bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–02–20
fourteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Germline pathogenic variants in cancer risk genes among patients with thyroid cancer and suspected predisposition.
  2. Molecular Features and Clinical Management of Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer.
  3. Linking germline variants to leukaemia pathogenesis.
  4. Rare Hereditary Gynecological Cancer Syndromes.
  5. Worldwide prevalence of Lynch syndrome in patients with colorectal cancer: Systematic review and meta-analysis.
  6. Potential Involvement of NSD1, KRT24 and ACACA in the Genetic Predisposition to Colorectal Cancer.
  7. Novel Insights From the Germline Landscape of Breast Cancer in Brazil.
  8. BRCA1/2 variants of unknown significance in hereditary breast and ovarian cancer (HBOC) syndrome: Looking for the hidden meaning.
  9. Whole-Exome Sequencing Identifies a Novel Germline Variant in PTK7 Gene in Familial Colorectal Cancer.
  10. Prevalence and Spectrum of Predisposition Genes With Germline Mutations Among Chinese Patients With Bowel Cancer.
  11. Case Report: A New Subtype of Lynch Syndrome Associated With MSH2 c.1024_1026 Identified in a Chinese Family.
  12. Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China.
  13. Family Adjustment to Hereditary Cancer Syndromes: A Systematic Review.
  14. Nonmalignant Features Associated with Inherited Colorectal Cancer Syndromes-Clues for Diagnosis.
  1. Cancer Med. 2022 Feb 17.
    Germline pathogenic variants in cancer risk genes among patients with thyroid cancer and suspected predisposition.
    Junne Kamihara, Jing Zhou, Holly LaDuca, Ari J Wassner, Emily Dalton, Judy E Garber, Mary Helen Black.
       PURPOSE: Multigene panels allow simultaneous testing of genes involved in cancer predisposition. Thyroid cancer (TCa) is a component tumor of several cancer predisposition syndromes, but the complete landscape of germline variants predisposing to TCa remains to be determined.
    METHODS: Clinical information and genetic test results were reviewed from over 170,000 individuals who had multigene panel testing for hereditary cancer at a single diagnostic laboratory. Germline pathogenic and likely pathogenic variants ("pathogenic variants") were examined among individuals with TCa. A cohort with breast cancer (BCa) was examined to serve as a comparison group and to determine the added contribution of TCa to the ascertainment of genetic risk.
    RESULTS: Of 3134 individuals with TCa, 291 (9.3%) were found to have one or more pathogenic variant(s). Among 904 individuals with TCa alone, 7.5% had one or more pathogenic variant(s), similar to those with BCa alone (8.4%). In all groups, CHEK2 was the gene with the highest number of pathogenic variants identified, with a significantly increased frequency among individuals with a history of both thyroid and BCa compared to BCa alone.
    CONCLUSIONS: A high prevalence of germline pathogenic variants was observed among individuals with TCa referred for hereditary cancer genetic testing, even in the absence of other cancer diagnoses. These data suggest that TCa may be an under-recognized component of cancer predisposition syndromes.
    Keywords:   CHEK2 ; cancer predisposition; germline; multigene panels; thyroid cancer
    DOI:  https://doi.org/10.1002/cam4.4549
  2. Int J Mol Sci. 2022 Jan 21. pii: 1205. [Epub ahead of print]23(3):
    Molecular Features and Clinical Management of Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer.
    Akiyoshi Kasuga, Takeshi Okamoto, Shohei Udagawa, Chinatsu Mori, Takafumi Mie, Takaaki Furukawa, Yuto Yamada, Tsuyoshi Takeda, Masato Matsuyama, Takashi Sasaki, Masato Ozaka, Arisa Ueki, Naoki Sasahira.
      Hereditary pancreatic cancers are caused by several inherited genes. Familial pancreatic cancer is defined as pancreatic cancer arising in a patient with at least two first-degree relatives with pancreatic cancer in the absence of an identified genetic cause. Hereditary pancreatic cancer syndromes and familial pancreatic cancers account for about 10% of pancreatic cancer cases. Germline mutations in BRCA1, BRCA2, ATM, PALB2, CDKN2A, STK11, and TP53 and mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) are among the well-known inherited susceptibility genes. Currently available targeted medications include poly (ADP-ribose) polymerase inhibitors (PARP) for cases with mutant BRCA and immune checkpoint inhibitors for cases with mismatch repair deficiency. Loss of heterozygosity of hereditary pancreatic cancer susceptibility genes such as BRCA1/2 plays a key role in carcinogenesis and sensitivity to PARP inhibitors. Signature 3 identified by whole genome sequencing is also associated with homologous recombination deficiency and sensitivity to targeted therapies. In this review, we summarize molecular features and treatments of hereditary pancreatic cancer syndromes and surveillance procedures for unaffected high-risk cases. We also review transgenic murine models to gain a better understanding of carcinogenesis in hereditary pancreatic cancer.
    Keywords:  PARP inhibitor; familial pancreatic cancer; germline mutation; hereditary pancreatic cancer syndrome; loss of heterozygosity; surveillance
    DOI:  https://doi.org/10.3390/ijms23031205
  3. Nat Rev Cancer. 2022 Feb 15.
    Linking germline variants to leukaemia pathogenesis.
    Sarah Seton-Rogers.
      
    DOI:  https://doi.org/10.1038/s41568-022-00455-4
  4. Int J Mol Sci. 2022 Jan 29. pii: 1563. [Epub ahead of print]23(3):
    Rare Hereditary Gynecological Cancer Syndromes.
    Takafumi Watanabe, Shu Soeda, Yuta Endo, Chikako Okabe, Tetsu Sato, Norihito Kamo, Makiko Ueda, Manabu Kojima, Shigenori Furukawa, Hidekazu Nishigori, Toshifumi Takahashi, Keiya Fujimori.
      Hereditary cancer syndromes, which are characterized by onset at an early age and an increased risk of developing certain tumors, are caused by germline pathogenic variants in tumor suppressor genes and are mostly inherited in an autosomal dominant manner. Therefore, hereditary cancer syndromes have been used as powerful models to identify and characterize susceptibility genes associated with cancer. Furthermore, clarification of the association between genotypes and phenotypes in one disease has provided insights into the etiology of other seemingly different diseases. Molecular genetic discoveries from the study of hereditary cancer syndrome have not only changed the methods of diagnosis and management, but have also shed light on the molecular regulatory pathways that are important in the development and treatment of sporadic tumors. The main cancer susceptibility syndromes that involve gynecologic cancers include hereditary breast and ovarian cancer syndrome as well as Lynch syndrome. However, in addition to these two hereditary cancer syndromes, there are several other hereditary syndromes associated with gynecologic cancers. In the present review, we provide an overview of the clinical features, and discuss the molecular genetics, of four rare hereditary gynecological cancer syndromes; Cowden syndrome, Peutz-Jeghers syndrome, DICER1 syndrome and rhabdoid tumor predisposition syndrome 2.
    Keywords:  Cowden syndrome; DICER1 syndrome; Peutz–Jeghers syndrome; molecular genetics; rare hereditary gynecological cancer; rhabdoid tumor predisposition syndrome 2
    DOI:  https://doi.org/10.3390/ijms23031563
  5. Genet Med. 2022 Feb 14. pii: S1098-3600(22)00030-2. [Epub ahead of print]
    Worldwide prevalence of Lynch syndrome in patients with colorectal cancer: Systematic review and meta-analysis.
    Nadine Abu-Ghazaleh, Varun Kaushik, Alexandra Gorelik, Mark Jenkins, Finlay Macrae.
       PURPOSE: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, with an estimated prevalence of 2% to 3% of CRC. A prevalence study is needed to provide accurate estimates of the true prevalence of LS.
    METHODS: MEDLINE (Ovid), Embase, and Web of Science were searched. Prevalence was calculated by random effects meta-analysis models. I2 score was used to assess heterogeneity across studies. Meta-regression was performed for between-study variance.
    RESULTS: A total of 51 studies were included in this review. The overall pooled yield of LS screening was 2.2% based on all methods of detection. Studies performing germline tests on all participants with CRC reported higher prevalence (5.1%) as opposed to studies only performing germline tests on participants with tumors with mismatch repair deficiency (1.6%) or microsatellite instability (1.1%). Selected cohorts of CRC had a higher prevalence of germline LS diagnoses.
    CONCLUSION: LS prevalence across multiple ethnic, geographic, and clinical populations is remarkably similar. Universal germline testing of patients presenting with cancer identifies that most CRCs are attributed to LS. Young patients presenting with CRC and those who fulfill criteria for a familial risk provide the highest returns for LS identification. Our study supports the universal germline CRC screening for LS.
    Keywords:  Colorectal cancer; Germline mutations; Lynch syndrome; Prevalence
    DOI:  https://doi.org/10.1016/j.gim.2022.01.014
  6. Cancers (Basel). 2022 Jan 29. pii: 699. [Epub ahead of print]14(3):
    Potential Involvement of NSD1, KRT24 and ACACA in the Genetic Predisposition to Colorectal Cancer.
    Isabel Quintana, Pilar Mur, Mariona Terradas, Sandra García-Mulero, Gemma Aiza, Matilde Navarro, Virginia Piñol, Joan Brunet, Victor Moreno, Rebeca Sanz-Pamplona, Gabriel Capellá, Laura Valle.
      The ALFRED (Allelic Loss Featuring Rare Damaging) in silico method was developed to identify cancer predisposition genes through the identification of somatic second hits. By applying ALFRED to ~10,000 tumor exomes, 49 candidate genes were identified. We aimed to assess the causal association of the identified genes with colorectal cancer (CRC) predisposition. Of the 49 genes, NSD1, HDAC10, KRT24, ACACA and TP63 were selected based on specific criteria relevant for hereditary CRC genes. Gene sequencing was performed in 736 patients with familial/early onset CRC or polyposis without germline pathogenic variants in known genes. Twelve (predicted) damaging variants in 18 patients were identified. A gene-based burden test in 1596 familial/early-onset CRC patients, 271 polyposis patients, 543 TCGA CRC patients and >134,000 controls (gnomAD, non-cancer), revealed no clear association with CRC for any of the studied genes. Nevertheless, (non-significant) over-representation of disruptive variants in NSD1, KRT24 and ACACA in CRC patients compared to controls was observed. A somatic second hit was identified in one of 20 tumors tested, corresponding to an NSD1 carrier. In conclusion, most genes identified through the ALFRED in silico method were not relevant for CRC predisposition, although a possible association was detected for NSD1, KRT24 and ACACA.
    Keywords:  cancer predisposition; hereditary cancer; hereditary colorectal cancer; polyposis; somatic second hit
    DOI:  https://doi.org/10.3390/cancers14030699
  7. Front Oncol. 2021 ;11 743231
    Novel Insights From the Germline Landscape of Breast Cancer in Brazil.
    Daniel Barbalho, Renata Sandoval, Erika Santos, Janina Pisani, Carla Quirino, Bernardo Garicochea, Benedito Rossi, Maria Isabel Achatz.
       Introduction: Breast cancer patients with germline pathogenic variants may benefit from risk-reducing surgeries, intensive screening, and targeted cancer therapies. There is a paucity of data regarding prevalence and distribution of germline pathogenic variants in the Brazilian population. Our primary endpoint was the description of prevalence and distribution of germline pathogenic variants among breast cancer patients who underwent next-generation sequencing (NGS) panel testing. Secondary endpoint was the assessment of predictive factors of a positive test.
    Methods: We analyzed NGS results, personal, and family history data from a prospectively collected cohort of breast cancer patients from August 2013 to May 2019. Exact logistic regression was used to perform multivariable analysis.
    Results: Of 370 breast cancer patients, we found 59 pathogenic variants in 57 (15%) patients. Pathogenic variants were identified in BRCA1 (24%), ATM (14%), BRCA2 (10%), TP53 (8%), PALB2 (8%), CHEK2 (7%), CDH1 (3%), RAD51C (3%), MITF (2%), PMS2 (2%), RAD51D (2%), and TERT (2%). Monoallelic MUTYH pathogenic variants were found in 15%. After multivariable analysis, age of diagnosis (OR 0.89, 95% CI: 0.81-0.95, for each year increase), triple-negative subtype (OR 17.2, 95% CI: 3.74-114.72), and number of breast cancers in the family (OR 2.46, 95% CI 1.57-4.03, for each additional case) were associated with BRCA1 pathogenic variants. In the present study, a quarter of triple-negative breast cancer patients harbored a germline pathogenic variant and two-thirds of those were BRCA1 carriers.
    Conclusions: Prevalence and distribution of germline pathogenic variants in this Brazilian sample of breast cancer patients are mostly similar to other populations. However, there is a trend to an overrepresentation of TP53 pathogenic variants that merits confirmation in further studies. Early-onset breast cancer patients should be offered genetic counseling, particularly those with triple-negative subtype.
    Keywords:  Brazil; breast neoplasms; genetic predictive testing; genetic predisposition to breast cancer; high-throughput nucleotide sequencing
    DOI:  https://doi.org/10.3389/fonc.2021.743231
  8. Crit Rev Oncol Hematol. 2022 Feb 10. pii: S1040-8428(22)00050-6. [Epub ahead of print]172 103626
    BRCA1/2 variants of unknown significance in hereditary breast and ovarian cancer (HBOC) syndrome: Looking for the hidden meaning.
    Daniele Fanale, Alessia Pivetti, Daniela Cancelliere, Antonio Spera, Marco Bono, Alessia Fiorino, Erika Pedone, Nadia Barraco, Chiara Brando, Alessandro Perez, Maria Francesca Guarneri, Tancredi Didier Bazan Russo, Salvatore Vieni, Girolamo Guarneri, Antonio Russo, Viviana Bazan.
      Hereditary breast and ovarian cancer syndrome is caused by germline mutations in BRCA1/2 genes. These genes are very large and their mutations are heterogeneous and scattered throughout the coding sequence. In addition to the above-mentioned mutations, variants of uncertain/unknown significance (VUSs) have been identified in BRCA genes, which make more difficult the clinical management of the patient and risk assessment. In the last decades, several laboratories have developed different databases that contain more than 2000 variants for the two genes and integrated strategies which include multifactorial prediction models based on direct and indirect genetic evidence, to classify the VUSs and attribute them a clinical significance associated with a deleterious, high/low or neutral risk. This review provides a comprehensive overview of literature studies concerning the VUSs, in order to assess their impact on the population and provide new insight useful for the appropriate patient management in clinical practice.
    Keywords:  BRCA1; BRCA2; Hereditary Breast and Ovarian Cancer Syndrome; Multifactorial prediction model; VUS; Variants of Uncertain Significance
    DOI:  https://doi.org/10.1016/j.critrevonc.2022.103626
  9. Int J Mol Sci. 2022 Jan 24. pii: 1295. [Epub ahead of print]23(3):
    Whole-Exome Sequencing Identifies a Novel Germline Variant in PTK7 Gene in Familial Colorectal Cancer.
    Beiping Miao, Diamanto Skopelitou, Aayushi Srivastava, Sara Giangiobbe, Dagmara Dymerska, Nagarajan Paramasivam, Abhishek Kumar, Magdalena Kuświk, Wojciech Kluźniak, Katarzyna Paszkowska-Szczur, Matthias Schlesner, Jan Lubinski, Kari Hemminki, Asta Försti, Obul Reddy Bandapalli.
      Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing on six members of a Polish family diagnosed with CRC and identified a novel germline variant in the protein tyrosine kinase 7 (inactive) gene (PTK7, ENST00000230419, V354M). Targeted screening of the variant in 1705 familial CRC cases and 1674 healthy elderly individuals identified the variant in an additional familial CRC case. Introduction of this variant in HT-29 cells resulted in increased cell proliferation, migration, and invasion; it also caused down-regulation of CREB, p21 and p53 mRNA and protein levels, and increased AKT phosphorylation. These changes indicated inhibition of apoptosis pathways and activation of AKT signaling. Our study confirmed the oncogenic function of PTK7 and supported its role in genetic predisposition of familial CRC.
    Keywords:  AKT signaling pathway; PTK7; colorectal cancer; familial cancer variant prioritization pipeline; familial cancers; germline variant
    DOI:  https://doi.org/10.3390/ijms23031295
  10. Front Genet. 2021 ;12 755629
    Prevalence and Spectrum of Predisposition Genes With Germline Mutations Among Chinese Patients With Bowel Cancer.
    Zhengyong Xie, Yongli Ke, Junyong Chen, Zehang Li, Changzheng Wang, Yuhong Chen, Hongliang Ding, Liyang Cheng.
      Background: Bowel cancer is the third-most common cancer and the second leading cause of cancer-related death worldwide. Bowel cancer has a substantial hereditary component; however, additional hereditary risk factors involved in bowel cancer pathogenesis have not been systematically defined. Materials and Methods: A total of 573 patients with bowel cancer were enrolled in the present study, of whom 93.72% had colorectal cancer (CRC). Germline mutations were integrated with somatic mutation information via utilizing target next-generation sequencing. Results: Pathogenic/Likely Pathogenic (P/LP) germline alterations were identified in 47 (8.2%) patients with bowel cancer and the ratio of the number of these patients with family history was significantly higher in the P/LP group than that noted in the non-pathogenic (Non-P) group. Certain rare germline alterations were noted, such as those noted in the following genes: FANCD2, CDH1, and FLCN. A total of 32 patients (68.1%) had germline alterations in the DNA-damage repair (DDR) genes and homologous recombination (HR) accounted for the highest proportion of this subgroup. By comparing 573 patients with bowel cancer with reference controls (China_MAPs database), significant associations (p < 0.01) were observed between the incidence of bowel cancer and the presence of mutations in APC, ATM, MLH1, FANCD2, MSH3, MSH6, PMS1, and RAD51D. Somatic gene differential analysis revealed a marked difference in 18 genes and a significant difference was also noted in tumor mutation burden (TMB) between germline mutation carriers and non-germline mutation subjects (p < 0.001). In addition, TMB in DDR mutation groups indicated a dramatic difference compared with the non-DDR mutation group (p < 0.01). However, no statistically significant differences in TMB were noted among detailed DDR pathways for patients with bowel cancer, irrespective of the presence of germline mutations. Moreover, a significantly higher level (p < 0.0001) of mutation count was observed in the DDR group from The Cancer Genome Atlas (TCGA) database and the DDR and non-DDR alteration groups displayed various immune profiles. Conclusion: Chinese patients with bowel cancer exhibited a distinct spectrum of germline variants, with distinct molecular characteristics such as TMB and DDR. Furthermore, the information on somatic mutations obtained from TCGA database indicated that a deeper understanding of the interactions among DDR and immune cells would be useful to further investigate the role of DDR in bowel cancer.
    Keywords:  DDR; P/LP (pathogenic/likely-pathogenic); TMB; bowel cancer; germline; somatic
    DOI:  https://doi.org/10.3389/fgene.2021.755629
  11. Front Med (Lausanne). 2022 ;9 811368
    Case Report: A New Subtype of Lynch Syndrome Associated With MSH2 c.1024_1026 Identified in a Chinese Family.
    Lu Li, Zhe Zhao, Lin Dong, Jia Jia, Ke Su, Hua Bai, Jie Wang.
       Background: Lynch syndrome is an autosomal dominant disorder associated with a high incidence of various cancer types. Multiple variants of mismatch repair genes have been reported for Lynch syndrome. However, the diagnosis in patients with atypical cancer types remains challenging. Specifically, little is known about the genetic background of Lynch syndrome-related renal carcinoma. We present a case wherein a renal carcinoma patient with multiple primary skin tumors harbored a variant that has not been previously shown to be associated with Lynch syndrome.
    Case Presentation: The proband was a 60-year-old Chinese man with a history of Lynch syndrome-related renal carcinoma and recurrent primary skin tumors. Immunohistochemistry revealed loss of MSH2 and MSH6. Sequencing of mismatch repair genes revealed a previously unknown germline MSH2 mutation (c.1024_1026), which results in an amino acid deletion (p.V342). This variant was co-segregated among the carcinoma-affected family members. After six cycles of immunotherapy, a marked regression of the skin tumors was observed.
    Conclusions: We clarify the pathogenic significance of this newly described mutation and suggest immunotherapy for patients with this subtype of Lynch syndrome.
    Keywords:  DNA mismatch repair; MutS homolog 2 protein; case report; hereditary nonpolyposis colorectal neoplasms; immunotherapy; skin neoplasms
    DOI:  https://doi.org/10.3389/fmed.2022.811368
  12. JAMA Netw Open. 2022 02 01. 5(2): e2148721
    Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China.
    Lingdi Yin, Jishu Wei, Zipeng Lu, Shimeng Huang, Hao Gao, Jianmin Chen, Feng Guo, Min Tu, Bin Xiao, Chunhua Xi, Kai Zhang, Qiang Li, Junli Wu, Wentao Gao, Kuirong Jiang, Jun Yu, Yi Miao.
       Importance: A higher incidence of pancreatic cancer has been reported in the Chinese population compared with the White population, but genetic differences are unknown to date. Large-sample germline testing for both familial and sporadic pancreatic cancers has been conducted predominantly in White populations, whereas similar studies in Chinese populations are limited.
    Objective: To assess the prevalence of germline sequence variations in patients with pancreatic diseases in China.
    Design, Setting, and Participants: This genetic association study was a case series that included genetic data from patients with pancreatic ductal adenocarcinoma (PDAC) or non-PDAC pancreatic diseases seen at The First Affiliated Hospital of Nanjing Medical University in Nanjing, China, between January 2006 and December 2017 (Nanjing cohort). Comparator group data were obtained for a US cohort from Johns Hopkins Hospital (JHH), a population from East Asia from the Exome Aggregation Consortium (ExAC) database, and the larger population from China from the ChinaMAP database. Data were updated and analyzed in July 2021.
    Main Outcomes and Measures: Next-generation sequencing technology was used to examine the prevalence of deleterious variations in 59 genes of the included Chinese patients with DNA extracted from peripheral blood samples. The Fisher exact test was used to assess differences among the frequencies of germline variations in the study patients vs the comparator groups.
    Results: A total of 1009 patients with PDAC (627 [62.1%] male; mean [SD] age, 62.8 [10.2] years) and 885 with non-PDAC diseases (477 [53.9%] male; mean [SD] age, 52.0 [15.9] years) from the Nanjing cohort were included for genetic analysis; all were Han Chinese individuals. Pathogenic variations were detected in 63 patients with PDAC (6.2%; 95% CI, 4.7%-7.7%). Variations in BRCA2 (odds ratio [OR], 3.2; 95% CI, 1.4-7.7; P = .008) and PALB2 (OR, 5.2; 95% CI, 1.6-17.0; P = .007) were significantly associated with pancreatic risk in the Nanjing cohort. Pathogenic variants of genes associated with homologous recombination DNA damage repair, including ATM, BRCA1/2, PALB2, BRIP1, FANCA, FANCC, RAD51D, and XRCC2, were found in 34 patients with PDAC (3.4%). No Ashkenazi Jewish-specific BRCA2 variation (p.Ser1982fs) was detected. The odds ratio of a SPINK1 variation in patients with PDAC was 3.2 (95% CI, 1.8-5.7; P < .001) in the Nanjing cohort compared with the ExAC cohort. Variations in the pancreatic secretory enzyme genes CPA1 and CPB1 were not detected in the Nanjing cohort.
    Conclusions and Relevance: In this genetic association study, sporadic pancreatic cancer was associated with pathogenic germline variations in a cohort from China. These findings provide insights into the genetic background of pancreatic cancer in the Han Chinese population with PDAC.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2021.48721
  13. Int J Environ Res Public Health. 2022 Jan 30. pii: 1603. [Epub ahead of print]19(3):
    Family Adjustment to Hereditary Cancer Syndromes: A Systematic Review.
    Pedro Gomes, Giada Pietrabissa, Eunice R Silva, João Silva, Paula Mena Matos, Maria Emília Costa, Vanessa Bertuzzi, Eliana Silva, Maria Carolina Neves, Célia M D Sales.
      Hereditary cancer syndromes are inherited pathogenic genetic variants that significantly increase the risk of developing cancer. When individuals become aware of their increased probability of having cancer, the whole family is affected by this new reality and needs to adjust. However, adjustment to hereditary cancer syndromes has been mainly studied at an individual level, and research about familial adjustment remains dispersed and disorganized. To overcome this gap, this review aims to understand how families adjust to genetic testing and risk management, and to what extent the family's adjustment influences the psychological response and risk management behaviors of mutation carriers. We conducted searches on the PubMed/Med Line, PsycInfo, SCOPUS, and Google Scholar databases and used the Mixed Methods Appraisal Tool (MMAT-v2018) to assess the methodological quality of each selected study. Thirty studies met the inclusion criteria. Most results highlighted the interdependent nature of adjustment of pathogenic variant carriers and their families. The way carriers adjust to the syndrome is highly dependent on family functioning and related to how family members react to the new genetic information, particularly partners and siblings. Couples who share their worries and communicate openly about cancer risk present a better long-term adjustment than couples who use protective buffering (not talking about it to avoid disturbing the partner) or emotional distancing. Parents need help dealing with disclosing genetic information to their children. These findings reinforce the importance of adopting a family-centered approach in the context of genetic counseling and the necessity of involving family members in research.
    Keywords:  cancer risk management; decision-making; family adjustment; genetic counseling; genetic testing; hereditary cancer syndromes
    DOI:  https://doi.org/10.3390/ijerph19031603
  14. Cancers (Basel). 2022 Jan 26. pii: 628. [Epub ahead of print]14(3):
    Nonmalignant Features Associated with Inherited Colorectal Cancer Syndromes-Clues for Diagnosis.
    Diana Haimov, Sari Lieberman, Sergi Castellvi-Bel, Maartje Nielsen, Yael Goldberg.
      Genetic diagnosis of affected individuals and predictive testing of their at-risk relatives, combined with intensive cancer surveillance, has an enormous cancer-preventive potential in these families. A lack of awareness may be part of the reason why the underlying germline cause remains unexplained in a large proportion of patients with CRC. Various extracolonic features, mainly dermatologic, ophthalmic, dental, endocrine, vascular, and reproductive manifestations occur in many of the cancer predisposition syndromes associated with CRC and polyposis. Some are mediated via the WNT, TGF-β, or mTOR pathways. However the pathogenesis of most features is still obscure. Here we review the extracolonic features of the main syndromes, the existing information regarding their prevalence, and the pathways involved in their pathogenesis. This knowledge could be useful for care managers from different professional disciplines, and used to raise awareness, enable diagnosis, and assist in the process of genetic testing and interpretation.
    Keywords:  TGF-β; WNT; colorectal cancer; diagnosis; extracolonic; genetic predisposition; germline; mTOR polyposis; mosaicism
    DOI:  https://doi.org/10.3390/cancers14030628
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:18.