly educated, or from a higher-income bracket.
    CONCLUSION: Here, we show the feasibility of delivering germline (inherited) genetic testing by a voluntary, patient-driven, Internet-based platform to men with mPC. Preliminary results show rates of germline DNA repair mutations, consistent with other cohorts. Although feasible for some, reduced steps for participation, more dedicated diverse outreach and participant support, and identification and addressing of additional barriers is needed to ensure equitable access and optimization.
    DOI:  https://doi.org/10.1200/PO.22.00104
  3. Hepatology. 2023 Jan 03.
    Is it a prime time for germline genetic testing for hepatocellular carcinoma?
    Takahiro Kodama, Tetsuo Takehara.
      
    DOI:  https://doi.org/10.1097/HEP.0000000000000033
  4. Breast Cancer Res Treat. 2023 Jan 13.
    Molecular characteristics of Asian male BRCA-related cancers.
    Ava Kwong, Cecilia Yuen Sze Ho, Vivian Yvonne Shin, Ada Tsui Lin Ng, Tsun Leung Chan, Edmond Shiu Kwan Ma.
       PURPOSE: Germline mutations of BRCA1 or BRCA2 predispose men to develop various cancers, including breast cancers and prostate cancers. Male breast cancer (MBC) is a rare disease while prostate cancer (PRC) is uncommon in young men at the age of less than 40. The prevalence of BRCA genes in Asian male patients has to be elevated.
    METHODS: Germline mutations screening was performed in 98 high-risk Chinese MBC and PRC patients.
    RESULT: We have identified 16 pathogenic BRCA2 mutation carriers, 12 were MBC patients, 2 were PRC patients and 2 were patients with both MBC and PRC. The mutation percentages were 18.8%, 6.7% and 50% for MBC, PRC and both MBC and PRC patients, respectively. BRCA2 gene mutations confer a significantly higher risk of breast/prostate cancers in men than those with BRCA1 mutations. BRCA mutated MBC patients had a younger age of diagnosis and strong family histories of breast cancers while BRCA mutated PRC patients had strong family histories of ovarian cancers.
    CONCLUSION: Male BRCA carriers with breast cancers or prostate cancers showed distinct clinical and molecular characteristics, a male-specific genetic screening model would be useful to identify male cancer patients who have a high risk of BRCA mutation.
    Keywords:  Asian; BRCA; Male breast cancers; Prostate cancer
    DOI:  https://doi.org/10.1007/s10549-022-06651-y
  5. Fam Cancer. 2023 Jan 11.
    Pilot study of the prevalence of autoimmune disorders in Li-Fraumeni syndrome.
    Ixtaccihuatl H Obregón, Kelvin C de Andrade, Renee C Bremer, Payal P Khincha, Sharon A Savage.
      
    Keywords:  Autoimmune disorder; Li-Fraumeni Syndrome; TP53
    DOI:  https://doi.org/10.1007/s10689-022-00326-9
  6. Blood. 2023 Jan 10. pii: blood.2022017735. [Epub ahead of print]
    Hereditary platelet disorders associated with germline variants in RUNX1, ETV6 and ANKRD26.
    Claire C Homan, Hamish S Scott, Anna L Brown.
      Hereditary platelet disorders (HPD) are a group of blood disorders with variable severity and clinical impact. Although phenotypically there is much overlap, known genetic causes are many, prompting the curation of multi-gene panels for clinical use, which are being deployed in increasingly large scale populations to uncover missing heritability more efficiently. For some of these disorders, in particular RUNX1, ETV6 and ANKRD26, pathogenic germline variants in these genes also come with a risk of development of hematological malignancy. While they may initially present as similarly mild-moderate thrombocytopenia, each of these three disorders have distinct penetrance of hematological malignancy and a different range of somatic alterations associated with malignancy development. As our ability to diagnose HPDs has improved, we are now faced with the challenges of integrating these advances into routine clinical practice for patients and how to optimize management and surveillance of patients and carriers who have not developed malignancy. The volume of genetic information now being generated has created new challenges in how to accurately assess and report identified variants. The answers to all of these questions involve international initiatives on rare disease to better understand the biology of these disorders and design appropriate models and therapies for pre-clinical testing and clinical trials. Partnered with this are continued technological developments, including rapid sharing of genetic variant information and automated integration with variant classification relevant data such as high throughput functional data. Collective progress in this area will drive timely diagnosis and, in time, leukemia preventative therapeutic interventions.
    DOI:  https://doi.org/10.1182/blood.2022017735
  7. Cancers (Basel). 2022 Dec 29. pii: 201. [Epub ahead of print]15(1):
    Low Frequency of Cancer-Predisposition Gene Mutations in Liver Transplant Candidates with Hepatocellular Carcinoma.
    Klara Horackova, Sona Frankova, Petra Zemankova, Petr Nehasil, Marta Cerna, Magdalena Neroldova, Barbora Otahalova, Jan Kral, Milena Hovhannisyan, Viktor Stranecky, Tomas Zima, Marketa Safarikova, Marta Kalousova, Czecanca Consortium, Jan Novotny, Jan Sperl, Marianna Borecka, Sandra Jelinkova, Michal Vocka, Marketa Janatova, Petra Kleiblova, Zdenek Kleibl, Milan Jirsa, Jana Soukupova.
      Hepatocellular carcinoma (HCC) mainly stems from liver cirrhosis and its genetic predisposition is believed to be rare. However, two recent studies describe pathogenic/likely pathogenic germline variants (PV) in cancer-predisposition genes (CPG). As the risk of de novo tumors might be increased in PV carriers, especially in immunosuppressed patients after a liver transplantation, we analyzed the prevalence of germline CPG variants in HCC patients considered for liver transplantation. Using the panel NGS targeting 226 CPGs, we analyzed germline DNA from 334 Czech HCC patients and 1662 population-matched controls. We identified 48 PVs in 35 genes in 47/334 patients (14.1%). However, only 7/334 (2.1%) patients carried a PV in an established CPG (PMS2, 4×NBN, FH or RET). Only the PV carriers in two MRN complex genes (NBN and RAD50) were significantly more frequent among patients over controls. We found no differences in clinicopathological characteristics between carriers and non-carriers. Our study indicated that the genetic component of HCC is rare. The HCC diagnosis itself does not meet criteria for routine germline CPG genetic testing. However, a low proportion of PV carriers may benefit from a tailored follow-up or targeted therapy and germline testing could be considered in liver transplant recipients.
    Keywords:  MRN complex; genetic predisposition; germline mutation; hepatocellular carcinoma; liver cirrhosis; liver transplantation; panel sequencing
    DOI:  https://doi.org/10.3390/cancers15010201
  8. J Neurosurg Pediatr. 2023 Jan 06. 1-10
    Surveillance imaging and early surgical intervention for improved CNS tumor outcomes in children with Li-Fraumeni syndrome: Children's National Hospital experience and literature review.
    Nirali Patel, Kathleen Felton, Surajit Bhattacharya, Maria Isabel Almira-Suarez, Augustine Eze, Joyce Turner, Robert Keating, Chima Oluigbo, Reuven J Schore, Lindsay Kilburn, Roger J Packer, John S Myseros, Miriam Bornhorst.
       OBJECTIVE: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by germline mutations in the TP53 gene. CNS tumors are the fourth most common tumor type in LFS, and recent screening guidelines demonstrate that early tumor detection is associated with improved long-term survival. However, there is a paucity of data regarding surgical intervention when lesions are identified in asymptomatic patients on surveillance imaging. The authors investigated this through their cohort and literature review.
    METHODS: The cohort consisted of children seen in the Pediatric Cancer Genetics Program at Children's National Hospital between August 2012 and August 2021. The authors also include a PubMed (MEDLINE) literature search of articles from 2006 to 2021 related to surveillance and CNS tumors in patients with LFS. Studies in which CNS tumors were not identified or detailed patient information was not provided were excluded. Patients from the selected articles and the authors' cohort were added for further analysis.
    RESULTS: Between August 2012 and August 2021, 10 children with LFS and CNS tumors were assessed at Children's National Hospital: 4 who were known carriers of the TP53 mutation had CNS lesions found on surveillance imaging, whereas 6 presented with symptomatic CNS lesions and were either known or subsequently found to have germline TP53 mutations. The literature search identified 148 articles, 7 of which were included in this review. Patients from the literature and the present cohort were added for a total of 56 CNS lesions. A majority of the low-grade CNS lesions (22/24, 92%) were found on surveillance protocols in asymptomatic patients, whereas the majority of the high-grade lesions (22/26, 85%) presented in symptomatic patients who were not undergoing routine surveillance or as the initial diagnosis of LFS. The authors noted a significant survival advantage in pediatric patients with low-grade lesions, with an overall survival of 100% at 30 months. Minor limitations of the study include patient sample size and limitations in the patient cohort due to this being a retrospective rather than a prospective study.
    CONCLUSIONS: Data presented in this study support surveillance protocols in LFS and demonstrate the importance of dedicated CNS imaging and early surgical intervention when lesions are identified. Systematic review registration no.: CRD42022372610 (www.crd.york.ac.uk/prospero).
    Keywords:  Li-Fraumeni syndrome; brain tumor; oncology; screening
    DOI:  https://doi.org/10.3171/2022.12.PEDS22261
  9. HGG Adv. 2023 Jan 12. 4(1): 100167
    Unexplained mismatch repair deficiency: Case closed.
    Ellis L Eikenboom, Sarah Moen, Lotte van Leeuwen, Willemina R R Geurts-Giele, Carli M J Tops, Tjakko J van Ham, Winand N M Dinjens, Hendrikus J Dubbink, Manon C W Spaander, Anja Wagner.
      To identify Lynch syndrome (LS) carriers, DNA mismatch repair (MMR) immunohistochemistry (IHC) is performed on colorectal cancers (CRCs). Upon subsequent LS diagnostics, MMR deficiency (MMRd) sometimes remains unexplained (UMMRd). Recently, the importance of complete LS diagnostics to explain UMMRd, involving MMR methylation, germline, and somatic analyses, was stressed. To explore why some MMRd CRCs remain unsolved, we performed a systematic review of the literature and mapped patients with UMMRd diagnosed in our center. A systematic literature search was performed in Ovid Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar for articles on UMMRd CRCs after complete LS diagnostics published until December 15, 2021. Additionally, UMMRd CRCs diagnosed in our center since 1993 were mapped. Of 754 identified articles, 17 were included, covering 74 patients with UMMRd. Five CRCs were microsatellite stable. Upon complete diagnostics, 39 patients had single somatic MMR hits, and six an MMR germline variant of unknown significance (VUS). Ten had somatic pathogenic variants (PVs) in POLD1, MLH3, MSH3, and APC. The remaining 14 patients were the only identifiable cases in the literature without a plausible identified cause of the UMMRd. Of those, nine were suspected to have LS. In our center, complete LS diagnostics in approximately 5,000 CRCs left seven MMRd CRCs unexplained. All had a somatic MMR hit or MMR germline VUS, indicative of a missed second MMR hit. In vitually all patients with UMMRd, complete LS diagnostics suggest MMR gene involvement. Optimizing detection of currently undetectable PVs and VUS interpretation might explain all UMMRd CRCs, considering UMMRd a case closed.
    Keywords:  Lynch syndrome; UMMRd; colorectal cancer; genetic testing; unexplained mismatch repair deficiency
    DOI:  https://doi.org/10.1016/j.xhgg.2022.100167
  10. JCO Precis Oncol. 2023 Jan;7 e2200415
    Cancer Risk Associated With PTEN Pathogenic Variants Identified Using Multigene Hereditary Cancer Panel Testing.
    Shelly Cummings, Andrew Alfonso, Elisha Hughes, Matt Kucera, Brent Mabey, Nanda Singh, Charis Eng.
       PURPOSE: PTEN-associated clinical syndromes such as Cowden syndrome (CS) increase cancer risk and have historically been diagnosed based upon phenotypic criteria. Because not all patients clinically diagnosed with CS have PTEN pathogenic variants (PVs), and not all patients with PTEN PVs have been clinically diagnosed with CS, the cancer risk conferred by PTEN PVs calculated from cohorts of patients with clinical diagnoses of CS/CS-like phenotypes may be inaccurate.
    METHODS: We assessed a consecutive cohort of 727,091 individuals tested clinically for hereditary cancer risk, with a multigene panel between September 2013 and February 2022. Multivariable logistic regression models accounting for personal and family cancer history, age, sex, and ancestry were used to quantify disease risks associated with PTEN PVs.
    RESULTS: PTEN PVs were detected in 0.027% (193/727,091) of the study population, and were associated with a high risk of female breast cancer (odds ratio [OR], 7.88; 95% CI, 5.57 to 11.16; P = 2.3 × 10-31), endometrial cancer (OR, 13.51; 95% CI, 8.77 to 20.83; P = 4.2 × 10-32), thyroid cancer (OR, 4.88; 95% CI, 2.64 to 9.01; P = 4.0 × 10-7), and colon polyposis (OR, 31.60; CI, 15.60 to 64.02; P = 9.0 × 10-22). We observed modest evidence suggesting that PTEN PVs may be associated with ovarian cancer risk (OR, 3.77; 95% CI, 1.71 to 8.32; P = 9.9 × 10-4). Among patients with similar personal/family history and ancestry, every 5-year increase in age of diagnosis decreased the likelihood of detecting a PTEN PV by roughly 60%.
    CONCLUSION: We demonstrate that PTEN PVs are associated with significantly increased risk for a range of cancers. Together with the observation that PTEN PV carriers had earlier disease onset relative to otherwise comparable noncarriers, our results may guide screening protocols, inform risk-management strategies, and warrant enhanced surveillance approaches that improve clinical outcomes for PTEN PV carriers, regardless of their clinical presentation.
    DOI:  https://doi.org/10.1200/PO.22.00415
  11. Am J Med Genet A. 2023 Feb;191(2): 319-320
    Evidence Grows for Universal Germline Genetic Testing for Patients with Breast Cancer.
      
    DOI:  https://doi.org/10.1002/ajmg.a.62791
  12. Nat Rev Genet. 2023 Jan 12.
    Advances of aneuploidy research in the maternal germline.
    Sergio D J Pena.
      
    DOI:  https://doi.org/10.1038/s41576-022-00573-7
  13. Cell Rep Med. 2022 Dec 23. pii: S2666-3791(22)00447-5. [Epub ahead of print] 100883
    Inherited mutations in Chinese patients with upper tract urothelial carcinoma.
    Junlong Wu, Shengming Jin, Chengyuan Gu, Yu Wei, Yao Zhu, Andrea Necchi, Shahrokh F Shariat, Jian Pan, Hualei Gan, Bo Dai, Hailiang Zhang, Guohai Shi, Yu Zhu, Yijun Shen, Yiping Zhu, Dingwei Ye.
      Upper tract urothelial carcinoma (UTUC) accounts for 10% of urothelial carcinomas (UCs) and has a substantial hereditary component. However, the majority of our knowledge of germline spectrum comes from bladder cancer (BCa) data in White populations. Here, we sequence 309 Chinese UTUC cases and identify 71 germline pathogenic/likely pathogenic (P/LP) mutations in 62 patients (20.1%). Compared with White cases, we observe disparities and similarities in inherited mutational profiles. Association analysis reveals that germline P/LP mutations in MSH2, BRCA2, BRCA1, and BRIP1 significantly increase UTUC risk in Chinese populations. Furthermore, germline P/LP mutation in homologous recombination genes indicates poor prognosis for non-metastatic UTUC. Finally, we perform paired sequencing and observe significant correlations between germline mutation patterns and tumor subtypes. This study highlights the importance of genetic testing in patients with UTUC and calls for germline data from various ethnicities to better understand this disease.
    Keywords:  Chinese population; germline mutation; predisposition; upper tract urothelial carcinoma
    DOI:  https://doi.org/10.1016/j.xcrm.2022.100883
  14. Cancers (Basel). 2023 Jan 02. pii: 306. [Epub ahead of print]15(1):
    Prevalence of Germline BRCA1/2 Variants in Ashkenazi and Non-Ashkenazi Prostate Cancer Populations: A Systematic Review and Meta-Analysis.
    Antonio Cioffi, Ottavio De Cobelli, Paolo Veronesi, Carlo La Vecchia, Patrick Maisonneuve, Giovanni Corso.
       BACKGROUND AND AIMS: International guidelines recommend testing BRCA2 in men with prostate cancer, due to the presence of a strong association with this gene. Some ethnicities present disparities in genetic distribution for the relation with specific founder variants. Ashkenazi Jewish people are, importantly, at high risk of breast cancer for their inherited cluster with germline BRCA1/2 variants. However, in Ashkenazi men with prostate cancer, the prevalence of BRCA1 and/or BRCA2 is not well defined. We assessed the frequency of these variants in Ashkenazi vs. non-Ashkenazi men with prostate cancer. Materials and Methods: In accord with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, we revised all germline BRCA variants reported in MEDLINE from 1996 to 2021 in Ashkenazi and non-Ashkenazi men with prostate cancer. Results: Thirty-five original studies were selected for the analysis. Among populations from Israel and North America, Ashkenazi Jewish men presented higher prevalence of BRCA1 variants [0.9% (0.4-1.5) vs. 0.5% (0.2-1.1), p = 0.09] and a lower prevalence of BRCA2 variants [1.5% (1.1-2.0) vs. 3.5% (1.7-5.9), p = 0.08] in comparison to the non-Ashkenazi population. Conclusions: Since germline BRCA1 variants are more prevalent and BRCA2 variants are less prevalent in PCa patients of Ashkenazi Jewish ethnicity in comparison to non-Ashkenazi patients, prostate cancer genetic screening in Ashkenazi men should not be restricted to the BRCA2 gene.
    Keywords:  Ashkenazi; BRCA1 mutations; BRCA2 mutations; meta-analysis; prostate cancer
    DOI:  https://doi.org/10.3390/cancers15010306
  15. Gynecol Oncol. 2023 Jan 05. pii: S0090-8258(22)02015-7. [Epub ahead of print]170 32-37
    Missed opportunities in the real-world genetic testing in BRCA gene variant carriers with cancers meeting NCCN criteria.
    Sarah S Lee, Pournami Rajeev, Skyler Finning, Cheongeun Oh, Bhavana Pothuri.
       OBJECTIVE: The objective of this study was to determine the proportion of patients meeting the National Comprehensive Cancer Network (NCCN)'s BRCA genetic testing criteria prior to a diagnosis of a BRCA-related cancer.
    METHODS: This was a cross-sectional study of patients with BRCA pathogenic variants and a diagnosis of a BRCA-related cancer. Patients were included if they had known dates of genetic testing and cancer diagnosis. NCCN criteria (version 2.2021) were applied to determine if patients met criteria for testing before a BRCA-related cancer diagnosis. The outcome of interest was the proportion of patients undergoing genetic testing following a diagnosis of a BRCA-related cancer who qualified for genetic testing based on NCCN criteria. Chi-square, Mann-Whitney U test, and logistic regression were performed with significance at p < 0.05.
    RESULTS: Of 270 patients with a BRCA-related cancer, 229 (85%) underwent genetic testing after a cancer diagnosis. Most patients (97%) met at least one NCCN criteria for BRCA testing; 166 (73%) of patients who were tested following a BRCA-related cancer diagnosis also met the criteria for testing by family history. Publicly insured or uninsured patients were three times more likely to undergo BRCA testing after a diagnosis of cancer (odds ratio [OR] 3.03, 95% confidence interval [CI] 1.09-8.40). Patients with a family history of pathogenic variants were more likely to undergo testing before a cancer diagnosis (OR 0.10, 95% CI 0.05-0.23).
    CONCLUSION: Most patients with BRCA-associated cancers undergo genetic testing after their cancer diagnosis. Increased education on genetic testing criteria and novel methods to improve testing are desperately needed.
    Keywords:  BRCA; Cancer risk reduction; Genetic testing; NCCN criteria
    DOI:  https://doi.org/10.1016/j.ygyno.2022.12.015
  16. Cancer Epidemiol. 2023 Jan 04. pii: S1877-7821(22)00219-3. [Epub ahead of print]82 102314
    Rates and outcomes of testing for lynch syndrome in a national colorectal cancer screening programme.
    Jane Cudmore, Lakshman Kumar, Neil O'Moráin, Garrett Cullen, Gareth Horgan, John Aird, Kieran Sheahan, Desmond C Winter, Rory Kennelly, Jan Leyden.
       BACKGROUND: Lynch Syndrome (LS), the most common cause of hereditary colorectal cancer (CRC), is characterised by pathogenic variants in mismatch repair (MMR) genes. Universal testing of all CRCs for LS can increase detection. Rates and outcomes of testing in Ireland's national CRC screening programme have not been examined previously.
    METHODS: CRCs diagnosed at two screening sites between 2015 and 2020 were identified. Patient records were used to determine if CRCs had been tested for MMR deficiency and if detected, what downstream testing to rule out LS or genetic testing to confirm LS was undertaken.
    RESULTS: Over five years, 206 CRCs were diagnosed. Testing for LS was carried out for 100% of CRCs at site A and 69% of CRCs at site B. Of CRCs tested for LS, 14 (8%) were MMR deficient. After downstream testing for BRAF mutation or hypermethylation of MLH1, three CRCs were identified as potentially LS-related. Of these two individuals declined genetic testing and one was lost to follow-up.
    CONCLUSIONS: By 2020 both sites had implemented universal testing of all CRCs for LS. A small number of individuals were identified as being eligible for genetic testing for LS, however those offered declined testing and one individual was lost to follow up. This highlights the importance of universal testing and the need for referral pathways to ensure all appropriate individuals are referred onwards to genetic services.
    Keywords:  Cancer screening; Colorectal cancer; DNA mismatch repair deficiency; Immunohistochemistry; Lynch syndrome
    DOI:  https://doi.org/10.1016/j.canep.2022.102314
  17. Gastroenterol Hepatol. 2023 Jan 09. pii: S0210-5705(23)00002-X. [Epub ahead of print]
    Hereditary gist syndrome secondary to germline mutation in kit.
    Eukene Rojo, Pablo Miranda, Raquel Herranz, Felipe de La Morena.
      
    Keywords:  GIST hereditario; KIT; mutación germinal
    DOI:  https://doi.org/10.1016/j.gastrohep.2022.12.011
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