bims-lifras 2021-04-04 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–04–04
twenty-one papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

The Inherited and Familial Component of Early-Onset Colorectal Cancer.
Hereditary and Sporadic Pancreatic Ductal Adenocarcinoma: Current Update on Genetics and Imaging.
Germline mutations in apoptosis pathway genes in ovarian cancer; the functional role of a TP53I3 (PIG3) variant in ROS production and DNA repair.
Next Generation Sequencing-Based Germline Panel Testing for Breast and Ovarian Cancers in Pakistan.
Modelling hereditary diffuse gastric cancer initiation using transgenic mouse-derived gastric organoids and single-cell sequencing.
Germline Mutations in Other Homologous Recombination Repair-Related Genes Than BRCA1/2: Predictive or Prognostic Factors?
Helping young children understand inherited cancer predisposition syndromes using bibliotherapy.
Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review.
Inherited predisposition to pancreatic cancer.
Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival.
New germline mutations in BRCA1, ATM, MUTYH, and RAD51D genes in Tuvans early-onset breast cancer patients.
Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer.
Genetic Gastric Cancer Risk Syndromes.
The Impact of Longitudinal Surveillance on Tumor Thickness for Melanoma-Prone Families with and without Pathogenic Germline Variants of CDKN2A and CDK4.
Subsequent Malignant Neoplasms in Retinoblastoma Survivors.
Trans-ethnic variation in germline variants of patients with renal cell carcinoma.
Generation of two induced pluripotent stem cell lines from blood cells of a prostate cancer patient carrying germline mutation in CHEK2.
Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.
A male with primary accessory breast carcinoma in an axilla is strongly suspected of having hereditary breast cancer.
Familial burden and other clinical factors associated with various types of cancer in individuals with Lynch syndrome.
Molecular Mechanisms of the Genetic Predisposition to Acute Megakaryoblastic Leukemia in Infants With Down Syndrome.

Cells. 2021 Mar 23. pii: 710. [Epub ahead of print]10(3):

The Inherited and Familial Component of Early-Onset Colorectal Cancer.

Maria Daca Alvarez, Isabel Quintana, Mariona Terradas, Pilar Mur, Francesc Balaguer, Laura Valle.

  Early-onset colorectal cancer (EOCRC), defined as that diagnosed before the age of 50, accounts for 10-12% of all new colorectal cancer (CRC) diagnoses. Epidemiological data indicate that EOCRC incidence is increasing, despite the observed heterogeneity among countries. Although the cause for such increase remains obscure, ≈13% (range: 9-26%) of EOCRC patients carry pathogenic germline variants in known cancer predisposition genes, including 2.5% of patients with germline pathogenic variants in hereditary cancer genes traditionally not associated with CRC predisposition. Approximately 28% of EOCRC patients have family history of the disease. This article recapitulates current evidence on the inherited syndromes that predispose to EOCRC and its familial component. The evidence gathered support that all patients diagnosed with an EOCRC should be referred to a specialized genetic counseling service and offered somatic and germline pancancer multigene panel testing. The identification of a germline pathogenic variant in a known hereditary cancer gene has relevant implications for the clinical management of the patient and his/her relatives, and it may guide surgical and therapeutic decisions. The relative high prevalence of hereditary cancer syndromes and familial component among EOCRC patients supports further research that helps understand the genetic background, either monogenic or polygenic, behind this increasingly common disease.

Keywords:  cancer genetics; cancer syndrome; colorectal cancer predisposition; hereditary cancer; lynch syndrome; polygenic risk score

DOI:  https://doi.org/10.3390/cells10030710
Radiol Imaging Cancer. 2020 Mar;2(2): e190020

Hereditary and Sporadic Pancreatic Ductal Adenocarcinoma: Current Update on Genetics and Imaging.

Ajaykumar C Morani, Abdelrahman K Hanafy, Nisha S Ramani, Venkata S Katabathina, Sireesha Yedururi, Anil K Dasyam, Srinivasa R Prasad.

Pancreatic ductal adenocarcinoma (PDAC) is a genetically heterogeneous, biologically aggressive malignancy with a uniformly poor prognosis. While most pancreatic cancers arise sporadically, a small subset of PDACs develop in patients with hereditary and familial predisposition. Detailed studies of the rare hereditary syndromes have led to identification of specific genetic abnormalities that contribute to malignancy. For example, germline mutations involving BRCA1, BRCA2, PRSS1, and mismatch repair genes predispose patients to PDAC. While patients with Lynch syndrome develop a rare "medullary" variant of adenocarcinoma, intraductal papillary mucinous tumors are observed in patients with McCune-Albright syndrome. It is now well established that PDACs originate via a multistep progression from microscopic and macroscopic precursors due to cumulative genetic abnormalities. Improved knowledge of tumor genetics and oncologic pathways has contributed to a better understanding of tumor biology with attendant implications on diagnosis, management, and prognosis. In this article, the genetic landscape of PDAC and its precursors will be described, the hereditary syndromes that predispose to PDAC will be reviewed, and the current role of imaging in screening and staging assessment, as well as the potential role of molecular tumor-targeted imaging for evaluation of patients with PDAC and its precursors, will be discussed. Keywords: Abdomen/GI, Genetic Defects, Oncology, Pancreas Supplemental material is available for this article. © RSNA, 2020.

DOI: https://doi.org/10.1148/rycan.2020190020
Cell Death Discov. 2021 Mar 29. 7(1): 62

Germline mutations in apoptosis pathway genes in ovarian cancer; the functional role of a TP53I3 (PIG3) variant in ROS production and DNA repair.

Sophia R Chaudhry, Jaime Lopes, Nancy K Levin, Hasini Kalpage, Michael A Tainsky.

Approximately 25% of all cases of ovarian cancer (OVCA) cases are associated with inherited risk. However, accurate risk assessment is limited by the presence of variants of unknown significance (VUS). Previously, we performed whole-exome sequencing on 48 OVCA patients with familial predisposition, yet negative for pathogenic BRCA1/2 mutations. In our cohort, we uncovered thirteen truncating mutations in genes associated with apoptosis (~35% of our patient cohort). The TP53I3 p.S252X premature stop gain was identified in two unrelated patients. TP53I3 is transcriptionally activated by p53 and believed to play a role in DNA damage response and reactive oxygen species-induced apoptosis. In addition, nonsense variants in apoptosis-related genes TP53AIP1, BCLAF1, and PIK3C2G were identified in our cohort; highlighting the potential relevance of genes involved in apoptotic processes to hereditary cancer. In the current study, we employed functional assays and demonstrated that cells expressing TP53I3 p.S252X displayed decreased homologous recombination repair efficiency and increased sensitivity to chemotherapeutic drugs bleomycin, mitomycin c, and etoposide. In addition, in the presence of oxidative stress from hydrogen peroxide or etoposide we observed a reduction in the formation of reactive oxygen species, an important precursor to apoptosis with this variant. Our findings suggest that the combination of in silico and wet laboratory approaches can better evaluate VUSs, establish novel germline predisposition genetic loci, and improve individual cancer risk estimates.

DOI: https://doi.org/10.1038/s41420-021-00442-y
Asian Pac J Cancer Prev. 2021 Mar 01. pii: 89508. [Epub ahead of print]22(3): 719-724

Next Generation Sequencing-Based Germline Panel Testing for Breast and Ovarian Cancers in Pakistan.

Hassan Tariq, Asma Gul, Tahir Khadim, Hafeez Ud-Din, Hamid Nawaz Tipu, Muhammad Asif, Rabia Ahmed.

   BACKGROUND: Pathogenic germline mutations in BRCA1/2 constitute the majority of hereditary breast and/or ovarian cancers worldwide. Incidence and mortality rate of breast and ovarian cancers in Pakistani women is high. Thus, to establish the diagnosis for targeted therapy in Pakistan, we conducted Next-generation sequencing-based germline testing for the detection of BRCA1/2 oncogenic variants associated with breast and ovarian cancer subtype.
METHODS: Peripheral blood of 24 women, diagnosed with breast and epithelial ovarian cancers, was taken from the recruited cases with the consent of performing germline genetic testing. DNA was isolated from the peripheral blood and subjected to indexed BRCA Panel libraries. Targeted NGS was performed for all coding regions and splicing sites of BRCA1 and BRCA2 genes using AmpliSeq for Illumina BRCA Panel and Illumina MiSeq sequencer (placed at AFIP). Analysis of the sequencing results has been done by using Illumina bioinformatics tools.
RESULTS: We detected 421 variants having a quality score of 100 in all cases under study. The list of identified variants in BRCA1 and BRCA2 genes was narrowed down after filtering out those which did not pass q30 and those with a minor allele frequency (MAF) > 0.05 based on gnomAD browser. To classify these variants, clinical significance was predicted using external curated databases. As a result, we interpreted (n = 4) 16.7% pathogenic variants in BRCA1 and (n = 6) 25% variants of uncertain significance (VUS) in both genes. Descriptive statistics depicted that the age and BMI of BRCA positive cases are less than BRCA negative cases.
CONCLUSION: Our findings exhibit an initial report for the NGS based cancer genetic testing in Pakistan. This will enable us to pursue screening and diagnosis of hereditary BRCA mutation utilizing the latest state-of-the-art technique locally available in Pakistan ultimately resulting in targeted cancer therapy.

Keywords:  BRCA1/2; High grade epithelial ovarian cancer; Second generation sequencing; germline mutations; triple negative breast cancer

DOI:  https://doi.org/10.31557/APJCP.2021.22.3.719
J Pathol. 2021 Apr 02.

Modelling hereditary diffuse gastric cancer initiation using transgenic mouse-derived gastric organoids and single-cell sequencing.

Katherine Dixon, Tom Brew, David Farnell, Tanis D Godwin, Simon Cheung, Christine Chow, Monica Ta, Germain Ho, Minh Bui, J Maxwell Douglas, Kieran R Campbell, Amal El-Naggar, Pardeep Kaurah, Steve E Kalloger, Howard J Lim, David F Schaeffer, Dawn Cochrane, Parry Guilford, David G Huntsman.

  Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome caused by germline variants in CDH1, the gene encoding the cell-cell adhesion molecule E-cadherin. Loss of E-cadherin in cancer is associated with cellular dedifferentiation and poor prognosis, but the mechanisms through which CDH1 loss initiates HDGC are not known. Using single-cell RNA sequencing, we explored the transcriptional landscape of a murine organoid model of HDGC to characterize the impact of CDH1 loss in early tumourigenesis. Progenitor populations of stratified squamous and simple columnar epithelium, characteristic of the mouse stomach, showed lineage-specific transcriptional programs. Cdh1 inactivation resulted in shifts along the squamous differentiation trajectory associated with aberrant expression of genes central to gastrointestinal epithelial differentiation. Remarkably, cytokeratin 7 (CK7), encoded by the differentiation-dependent gene Krt7, was a specific marker for early neoplastic lesions in CDH1 carriers. Our findings suggest that deregulation of developmental transcriptional programs may precede malignancy in HDGC. This article is protected by copyright. All rights reserved.

Keywords:  epithelial differentiation; hereditary diffuse gastric cancer; organoids; single-cell RNA sequencing

DOI:  https://doi.org/10.1002/path.5675
J Pers Med. 2021 Mar 28. pii: 245. [Epub ahead of print]11(4):

Germline Mutations in Other Homologous Recombination Repair-Related Genes Than BRCA1/2: Predictive or Prognostic Factors?

Laura Cortesi, Claudia Piombino, Angela Toss.

  The homologous recombination repair (HRR) pathway repairs double-strand DNA breaks, mostly by BRCA1 and BRCA2, although other proteins such as ATM, CHEK2, and PALB2 are also involved. BRCA1/2 germline mutations are targeted by PARP inhibitors. The aim of this commentary is to explore whether germline mutations in HRR-related genes other than BRCA1/2 have to be considered as prognostic factors or predictive to therapies by discussing the results of two articles published in December 2020. The TBCRC 048 trial published by Tung et al. showed an impressive objective response rate to olaparib in metastatic breast cancer patients with germline PALB2 mutation compared to germline ATM and CHEK2 mutation carriers. Additionally, Yadav et al. observed a significantly longer overall survival in pancreatic adenocarcinoma patients with germline HRR mutations compared to non-carriers. In our opinion, assuming that PALB2 is a high-penetrant gene with a key role in the HRR system, PALB2 mutations are predictive factors for response to treatment. Moreover, germline mutations in the ATM gene provide a better outcome in pancreatic adenocarcinoma, being more often associated to wild-type KRAS. In conclusion, sequencing of HRR-related genes other than BRCA1/2 should be routinely offered as part of a biological characterization of pancreatic and breast cancers.

Keywords:  BRCA1; BRCA2; PALB2; homologous recombination repair

DOI:  https://doi.org/10.3390/jpm11040245
J Genet Couns. 2021 Mar 31.

Helping young children understand inherited cancer predisposition syndromes using bibliotherapy.

Georgina M Schlub, Ashley Crook, Kristine Barlow-Stewart, Jane Fleming, Judy Kirk, Kathy Tucker, Sian Greening.

  Communication with children about hereditary conditions in the family can be difficult for parents. Yet, good communication strategies are leading determinants of adaptation and resilience. With inherited cancer predisposition syndromes that can affect young children such as Li-Fraumeni syndrome (LFS) and hereditary pheochromocytoma and paraganglioma syndrome (HPPS), genetic testing and subsequent surveillance in at-risk children is the optimal intervention. Given testing often commences early, providing children and their parents with appropriate genetic counseling and communication strategies is important for informed decision making. To inform such communication strategies, we used a bibliotherapeutic framework, where stories are delivered prescriptively (i.e., 'bibliotherapy'), to develop a psycho-educational resource for children aged 5-10 years old at risk of either LFS or HPPS. Illustrated storybooks for children were created based on models of developmental comprehension. To ascertain their experience, parents were invited to read a storybook to their child/ren and participate in semi-structured qualitative interviews. Transcripts were analyzed thematically using a general inductive approach. The bibliotherapeutic resource reportedly supported parents with communication about these issues without raising emotional distress in either themselves or their children. The key stages of a bibliotherapeutic interaction were facilitated by the use of this resource, and all parents reported that it would have been useful when their children were first tested and/or diagnosed. This study lays the foundation for the application of bibliotherapy as a psycho-educational intervention in genetic counseling and demonstrates that bibliotherapy may improve the process of communication between parents and children regarding pediatric-inherited cancer syndromes.

Keywords:  Li-Fraumeni syndrome; SDH mutation; bibliotherapy; education; genetic counseling; intervention; pediatrics

DOI:  https://doi.org/10.1002/jgc4.1396
Cancers (Basel). 2021 Mar 12. pii: 1269. [Epub ahead of print]13(6):

Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review.

Giovanni Corso, Federica Corso, Federica Bellerba, Patrícia Carneiro, Susana Seixas, Antonio Cioffi, Carlo La Vecchia, Francesca Magnoni, Bernardo Bonanni, Paolo Veronesi, Sara Gandini, Joana Figueiredo.

  Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by CDH1 germline mutations. Nevertheless, current CDH1 genetic screening recommendations disregard an unbalanced worldwide distribution of CDH1 variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing CDH1 variants in gastric cancer patients originating from both high- and low-prevalence countries. Selected studies were categorized as family study, series study, and unknown study, according to the implementation of HDGC clinical criteria for genetic testing. Our results indicate that CDH1 mutations are more frequently identified in gastric cancer low-incidence countries, and in the family study group that encompasses cases fulfilling criteria. Considering the type of CDH1 alterations, we verified that the relative frequency of mutation types varies within study groups and geographical areas. In the series study, the missense variant frequency is higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. However, application of variant scoring for putative relevance led to a strong reduction of CDH1 variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for CDH1 genetic screening are critical for identification of individuals carrying mutations with clinical significance. Further, we propose that future guidelines for testing should consider GC incidence across geographical regions for improved surveillance programs and early diagnosis of disease.

Keywords:  CDH1 mutation; E-cadherin; cancer geographical distribution; gastric cancer

DOI:  https://doi.org/10.3390/cancers13061269
Semin Oncol. 2021 Mar 11. pii: S0093-7754(21)00011-7. [Epub ahead of print]

Inherited predisposition to pancreatic cancer.

Kimberly J Hilfrank, Sheila D Rustgi, Fay Kastrinos.

  Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the US by 2030. There are multiple germline pathogenic variants and cancer syndromes associated with an increased risk of PDAC. Precision treatment, informed by germline genetic testing and molecular tumor analysis, can optimize therapeutic regimens and outcomes for those diagnosed with PDAC. As a result, the National Comprehensive Cancer Network currently recommends genetic testing for all newly diagnosed PDAC patients given the clinical implications for treatment but also for the identification of at-risk family members who can benefit from pancreatic cancer screening and other cancer prevention strategies. This article reviews inherited risk factors for the development of PDAC and current screening strategies for the early detection of PDAC in high-risk populations.

Keywords:  Familial pancreatic cancer; Genetic risk assessment; Genetic testing; Inherited Cancer Syndromes; Pancreatic cancer; Screening and early detection

DOI:  https://doi.org/10.1053/j.seminoncol.2021.02.006
Cancers (Basel). 2021 Mar 31. pii: 1612. [Epub ahead of print]13(7):

Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival.

Julie Earl, Emma Barreto, María E Castillo, Raquel Fuentes, Mercedes Rodríguez-Garrote, Reyes Ferreiro, Pablo Reguera, Gloria Muñoz, David Garcia-Seisdedos, Jorge Villalón López, Bruno Sainz, Nuria Malats, Alfredo Carrato.

  Pancreatic ductal adenocarcinoma (PDAC) presents many challenges in the clinic and there are many areas for improvement in diagnostics and patient management. The five-year survival rate is around 7.2% as the majority of patients present with advanced disease at diagnosis that is treatment resistant. Approximately 10-15% of PDAC cases have a hereditary basis or Familial Pancreatic Cancer (FPC). Here we demonstrate the use of circulating free DNA (cfDNA) in plasma as a prognostic biomarker in PDAC. The levels of cfDNA correlated with disease status, disease stage, and overall survival. Furthermore, we show for the first time via BEAMing that the majority of hereditary or familial PDAC cases (around 84%) are negative for a KRAS somatic mutation. In addition, KRAS mutation negative cases harbor somatic mutations in potentially druggable genes such as KIT, PDGFR, MET, BRAF, and PIK3CA that could be exploited in the clinic. Finally, familial or hereditary cases have a longer overall survival compared to sporadic cases (10.2 vs. 21.7 months, respectively). Currently, all patients are treated the same in the clinic with cytotoxic agents, although here we demonstrate that there are different subtypes of tumors at the genetic level that could pave the way to personalized treatment.

Keywords:  cfDNA; hereditary and familial pancreatic cancer; liquid biopsy; potentially druggable genes; somatic mutation profiling

DOI:  https://doi.org/10.3390/cancers13071612
Exp Oncol. 2021 03;43(1): 52-55

New germline mutations in BRCA1, ATM, MUTYH, and RAD51D genes in Tuvans early-onset breast cancer patients.

P Gervas, A Molokov, A Ivanova, Ye Panferova, A Kiselev, A Chernyshova, L Pisareva, E Choynzonov, N Cherdyntseva.

BACKGROUND: In Russia, more than 50,000 women are diagnosed with breast cancer (BC) every year. Russia is a multinational country - about 200 ethnic groups live on its territory. Khakass, Buryats, Tuvans and other ethnic groups show higher rate of increase in BC incidence and a younger age of first diagnosed BC compared to Caucasian ethnicities. We focused on Tuvan ethnic group to find specific genetic aberrations associated with BC. There are no BC prevention models as well as standards for the treatment of inherited BC in Tuvans. In this context, the search for genetic markers of early cancer detection and the development of criteria for therapy response are relevant.
AIM: To identify hereditary mutations in BC-associated genes in Tuvan women.
MATERIALS AND METHODS: 24 patients with early-onset BC (range, 25 to 46 years) were enrolled in the study. Genomic DNA isolated from blood samples was used to prepare libraries using a capture-based target enrichment kit covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). Next-generation sequencing was performed using the Illumina NextSeq500 System.
RESULTS: In our study, one pathogenic mutation was detected in BRCA1 (rs80357868) gene (prevalence of 4%, 1/24). We identified the truncating 3875_3878delGTCT mutation of BRCA1 gene in Tuvans BC patient aged 34 years. We also detected three mutations that were probably damaging by PolyPhen2 and/or deleterious by SIFT in ATM (rs781023264), MUTYH (rs199840380) and RAD51D (rs145309168) genes.
CONCLUSION: To the best of our knowledge, this is the first report that describes the highly pathogenic variant in the BRCA1 gene (rs80357868) and possibly damaging (PolyPhen2) germline variants in the ATM (rs781023264), MUTYH (rs199840380) and RAD51D (rs145309168) genes in young Tuvans BC patient.
Cancers (Basel). 2021 Mar 24. pii: 1495. [Epub ahead of print]13(7):

Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer.

Tú Nguyen-Dumont, James G Dowty, Robert J MacInnis, Jason A Steen, Moeen Riaz, Pierre-Antoine Dugué, Anne-Laure Renault, Fleur Hammet, Maryam Mahmoodi, Derrick Theys, Helen Tsimiklis, Gianluca Severi, Damien Bolton, Paul Lacaze, Robert Sebra, Eric Schadt, John McNeil, Graham G Giles, Roger L Milne, Melissa C Southey.

  While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant (p < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in BRCA2 (5.8 (2.7-12.4)), BRCA1 (5.5 (1.8-16.6)), and ATM (3.8 (1.6-9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment.

Keywords:  aggressive prostate cancer; gene panel testing; genetic risk factors; predisposition

DOI:  https://doi.org/10.3390/cancers13071495
Curr Treat Options Gastroenterol. 2020 Dec;18(4): 604-615

Genetic Gastric Cancer Risk Syndromes.

Benjamin A Lerner, Xavier Llor.

   Purpose of review: Gastric cancer is a leading cause of cancer death in the world. Between 1% and 3% of cases are associated with specific genetic cancer risk syndromes. The purpose of this article is to review the latest insights, as well as gaps in knowledge, regarding some of the most common hereditary gastric cancer syndromes: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), Lynch syndrome, the adenomatous polyposis syndromes, and the hamartomatous polyposis syndromes.
Recent findings: Patients carrying pathogenic variants in CDH1, but not meeting clinical criteria for HDGC, are increasingly being identified thanks to multigene panel testing; their absence from previous analyses overestimated gastric cancer penetrance. GAPPS is a recently described hereditary gastric cancer syndrome associated with specific point mutations in the promoter 1B region of the APC gene.
Summary: Risk of gastric cancer is highest among carriers of pathogenic variants in CDH1, with cumulative incidences approximately 40% and 30% for men and women, respectively. Mutations associated with Lynch syndrome and adenomatous polyposis syndromes confer greatest risk for gastric cancer in East Asian populations. Risk of gastric cancer in GAPPS and hamartomatous polyposis syndromes is difficult to estimate due to their rarity, but mutation status likely determines risk. Future research is needed to more precisely define risk of gastric cancer in these syndromes, so strategies for screening and prophylactic gastrectomy can be optimized.

Keywords:  diffuse gastric cancer; gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS); gastric polyps; hereditary gastric cancer; inherited gastric cancer

DOI:  https://doi.org/10.1007/s11938-020-00312-z
Cancer Epidemiol Biomarkers Prev. 2021 Apr;30(4): 676-681

The Impact of Longitudinal Surveillance on Tumor Thickness for Melanoma-Prone Families with and without Pathogenic Germline Variants of CDKN2A and CDK4.

Michael R Sargen, Ruth M Pfeiffer, David E Elder, Xiaohong R Yang, Alisa M Goldstein, Margaret A Tucker.

BACKGROUND: Skin cancer screening is routinely performed for members of melanoma-prone families, but longitudinal studies evaluating the efficacy of surveillance in this high-risk population are lacking.
METHODS: We evaluated thickness for first primary melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) enrolled in NCT00040352 (NCI familial melanoma study) from 1976 through 2014; enrolled patients received routine skin cancer screening and education about skin self-exams. We used linear and ordinal logistic regression models adjusted for gender and age with a generalized estimating equations approach to report changes in thickness and tumor (T) stage over time, comparing outcomes for NCI cases diagnosed before (pre-study) versus after study participation (prospective) and for NCI cases versus nonfamilial cases [Surveillance, Epidemiology, and End Results (SEER) 9 registries].
RESULTS: Tumor thickness was evaluated for 293 NCI (pre-study = 246; prospective = 47) patients. Compared with NCI pre-study cases, NCI prospective melanomas were thinner (0.6 vs. 1.1 mm; P < 0.001) and more likely to be T1 stage [39/47 (83%) vs. 98/246 (40%); P < 0.001]. Similar findings (P < 0.05) were observed for familial cases with and without germline CDKN2A and CDK4 mutations. Peters-Belson modeling suggested that calendar period effects of decreasing thickness in the general population (SEER 9) did not fully explain thickness trends in NCI families.
CONCLUSIONS: Participation in a longitudinal surveillance program providing skin cancer screening and education about skin self-exams was associated with thinner melanomas for members of melanoma-prone families.
IMPACT: The study findings support the clinical benefit of screening (physician and self) for this high-risk population.

DOI: https://doi.org/10.1158/1055-9965.EPI-20-1521
Cancers (Basel). 2021 Mar 10. pii: 1200. [Epub ahead of print]13(6):

Subsequent Malignant Neoplasms in Retinoblastoma Survivors.

Armida W M Fabius, Milo van Hoefen Wijsard, Flora E van Leeuwen, Annette C Moll.

  Retinoblastoma (Rb) is a pediatric malignant eye tumor. Subsequent malignant neoplasms (SMNs) and trilateral Rb (TRb) are the leading cause of death in heritable Rb patients in developed countries. The high rate of SMNs in heritable Rb patients is attributed to the presence of a mutation in the RB1 tumor suppressor gene. In addition, Rb therapy choices also influence SMN incidence in this patient group. The incidence rates and age of occurrence for the most frequent SMNs and TRb will be discussed. In addition, the impact of genetic predisposition and Rb treatments on the development of SMNs will be evaluated. Furthermore, screening and other prevention methods will be reviewed.

Keywords:  heritable Rb; long-term surveillance; retinoblastoma; second primary malignancies; subsequent malignant neoplasms; trilateral Rb

DOI:  https://doi.org/10.3390/cancers13061200
Cell Rep. 2021 Mar 30. pii: S2211-1247(21)00240-0. [Epub ahead of print]34(13): 108926

Trans-ethnic variation in germline variants of patients with renal cell carcinoma.

Sarah Abou Alaiwi, Amin H Nassar, Elio Adib, Stefan M Groha, Elie W Akl, Bradley A McGregor, Edward D Esplin, Shan Yang, Kathryn Hatchell, Vincent Fusaro, Sarah Nielsen, David J Kwiatkowski, Guru P Sonpavde, Mark Pomerantz, Judy E Garber, Matthew L Freedman, Huma Q Rana, Alexander Gusev, Toni K Choueiri.

  Prior studies of the renal cell carcinoma (RCC) germline landscape investigated predominantly patients of European ancestry. We examine the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 1,829 patients with RCC from various ancestries. Overall, P/LP variants are found in 17% of patients, among whom 10.3% harbor one or more clinically actionable variants with potential preventive or therapeutic utility. Patients of African ancestry with RCC harbor significantly more P/LP variants in FH compared to patients of non-African ancestry with RCC and African controls from the Genome Aggregation Database (gnomAD). Patients of non-African ancestry have significantly more P/LP variants in CHEK2 compared to patients of African ancestry with RCC and non-Finnish Europeans controls. Non-Africans with RCC have more actionable variants compared to Africans with RCC. This work helps understand the underlying biological differences in RCC between Africans and non-Africans and paves the way to more comprehensive genomic characterization of underrepresented populations.

Keywords:  Ancestry; DNA damage repair; clinical genetics; germline variants; kidney cancer; renal cell carcinoma

DOI:  https://doi.org/10.1016/j.celrep.2021.108926
Stem Cell Res. 2021 Mar 18. pii: S1873-5061(21)00145-8. [Epub ahead of print]53 102299

Generation of two induced pluripotent stem cell lines from blood cells of a prostate cancer patient carrying germline mutation in CHEK2.

Ran Liu, Kaiyu Qian, Yu Xiao, Wei Jiang.

Germline mutations of CHEK2 have been reported in various types of disease including breast cancer, ovarian cancer, colorectal cancer and prostate cancer. We generated two iPSC lines ZNHi001-A and ZNHi001-B from a prostate cancer patient carrying germline mutation in CHEK2 (c.667C＞T, also p.R223C) which may increase the risk of prostate cancer. Pluripotency and multi-lineage differentiation capacity of the two iPSC lines were confirmed by gene expression and teratoma assay. The generated iPSC lines carrying specific CHEK2 mutation might be a useful resource to study the pathogenic mechanism and develop potential therapeutic strategy of prostate cancer.

DOI: https://doi.org/10.1016/j.scr.2021.102299
Prostate. 2021 Apr 01.

Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

Elisa M Ledet, Earle F Burgess, Alexandra O Sokolova, Ellen B Jaeger, Whitley Hatton, Marcus Moses, Patrick Miller, Patrick Cotogno, Jodi Layton, Pedro Barata, Brian E Lewis, Mari Nakazawa, Jason Zhu, Beth Dellinger, Sara Elrefai, Nellie N Nafissi, Jan B Egan, Neal Shore, Rana R McKay, Alan H Bryce, Heather H Cheng, Emmanuel S Antonarakis, Oliver Sartor.

   BACKGROUND: The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations.
METHODS: African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed.
RESULTS: A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely-pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non-BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African-Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men.
CONCLUSIONS: In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non-BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.

Keywords:  African American; genetics; germline; metastatic prostate cancer; pathogenic variants; racial disparity

DOI:  https://doi.org/10.1002/pros.24123
Int Cancer Conf J. 2021 Apr;10(2): 107-111

A male with primary accessory breast carcinoma in an axilla is strongly suspected of having hereditary breast cancer.

Eriko Takahashi, Kaori Terata, Hiroshi Nanjo, Koichi Ishiyama, Yuko Hiroshima, Ayuko Yamaguchi, Misako Yatsuyanagi, Chiaki Kudo, Akiyuki Wakita, Shinogu Takashima, Yusuke Sato, Kazuhiro Imai, Satoru Motoyama, Yoshihiro Minamiya.

  We herein report on a male with primary accessory breast cancer in an axilla. A 75-year-old man first noticed a subcutaneous nodule about 2 cm in diameter in the area of his right axilla. The patient underwent extirpation of the mass in a public hospital. Histological examination revealed invasive breast carcinoma of no special type associated with mucinous carcinoma, invasive micropapillary carcinoma and intraductal components. Immunohistochemical analysis showed that the tumor cells were positive for Gross cystic disease fluid protein (GCDFP)-15, mammaglobin and GATA3. Staining for estrogen receptor (ER) and progesterone receptor (PR) was positive, and human epidermal growth factor receptor 2 (HER2) was negative. The Ki67 labeling index (LI) was 33.6%. Imaging revealed no evidence of a primary tumor in any other organ or in the bilateral mammary gland. We performed radical resection of the right axilla, including the scar, and axillary lymph node dissection. The final pathological examination of the surgical specimen showed normal mammary gland tissue that was not connected to the proper mammary gland, and no residual cancer or metastatic lymph nodes. Based on our clinical and pathological findings, this tumor was diagnosed as breast cancer originating from the accessory mammary gland in the right axilla. After surgery, tamoxifen was administered as adjuvant therapy. Since the surgery, 2 years ago, there has been no evidence of recurrence. Hereditary Breast and Ovarian Cancer syndrome was suspected in this case because the patient was a male with breast cancer, and he had two first-degree relatives with breast cancer. This patient had no BRCA mutations on genetic testing. Nonetheless, in cases of male breast cancer, it is necessary to obtain genetic information due to the possibility of hereditary breast cancer, including cancers associated with BRCA gene mutation.

Keywords:  Accessory breast cancer; BRCA genetic testing; Hereditary breast and ovarian cancer syndrome; Hereditary breast cancer genes; Male breast cancer

DOI:  https://doi.org/10.1007/s13691-020-00466-8
Gastroenterology. 2021 Mar 25. pii: S0016-5085(21)00549-7. [Epub ahead of print]

Familial burden and other clinical factors associated with various types of cancer in individuals with Lynch syndrome.

Leah H Biller, Miki Horiguchi, Hajime Uno, Chinedu Ukaegbu, Sapna Syngal, Matthew B Yurgelun.

   BACKGROUND & AIMS: Lynch syndrome (LS) is associated with increased risks of various gastrointestinal, gynecologic, genitourinary, and other cancers. Many clinical practice guidelines recommend that LS carriers' screening strategies be devised based on their family history of various cancers, in addition to age-/sex-/gene-specific considerations. The aim of this study was to examine the association between family history and other clinical factors with LS carriers' histories of various cancers.
METHODS: Two cohorts of LS carriers were analyzed: a laboratory-based cohort of consecutively-ascertained individuals undergoing germline LS testing and a clinic-based cohort of LS carriers undergoing clinical care at an academic medical center. Multivariable logistic regression was performed to assess clinical factors associated with LS carriers' histories of various cancers/neoplasms. Familial burden was defined as LS carriers' aggregate number of first-/second-degree relatives with a history of a given malignancy.
RESULTS: Multivariable analysis of the laboratory-based cohort (3828 LS carriers) identified familial burden as being incrementally associated with LS carriers' personal history of endometrial (OR 1.37 per affected first-/second-degree relative; 95% CI 1.21-1.56), urinary tract (OR 2.72; 95% CI 2.02-3.67), small bowel (OR 3.17; 95% CI 1.65-6.12), gastric (OR 1.93; 95% CI 1.24-3.02), and pancreaticobiliary cancers (OR 2.10; 95% CI 1.21-3.65) and sebaceous neoplasms (OR 7.39; 95% CI 2.71-20.15). Multivariable analysis of the clinic-based cohort (607 LS carriers) confirmed a significant association of familial burden of endometrial and urinary tract cancers.
CONCLUSIONS: Familial burden - in addition to age, sex, and gene - should be used to assess LS carriers' risks of specific cancers and guide decision-making about organ-specific surveillance.

Keywords:  HNPCC; extracolonic; screening

DOI:  https://doi.org/10.1053/j.gastro.2021.03.039
Front Oncol. 2021 ;11 636633

Molecular Mechanisms of the Genetic Predisposition to Acute Megakaryoblastic Leukemia in Infants With Down Syndrome.

Juliane Grimm, Dirk Heckl, Jan-Henning Klusmann.

  Individuals with Down syndrome are genetically predisposed to developing acute megakaryoblastic leukemia. This myeloid leukemia associated with Down syndrome (ML-DS) demonstrates a model of step-wise leukemogenesis with perturbed hematopoiesis already presenting in utero, facilitating the acquisition of additional driver mutations such as truncating GATA1 variants, which are pathognomonic to the disease. Consequently, the affected individuals suffer from a transient abnormal myelopoiesis (TAM)-a pre-leukemic state preceding the progression to ML-DS. In our review, we focus on the molecular mechanisms of the different steps of clonal evolution in Down syndrome leukemogenesis, and aim to provide a comprehensive view on the complex interplay between gene dosage imbalances, GATA1 mutations and somatic mutations affecting JAK-STAT signaling, the cohesin complex and epigenetic regulators.

Keywords:  ML–DS; TAM; Trisomy 21 (Down syndrome); acute megakaryoblastic leukemia; acute myeloid leukemia; genetic predisposition; transient myeloproliferative disorder of Down syndrome

DOI:  https://doi.org/10.3389/fonc.2021.636633