bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2024–02–18
six papers selected by
Joanna Zawacka, Karolinska Institutet
  1. LFSPROShiny: An Interactive R/Shiny App for Prediction and Visualization of Cancer Risks in Families With Deleterious Germline TP53 Mutations.
  2. Germline mutations of 4567 patients with hereditary breast-ovarian cancer spectrum in Thailand.
  3. Germline mutations of homologous recombination genes and clinical outcomes in pancreatic cancer: a multicenter study in Taiwan.
  4. Health-related quality of life and fear of progression in individuals with Li-Fraumeni syndrome.
  5. The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2.
  6. A Randomized Trial of Two Remote Healthcare Delivery Models on the Uptake of Genetic Testing and Impact on Patient-Reported Psychological Outcomes in Families With Pancreatic Cancer: The Genetic Education, Risk Assessment, and Testing (GENERATE) Study.
  1. JCO Clin Cancer Inform. 2024 Feb;8 e2300167
    LFSPROShiny: An Interactive R/Shiny App for Prediction and Visualization of Cancer Risks in Families With Deleterious Germline TP53 Mutations.
    Nam H Nguyen, Elissa B Dodd-Eaton, Gang Peng, Jessica L Corredor, Wenwei Jiao, Jacynda Woodman-Ross, Banu K Arun, Wenyi Wang.
       PURPOSE: LFSPRO is an R library that implements risk prediction models for Li-Fraumeni syndrome (LFS), a genetic disorder characterized by deleterious germline mutations in the TP53 gene. To facilitate the use of these models in clinics, we developed LFSPROShiny, an interactive R/Shiny interface of LFSPRO that allows genetic counselors (GCs) to perform risk predictions without any programming components and further visualize the risk profiles of their patients to aid the decision-making process.
    METHODS: LFSPROShiny implements two models that have been validated on multiple LFS patient cohorts: a competing risk model that predicts cancer-specific risks for the first primary and a recurrent-event model that predicts the risk of a second primary tumor. Starting with a visualization template, we keep regular contact with GCs, who ran LFSPROShiny in their counseling sessions, to collect feedback and discuss potential improvement. On receiving the family history as input, LFSPROShiny renders the family into a pedigree and displays the risk estimates of the family members in a tabular format. The software offers interactive overlaid side-by-side bar charts for visualization of the patients' cancer risks relative to the general population.
    RESULTS: We walk through a detailed example to illustrate how GCs can run LFSPROShiny in clinics from data preparation to downstream analyses and interpretation of results with an emphasis on the utilities that LFSPROShiny provides to aid decision making.
    CONCLUSION: Since December 2021, we have applied LFSPROShiny to over 100 families from counseling sessions at the MD Anderson Cancer Center. Our study suggests that software tools with easy-to-use interfaces are crucial for the dissemination of risk prediction models in clinical settings, hence serving as a guideline for future development of similar models.
    DOI:  https://doi.org/10.1200/CCI.23.00167
  2. NPJ Genom Med. 2024 Feb 14. 9(1): 9
    Germline mutations of 4567 patients with hereditary breast-ovarian cancer spectrum in Thailand.
    Chalermkiat Kansuttiviwat, Pongtawat Lertwilaiwittaya, Ekkapong Roothumnong, Panee Nakthong, Peerawat Dungort, Chutima Meesamarnpong, Warisara Tansa-Nga, Khontawan Pongsuktavorn, Supakit Wiboonthanasarn, Warunya Tititumjariya, Nannipa Phuphuripan, Chittapat Lertbussarakam, Jantanee Wattanarangsan, Jiraporn Sritun, Kittiporn Punuch, Jirayu Kammarabutr, Pornthira Mutirangura, Wanna Thongnoppakhun, Chanin Limwongse, Manop Pithukpakorn.
      Multi-gene panel testing has led to the detection of pathogenic/likely pathogenic (P/LP) variants in many cancer susceptibility genes in patients with breast-ovarian cancer spectrum. However, the clinical and genomic data of Asian populations, including Thai cancer patients, was underrepresented, and the clinical significance of multi-gene panel testing in Thailand remains undetermined. In this study, we collected the clinical and genetic data from 4567 Thai patients with cancer in the hereditary breast-ovarian cancer (HBOC) spectrum who underwent multi-gene panel testing. Six hundred and ten individuals (13.4%) had germline P/LP variants. Detection rates of germline P/LP variants in breast, ovarian, pancreatic, and prostate cancer were 11.8%, 19.8%, 14.0%, and 7.1%, respectively. Non-BRCA gene mutations accounted for 35% of patients with germline P/LP variants. ATM was the most common non-BRCA gene mutation. Four hundred and thirty-two breast cancer patients with germline P/LP variants (80.4%) met the current NCCN genetic testing criteria. The most common indication was early-onset breast cancer. Ten patients harbored double pathogenic variants in this cohort. Our result showed that a significant proportion of non-BRCA P/LP variants were identified in patients with HBOC-related cancers. These findings support the benefit of multi-gene panel testing for inherited cancer susceptibility among Thai HBOC patients. Some modifications of the testing policy may be appropriate for implementation in diverse populations.
    DOI:  https://doi.org/10.1038/s41525-024-00400-4
  3. J Biomed Sci. 2024 Feb 13. 31(1): 21
    Germline mutations of homologous recombination genes and clinical outcomes in pancreatic cancer: a multicenter study in Taiwan.
    Siao Muk Cheng, Yung-Yeh Su, Nai-Jung Chiang, Chih-Jung Wang, Ying-Jui Chao, Chien-Jui Huang, Hui-Jen Tsai, Shang-Hung Chen, Chi-Yen Chang, Chia-Rung Tsai, Yi-Jie Li, Chia-Jui Yen, Shih-Chang Chuang, Jeffrey Shu-Ming Chang, Yan-Shen Shan, Daw-Yang Hwang, Li-Tzong Chen.
       BACKGROUND: Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian population.
    METHODS: Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHRmut, including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy.
    RESULTS: Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0-43.7), the median overall survival (OS) was not significantly different among patients with gHRmut, non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHRmut. Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7-33.7) versus 9.6 months (95% CI 5.9-17.6), P = 0.001. However, the median OS of patients without gHRmut was 14.5 months (95% CI 13.2-16.9) and 12.6 months (95% CI 10.8-14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis.
    CONCLUSIONS: Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHRmut patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis.
    Keywords:  Chemotherapy; Homologous recombination; Next-generation sequencing; Platinum
    DOI:  https://doi.org/10.1186/s12929-024-01008-7
  4. J Genet Couns. 2024 Feb 13.
    Health-related quality of life and fear of progression in individuals with Li-Fraumeni syndrome.
    Senta Kiermeier, Sarah Schott, Juliane Nees, Christina Dutzmann, Farina Strüwe, Christian P Kratz, Christina Sauer, Anna Fleischer, Myriam Keymling, Imad Maatouk.
      Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome associated with a highly elevated lifetime cancer risk. This and the recommended intense surveillance program represent a large psychological burden on families. In order to develop targeted psychosocial interventions, we conducted a needs assessment. Adults (≥18 years) with LFS were included via regular hospital visits and online support groups and newsletters. Individuals filled out a questionnaire addressing among others: fear of progression (FoP-questionnaire, short-form), health-related quality of life (HRQoL, Short-Form Health Survey-12), distress (National Comprehensive Cancer Network distress thermometer), perceived cancer risk, and aspects of surveillance adherence. Collecting data over a 14-month period (March 2020 - June 2021), 70 adults were recruited (female = 58, 82.9%; mean age = 41.53 years). With mean mental component scores (MCS) of 42.28 (SD = 10.79), and physical component scores (PCS) of 48.83 (SD = 10.46), HRQoL was low in 34.8% (physical) and 59.4% (mental) of individuals when applying a mean cut-off of 45.4 (PCS) and 47.5 (MCS) to indicate poor HRQoL. High levels of FoP and distress were present in 68.6% and 69.1% of the participants, respectively. Performing a multiple linear regression on MCS and PCS, no sociodemographic variable was shown to be significant. FoP (β = -0.33, p < 0.05) and distress (β = -0.34, p < 0.05) were significantly associated with MCS. Individuals in our sample were burdened more than expected, with the majority reporting low levels of (mental) HRQoL, high distress, and FoP. Psychosocial support is necessary to help individuals with LFS (survivors as well as "previvors") increase their HRQoL, as it is crucial to survival.
    Keywords:  Li-Fraumeni syndrome; distress; fear of progression; mental health; psychosocial; quality of life
    DOI:  https://doi.org/10.1002/jgc4.1859
  5. Genet Med. 2024 Feb 12. pii: S1098-3600(24)00034-0. [Epub ahead of print] 101101
    The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2.
    Snežana Hinić, Cezary Cybulski, Rachel S Van der Post, Janet R Vos, Janneke Schuurs-Hoeijmakers, Fulvia Brugnoletti, Saskia Koene, Lilian Vreede, Wendy A G van Zelst-Stams, C Marleen Kets, Maaike Haadsma, Liesbeth Spruijt, Marijke R Wevers, D Gareth Evans, Katharina Wimmer, Simon Schnaiter, Alexander E Volk, Anna Möllring, Robin de Putter, Leila Soikkonen, Tiina Kahre, Mikk Tooming, Mirjam M de Jong, Fátima Vaz, Arjen R Mensenkamp, Maurizio Genuardi, Jan Lubinski, Marjolijn Ligtenberg, Nicoline Hoogerbrugge, Richarda M de Voer.
       PURPOSE: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies.
    METHODS: Exome sequencing of individuals who developed multiple primary malignancies identified three individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n=291).
    RESULTS: In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n=19), thyroid- (n=19) and prostate (pre)malignancies (n=12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared to females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins.
    CONCLUSION: Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.
    Keywords:  CHEK2; breast cancer; genetic tumor risk syndrome; multiple primary malignancies
    DOI:  https://doi.org/10.1016/j.gim.2024.101101
  6. Gastroenterology. 2024 Feb 04. pii: S0016-5085(24)00129-X. [Epub ahead of print]
    A Randomized Trial of Two Remote Healthcare Delivery Models on the Uptake of Genetic Testing and Impact on Patient-Reported Psychological Outcomes in Families With Pancreatic Cancer: The Genetic Education, Risk Assessment, and Testing (GENERATE) Study.
    Nicolette J Rodriguez, C Sloane Furniss, Matthew B Yurgelun, Chinedu Ukaegbu, Pamela E Constantinou, Ileana Fortes, Alyson Caruso, Alison N Schwartz, Jill E Stopfer, Meghan Underhill-Blazey, Barbara Kenner, Scott H Nelson, Sydney Okumura, Alicia Y Zhou, Tara B Coffin, Hajime Uno, Miki Horiguchi, Allyson J Ocean, Florencia McAllister, Andrew M Lowy, Alison P Klein, Lisa Madlensky, Gloria M Petersen, Judy E Garber, Scott M Lippman, Michael G Goggins, Anirban Maitra, Sapna Syngal.
       BACKGROUND AND AIMS: Genetic testing uptake for cancer susceptibility in family members of cancer patients is suboptimal. Among relatives of pancreatic ductal adenocarcinoma (PDAC) patients, The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated two online genetic education/testing delivery models and their impact on patient-reported psychological outcomes (PRPOs).
    METHODS: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in one of thirteen PDAC predisposition genes. Participants were randomized by family, between 5/8/2019-6/1/2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3-months post-intervention.
    RESULTS: 424 families were randomized, including 601 participants (n=296 Arm 1; n=305 Arm 2), 90% of whom completed genetic testing (Arm 1 (87%); Arm 2 (93%), p=0.014). Arm 1 participants were significantly less likely to complete genetic testing compared to Arm 2 (adjusted ratio (Arm1/Arm2) 0.90, 95% confidence interval 0.78-0.98). Among participants who completed PRPO questionnaires (Arm 1 (n=194); Arm 2 (n=206)), the intervention did not impact mean anxiety, depression or cancer worry scores.
    CONCLUSIONS: Remote genetic education and testing can be a successful and complementary option for delivering genetics care.
    Keywords:  Healthcare delivery; cascade genetic testing
    DOI:  https://doi.org/10.1053/j.gastro.2024.01.042
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒16 at 10:11.