bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023‒04‒30
twelve papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Factors Associated with Detection of Hereditary Diffuse Gastric Cancer on Endoscopy in Individuals with Germline CDH1 Mutations.
  2. Germline DNA-Repair Genes and HOXB13 Mutations in Korean Men with Metastatic Prostate Cancer: Data from a Large Korean Cohort.
  3. Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing.
  4. Nuclear autophagy promotes longevity and germline immortality.
  5. Germline dysfunction accelerates organismal aging.
  6. Clinical risk management of breast, ovarian, pancreatic, and prostatic cancers for BRCA1/2 variant carriers in Japan.
  7. Impact of Breast Cancer and Germline BRCA Pathogenic Variants on Fertility Preservation in Young Women.
  8. What is the appropriate genetic testing criteria for breast cancer in the Chinese population?-Analysis of genetic and clinical features from a single cancer center database.
  9. Lynch syndrome: influence of additional susceptibility variants on cancer risk.
  10. Emerging bone marrow failure syndromes- new pieces to an unsolved puzzle.
  11. Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants.
  12. Surgical Management of Germline Gastrointestinal Stromal Tumor.
  1. Gastrointest Endosc. 2023 Apr 22. pii: S0016-5107(23)02457-4. [Epub ahead of print]
    Factors Associated with Detection of Hereditary Diffuse Gastric Cancer on Endoscopy in Individuals with Germline CDH1 Mutations.
    Monika Laszkowska, Laura Tang, Elvira Vos, Stephanie King, Erin Salo-Mullen, Patrick T Magahis, Miseker Abate, Amanda Catchings, Ann G Zauber, Anne I Hahn, Mark Schattner, Daniel Coit, Zsofia K Stadler, Vivian E Strong, Arnold J Markowitz.
      BACKGROUND & AIMS: Individuals with germline pathogenic CDH1 variants have a high risk of hereditary diffuse gastric cancer. Sensitivity of esophagogastroduodenoscopy (EGD) in detecting signet ring cell carcinoma (SRCC) in this population is low. We aimed to identify endoscopic findings and biopsy practices associated with detection of SRCC.METHODS: This retrospective cohort included individuals with a germline pathogenic/likely pathogenic CDH1 variant undergoing at least one EGD at Memorial Sloan Kettering Cancer Center between January 1, 2006 and March 25, 2022. The primary outcome was detection of SRCC on EGD. Findings on gastrectomy were also assessed. The study included periods before and after implementation of the Cambridge protocol for endoscopic surveillance, allowing for assessment of a spectrum of biopsy practices.
    RESULTS: Ninety-eight CDH1 patients underwent at least one EGD at our institution. SRCC was detected in 20 (20%) individuals on EGD overall, and in 50/58 (86%) of those undergoing gastrectomy. Most SRCC foci were detected in the gastric cardia/fundus (EGD: 50%, gastrectomy: 62%) and body/transition zone (EGD: 60%, gastrectomy: 62%). Biopsies of gastric pale mucosal areas were associated with detection of SRCC (p<0.01). The total number of biopsies taken on EGD was associated with increased detection of SRCC (p=0.01), with 43% detected when 40 or more biopsies were taken.
    CONCLUSIONS: Targeted biopsies of gastric pale mucosal areas and increasing number of biopsies taken on EGD were associated with detection of SRCC. SRCC foci were mostly detected in the proximal stomach, supporting updated endoscopic surveillance guidelines. Further studies are needed to refine endoscopic protocols to improve SRCC detection in this high-risk population.
    Keywords:  CDH1; endoscopy; hereditary diffuse gastric cancer; signet ring cell carcinoma
    DOI:  https://doi.org/10.1016/j.gie.2023.04.2071
  2. World J Mens Health. 2023 Mar 27.
    Germline DNA-Repair Genes and HOXB13 Mutations in Korean Men with Metastatic Prostate Cancer: Data from a Large Korean Cohort.
    Sang Hun Song, Hak-Min Kim, Yu Jin Jung, Ha Rim Kook, Sungwon Jeon, Jong Bhak, Jin Hyuck Kim, Hakmin Lee, Jong Jin Oh, Sangchul Lee, Sung Kyu Hong, Seok-Soo Byun.
      PURPOSE: Germline mutations in DNA damage repair (DDR) genes such as BRCA2 have been associated with prostate cancer (PC) risk but has not been thoroughly evaluated for metastatic prostate cancer (mPC) in Asian men. This study attempts to evaluate frequency of DDR mutations in the largest cohort of Koreans.MATERIALS AND METHODS: We recruited 340 patients with mPC unselected for family history of cancer and compared to 495 controls. Whole genome sequencing was applied to assess germline pathogenic/likely pathogenic variants (PV/LPVs) in 26 DDR genes and HOXB13, including 7 genes (ATM, BRCA1/2, CHEK2, BRIP1, PALB2, and NBN) associated with hereditary PC. Comparisons to published Caucasian and Japanese cohorts were performed.
    RESULTS: Total of 28 PV/LPVs were identified in 30 (8.8%) patients; mutations were found in 13 genes, including BRCA2 (15 men [4.41%]), ATM (2 men [0.59%]), NBN (2 men [0.59%], and BRIP1 (2 men [0.59%]). Only one patient had HOXB13 mutation (0.29%). A lower rate of overall germline variant frequency was observed in Korean mPC compared to Caucasians (8.8% vs. 11.8%), but individual variants notably differed from Caucasian and geographically similar Japanese cohorts. PV/LPVs in DDR genes tended to increase gradually with higher Gleason scores (GS 7, 7.1%; GS 8, 7.5%; GS 9-10, 9.9%).
    CONCLUSIONS: BRCA2 was the most frequently mutated gene common to different cohorts supporting its importance, but differences in variant distribution in Korean mPC underscore the need for ethnic-specific genetic models. Future ethnic-specific analyses are warranted to verify our findings.
    Keywords:  Asians; DNA damage; Genetics; Prostatic neoplasms
    DOI:  https://doi.org/10.5534/wjmh.220190
  3. BMC Genomics. 2023 Apr 24. 24(1): 212
    Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing.
    Elena V Demidova, Ilya G Serebriiskii, Ramilia Vlasenkova, Simon Kelow, Mark D Andrake, Tiffiney R Hartman, Tatiana Kent, James Virtucio, Gail L Rosen, Richard T Pomerantz, Roland L Dunbrack, Erica A Golemis, Michael J Hall, David Y T Chen, Mary B Daly, Sanjeevani Arora.
      BACKGROUND: Early-onset renal cell carcinoma (eoRCC) is typically associated with pathogenic germline variants (PGVs) in RCC familial syndrome genes. However, most eoRCC patients lack PGVs in familial RCC genes and their genetic risk remains undefined.METHODS: Here, we analyzed biospecimens from 22 eoRCC patients that were seen at our institution for genetic counseling and tested negative for PGVs in RCC familial syndrome genes.
    RESULTS: Analysis of whole-exome sequencing (WES) data found enrichment of candidate pathogenic germline variants in DNA repair and replication genes, including multiple DNA polymerases. Induction of DNA damage in peripheral blood monocytes (PBMCs) significantly elevated numbers of [Formula: see text]H2AX foci, a marker of double-stranded breaks, in PBMCs from eoRCC patients versus PBMCs from matched cancer-free controls. Knockdown of candidate variant genes in Caki RCC cells increased [Formula: see text]H2AX foci. Immortalized patient-derived B cell lines bearing the candidate variants in DNA polymerase genes (POLD1, POLH, POLE, POLK) had DNA replication defects compared to control cells. Renal tumors carrying these DNA polymerase variants were microsatellite stable but had a high mutational burden. Direct biochemical analysis of the variant Pol δ and Pol η polymerases revealed defective enzymatic activities.
    CONCLUSIONS: Together, these results suggest that constitutional defects in DNA repair underlie a subset of eoRCC cases. Screening patient lymphocytes to identify these defects may provide insight into mechanisms of carcinogenesis in a subset of genetically undefined eoRCCs. Evaluation of DNA repair defects may also provide insight into the cancer initiation mechanisms for subsets of eoRCCs and lay the foundation for targeting DNA repair vulnerabilities in eoRCC.
    Keywords:  DNA repair; DNA replication; Germline; Renal cancer
    DOI:  https://doi.org/10.1186/s12864-023-09310-8
  4. Nat Aging. 2023 Jan;3(1): 11-12
    Nuclear autophagy promotes longevity and germline immortality.
      
    DOI:  https://doi.org/10.1038/s43587-022-00336-3
  5. Nat Aging. 2022 Nov;2(11): 977
    Germline dysfunction accelerates organismal aging.
    Sebastien Thuault.
      
    DOI:  https://doi.org/10.1038/s43587-022-00314-9
  6. J Hum Genet. 2023 Apr 24.
    Clinical risk management of breast, ovarian, pancreatic, and prostatic cancers for BRCA1/2 variant carriers in Japan.
    Arisa Ueki, Reiko Yoshida, Takeo Kosaka, Hiroyuki Matsubayashi.
      Opportunities for genetic counseling and germline BRCA1/2 (BRCA) testing are increasing in Japan owing to cancer genomic profiling testing and companion diagnostics being covered by national health insurance for patients with BRCA-related cancers. These tests are useful not only to judge whether platinum agents and PARP inhibitors are indicated but also to reveal an autosomal-dominant inherited cancer syndrome: hereditary breast and ovarian cancer. In individuals with germline BRCA variants, risk of cancers of the breast, ovary, pancreas, and prostate is significantly increased at various ages of onset, but the stomach, uterus, biliary tract, and skin might also be at risk. For women with pathogenic BRCA variants, breast awareness and image analyses should be initiated in their 20s, and risk-reducing procedures such as mastectomy are recommended starting in their 30s, with salpingo-oophorectomy in their late 30s. For male BRCA pathogenic variant carriers, prostatic surveillance should be applied using serum prostate-specific antigen starting in their 40s. For both sexes, image examinations ideally using endoscopic ultrasound and magnetic resonance cholangiopancreatography and blood testing should begin in their 50s for pancreatic surveillance. Homologous recombination pathway-associated genes are also causative candidates. Variant pathogenicity needs to be evaluated every 6-12 months when results are uncertain for clinical significance. Genetic counseling needs to be offered to the blood relatives of the pathogenic variant carriers with suitable timing. We review the recommended cross-organ BRCA risk management in Japan.
    DOI:  https://doi.org/10.1038/s10038-023-01153-1
  7. Life (Basel). 2023 Apr 01. pii: 930. [Epub ahead of print]13(4):
    Impact of Breast Cancer and Germline BRCA Pathogenic Variants on Fertility Preservation in Young Women.
    Elze Prokurotaite, Margherita Condorelli, Julie Dechene, Jason Bouziotis, Matteo Lambertini, Isabelle Demeestere.
      BACKGROUND: Several studies have suggested that breast cancer (BC) and germline BRCA pathogenic variants (gBRCA PVs) could have a deleterious impact on ovarian reserve. Nevertheless, data are limited and mixed. Our objective was to evaluate the performance of fertility preservation (FP) in terms of the number of collected mature oocytes after ovarian stimulation (OS) in young women carrying a gBRCA PV, associated or not with BC.METHODS: We conducted a retrospective monocentric study at HUB-Hôpital Erasme in Brussels. All women aged between 18 and 41 years diagnosed with invasive non-metastatic BC and/or gBRCA PV carriers who underwent OS for FP or preimplantation genetic testing for monogenic disorder (PGT-M) between November 2012 and October 2021 were included. Three groups were compared: BC patients without a gBRCA PV, BC patients with a gBRCA PV, and healthy gBRCA PV carriers. Ovarian reserve was evaluated based on the efficacy of OS and AMH levels.
    RESULTS: A total of 85 patients underwent 100 cycles. The mean age (32.2 ± 3.9 years; p = 0.61) and median AMH level (1.9 [0.2-13] μg/L; p = 0.22) were similar between groups. Correlations between the number of mature oocytes and AMH level (p < 0.001) and between AMH and age (p < 0.001) were observed. No differences in the number of retrieved mature oocytes were observed between groups (p = 0.41), or for other OS parameters.
    CONCLUSION: Neither BC nor a gBRCA PV significantly affects ovarian reserve and FP efficacy in terms of the number of mature oocytes retrieved.
    Keywords:  BRCA mutation; breast cancer; fertility preservation; germline BRCA pathogenic variants; oocyte cryopreservation; ovarian reserve; pregnancy and follow-up; preimplantation genetic diagnosis
    DOI:  https://doi.org/10.3390/life13040930
  8. Cancer Med. 2023 Apr 25.
    What is the appropriate genetic testing criteria for breast cancer in the Chinese population?-Analysis of genetic and clinical features from a single cancer center database.
    Mengqian Ni, Fang Wang, Anli Yang, Qiong Shao, Cong Xue, Wen Xia, Fei Xu, Xi Lin, Jiajia Huang, Xiwen Bi, Ruoxi Hong, Meiting Chen, Qiufan Zheng, Kuikui Jiang, Xinhua Xie, Jun Tang, Xi Wang, Zhongyu Yuan, Shusen Wang, Yanxia Shi, Xin An.
      BACKGROUND: Genetic testing plays an important role in guiding screening, diagnosis, and precision treatment of breast cancer (BC). However, the appropriate genetic testing criteria remain controversial. The current study aims to facilitate the development of suitable strategies by analyzing the germline mutational profiles and clinicopathological features of large-scale Chinese BC patients.METHODS: BC patients who had undergone genetic testing at the Sun Yat-sen University Cancer Center (SYSUCC) from September 2014 to March 2022 were retrospectively reviewed. Different screening criteria were applied and compared in the population cohort.
    RESULTS: A total of 1035 BC patients were enrolled, 237 pathogenic or likely pathogenic variants (P/LPV) were identified in 235 patients, including 41 out of 203 (19.6%) patients tested only for BRCA1/2 genes, and 194 out of 832 (23.3%) received 21 genes panel testing. Among the 235 P/LPV carriers, 222 (94.5%) met the NCCN high-risk criteria, and 13 (5.5%) did not. While using Desai's criteria of testing, all females diagnosed with BC by 60 years and NCCN criteria for older patients, 234 (99.6%) met the high-risk standard, and only one did not. The 21 genes panel testing identified 4.9% of non-BRCA P/LPVs and a significantly high rate of variants of uncertain significance (VUSs) (33.9%). The most common non-BRCA P/LPVs were PALB2 (11, 1.3%), TP53 (10, 1.2%), PTEN (3, 0.4%), CHEK2 (3, 0.4%), ATM (3, 0.4%), BARD1 (3, 0.4%), and RAD51C (2, 0.2%). Compared with BRCA1/2 P/LPVs, non-BRCA P/LPVs showed a significantly low incidence of NCCN criteria listed family history, second primary cancer, and different molecular subtypes.
    CONCLUSIONS: Desai's criteria might be a more appropriate genetic testing strategy for Chinese BC patients. Panel testing could identify more non-BRCA P/LPVs than BRCA1/2 testing alone. Compared with BRCA1/2 P/LPVs, non-BRCA P/LPVs exhibited different personal and family histories of cancer and molecular subtype distributions. The optimal genetic testing strategy for BC still needs to be investigated with larger continuous population studies.
    Keywords:  BRCA1/2 genes; genetic testing criteria; hereditary breast cancer; multigene panel testing; non-BRCA genes; pathogenic or likely pathogenic variants
    DOI:  https://doi.org/10.1002/cam4.5976
  9. Eur J Hum Genet. 2023 Apr 24.
    Lynch syndrome: influence of additional susceptibility variants on cancer risk.
    Roseline Vibert, Jasmine Hasnaoui, Alexandre Perrier, Alexandra Lefebvre, Chrystelle Colas, Marion Dhooge, Noémie Basset, Albain Chansavang, Camille Desseignes, Alex Duval, Solenne Farelly, Nadim Hamzaoui, Pierre Laurent-Puig, Julie Metras, Diane Moliere, Martine Muleris, Jeanne Netter, Mehdi Touat, Franck Bielle, Karim Labreche, Romain Nicolle, Géraldine Perkins, Mathilde Warcoin, Florence Coulet, Patrick R Benusiglio.
      Some patients with Lynch syndrome (LS) have extreme phenotypes, i.e. cancer before the recommended screening age, or cancer for which there are no screening guidelines. We made the hypothesis that additional germline variants in cancer susceptibility genes (CSG) could explain some of these phenotypes. We compared the prevalence of additional CSG variants in LS patients with a cancer diagnosis before age 30 (early-onset, EO group) and after 40 (usual-onset, UO group). While there was no overall difference, we did find an excess of pathogenic variants and variants of unknown significance in EO cases when only gastrointestinal CSG were considered (OR 2.25; 95% CI: 1.01-5.06, p value = 0.04). Four EO cases stood out: two with POLE/POLD1 variants in the key exonuclease domain, one with a BMPR1A duplication and one with an EPCAM deletion. Additional germline variants should be considered in future screening recommendations, as they might influence cancer risk.
    DOI:  https://doi.org/10.1038/s41431-023-01367-z
  10. Front Oncol. 2023 ;13 1128533
    Emerging bone marrow failure syndromes- new pieces to an unsolved puzzle.
    Simone Feurstein.
      Inherited bone marrow failure (BMF) syndromes are genetically diverse - more than 100 genes have been associated with those syndromes and the list is rapidly expanding. Risk assessment and genetic counseling of patients with recently discovered BMF syndromes is inherently difficult as disease mechanisms, penetrance, genotype-phenotype associations, phenotypic heterogeneity, risk of hematologic malignancies and clonal markers of disease progression are unknown or unclear. This review aims to shed light on recently described BMF syndromes with sparse concise data and with an emphasis on those associated with germline variants in ADH5/ALDH2, DNAJC21, ERCC6L2 and MECOM. This will provide important data that may help to individualize and improve care for these patients.
    Keywords:  ADH5; ALDH2; DNAJC21; ERCC6L2; MECOM; bone marrow failure; early onset myeloid malignancies
    DOI:  https://doi.org/10.3389/fonc.2023.1128533
  11. JAMA Netw Open. 2023 Apr 03. 6(4): e239705
    Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants.
    Lamis Yehia, Gilman Plitt, Ann M Tushar, Julia Joo, Carol A Burke, Steven C Campbell, Katherine Heiden, Judy Jin, Carole Macaron, Chad M Michener, Holly J Pederson, Kadakkal Radhakrishnan, Joyce Shin, Joan Tamburro, Sujata Patil, Charis Eng.
      Importance: Identifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD).Objective: To evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS.
    Design, Setting, and Participants: Prospective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023.
    Exposures: Review of physical and electronic medical records, and follow-up through clinical visits or telephone interviews.
    Main Outcomes and Measures: Lifetime cancer risks in PHTS relative to the general population.
    Results: A total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P < .001) of thyroid (age-adjusted standardized incidence ratios [SIR], 32.1; 95% CI, 26.0-39.0), kidney (SIR, 26.5; 95% CI, 18.8-36.3), endometrial (SIR, 26.0; 95% CI, 19.5-34.1), breast (SIR, 20.3; 95% CI, 17.3-23.7), and colorectal (SIR, 7.9; 95% CI, 5.2-11.7) cancers, and melanoma (SIR, 6.3; 95% CI, 3.5-10.5) were observed. Of the 341 patients with PHTS with cancer, 51 (15%) had 1 or more cancers diagnosed at age 29 years or younger, and 16 (31.4%) of those developed SMN at final follow-up. Twenty-three patients with PHTS with NDD and cancer were identified, with 5 (22%) having developed SMN at final follow-up. Individuals with PHTS and NDD showed higher lifetime cancer risks compared with individuals with PHTS but without NDD (hazard ratio, 2.7; 95% CI, 1.7-4.2; P < .001).
    Conclusions and Relevance: This cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2023.9705
  12. Ann Surg Oncol. 2023 Apr 28.
    Surgical Management of Germline Gastrointestinal Stromal Tumor.
    Hyunjee V Kwak, Katherine J Tardy, Andrew Allbee, Kristen Stashek, Ronald P DeMatteo.
      Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and usually results from a sporadic mutation in KIT or, less frequently, platelet-derived growth factor alpha (PDGFRA). Rarely, a germline mutation in the KIT, PDGFRA, succinate dehydrogenase (SDH), or neurofibromatosis 1 (NF1) gene is responsible for GIST. These tumors are found in the stomach (PDGFRA and SDH), small bowel (NF1), or a combination of both (KIT). There is a need to improve care for these patients regarding genetic testing, screening, and surveillance. Since most GISTs due to a germline mutation do not respond to tyrosine kinase inhibitors, the role of surgery is critical, especially when considering germline gastric GIST. However, in contrast to the established recommendation for prophylactic total gastrectomy in cadherin 1 (CDH1) mutation carriers once they reach adulthood, there are no formal guidelines as to the timing or extent of surgical resection for patients who are either carriers of a germline GIST mutation causing gastric GIST or have already developed gastric GIST(s). Surgeons must balance treating what is often multicentric, yet initially indolent disease with the chance of cure and the complications associated with total gastrectomy. Here, we consider the major issues in performing surgery in patients with germline GIST and illustrate the principles with a previously unreported patient harboring a germline KIT 579 deletion.
    Keywords:  GIST; Mutation; Surgery; Tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1245/s10434-023-13519-y
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