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Genetic Epidemiology of Inherited Cancers
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Genetic Epidemiology of Inherited Cancers

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 31788

Special Issue Editors

Prof. Dr. D. Gareth Evans

E-Mail Website
Guest Editor
Division of Evolution and Genomic Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK
Interests: BRCA1; BRCA2; Lynch syndrome; familial breast cancer; neurofibromatosis; Gorlin syndrome
Special Issues, Collections and Topics in MDPI journals
Dr. Pål Møller

E-Mail Website
Co-Guest Editor
Department of Tumor Biology, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway
Interests: inherited breast and colorectal cancer; prevention of inheritable breast cancer; founder variants causing cancer; panel testing for inherited cancer genes; The Prospective Lynch Syndrome Database (PLSD—www.plsd.eu)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We will update the concepts and current knowledge of inherited cancers: What is the conceptual meaning of inherited cancer? how do we identify inherited cancer, and current knowledge of the most frequent and clinically important forms of inherited cancers. The concept of inherited cancer emerged from the recognized distributions of young onset cancers in families more than 100 years ago. The last three decades has seen the causative genes for most of the high-penetrant cancer syndromes with Mendelian inheritance identified, and their genetic epidemiology is now being described. Crucial to such descriptions is how to identify pathogenic variants of the causative genes, which are instrumental to demonstrate their associations with disease. From the starting point of identifying the genes causing cancer with very high penetrance in childhood, adolescence and early adult life, we are now facing even more complex challenges of describing genetic variants with lower risk to develop cancer, and their interactions with other genes and environment. The delineation between normal variation and genetic variants with a low but increased risk for cancer is both a theoretical and a practical problem. All the above problems are now becoming clinical problems when we are moving from single-gene testing based on family history to implementing panel testing for germline genetic variants giving risk for cancer, and panel testing for de-novo somatic mutations in the tumors in incident cancer cases to select precision knowledge-based medicine to treat the patients with the new design-drugs counteracting the causative genes. This issue aims at update on these topics, present new knowledge, and discuss how to go forward to gain more knowledge instrumental to prevent, detect early and cure inherited cancers.

Prof. Dr. D. Gareth Evans
Dr. Pål Møller
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Inherited cancers
  • Genetic epidemiology
  • Pathogenic genetic variants
  • Prevention
  • Early Detection
  • Precision knowledge-based cancer treatment
  • BRCA1, MLH1, … (all genes described in the issue)

Published Papers (7 papers)

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Research

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16 pages, 1764 KiB  
Article
Spectrum and Frequency of Tumors, Cancer Risk and Survival in Chilean Families with Lynch Syndrome: Experience of the Implementation of a Registry
by Karin Álvarez, Paulina Orellana, Marjorie De la Fuente, Tamara Canales, Eliana Pinto, Claudio Heine, Benjamín Solar, Claudia Hurtado, Pål Møller, Udo Kronberg, Alejandro José Zarate, Mev Dominguez-Valentin and Francisco López-Köstner
J. Clin. Med. 2020, 9(6), 1861; https://doi.org/10.3390/jcm9061861 - 15 Jun 2020
Cited by 1 | Viewed by 2573
Abstract
Lynch syndrome (LS) is associated with the highest risk of colorectal (CRC) and several extracolonic cancers. In our effort to characterize LS families from Latin America, this study aimed to describe the spectrum of neoplasms and cancer risk by gender, age and gene, [...] Read more.
Lynch syndrome (LS) is associated with the highest risk of colorectal (CRC) and several extracolonic cancers. In our effort to characterize LS families from Latin America, this study aimed to describe the spectrum of neoplasms and cancer risk by gender, age and gene, and survival in 34 Chilean LS families. Of them, 59% harbored path_MLH1, 23% path_MSH2, 12% path_PMS2 and 6% path_EPCAM variants. A total of 866 individuals at risk were identified, of which 213 (24.6%) developed 308 neoplasms. In males, CRC was the most common cancer (72.6%), while females showed a greater frequency of extracolonic cancers (58.4%), including uterus and breast (p < 0.0001). The cumulative incidence of extracolonic cancers was higher in females than males (p = 0.001). Path_MLH1 variants are significantly more associated with the development of CRC than extracolonic tumors (59.5% vs. 40.5%) when compared to path_MSH2 (47.5% vs. 52.5%) variants (p = 0.05018). The cumulative incidence of CRC was higher in path_MLH1/path_MSH2 carriers compared to path_PMS2 carriers (p = 0.03). In addition, path_MSH2 carriers showed higher risk of extracolonic tumors (p = 0.002). In conclusion, this study provides a snapshot of the LS profile from Chile and the current LS-associated diagnostic practice and output in Chile. Categorizing cancer risks associated with each population is relevant in the genetic counselling of LS patients. Full article
(This article belongs to the Special Issue Genetic Epidemiology of Inherited Cancers)
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9 pages, 447 KiB  
Article
Feasibility of Gynaecologist Led Lynch Syndrome Testing in Women with Endometrial Cancer
by Neil A. J. Ryan, Louise Donnelly, Katie Stocking, D. Gareth Evans and Emma J. Crosbie
J. Clin. Med. 2020, 9(6), 1842; https://doi.org/10.3390/jcm9061842 - 12 Jun 2020
Cited by 10 | Viewed by 3324
Abstract
A barrier to Lynch syndrome testing is the need for prior genetic counselling, a resource demanding process for both patients and healthcare services. We explored the impact of gynaecologist led Lynch syndrome testing in women with endometrial cancer. Women were approached before surgery, [...] Read more.
A barrier to Lynch syndrome testing is the need for prior genetic counselling, a resource demanding process for both patients and healthcare services. We explored the impact of gynaecologist led Lynch syndrome testing in women with endometrial cancer. Women were approached before surgery, on the day of surgery or during routine follow up. Lynch syndrome testing was offered irrespective of age, family history or tumour characteristics. Women’s reasons for being tested were explored using the Motivations and Concerns for GeNEtic Testing (MACGNET) instrument. The short form State-Trait Anxiety Inventory (STAI-6) was used to measure anxiety levels. Only 3/305 women declined Lynch syndrome testing. In total, 175/220 completed MACGNET and STAI-6 psychological instruments. The consent process took an average of 7 min 36 s (SD 5 min 16 s) to complete. The point of care at which consent was taken (before, day of surgery, during follow up) did not influence motivation for Lynch syndrome testing. Anxiety levels were significantly lower when women were consented during follow up (mean reversed STAI-6 score 32 vs. 42, p = 0.001). Anxiety levels were not affected by familial cancer history (p = 0.41). Gynaecologist led Lynch syndrome testing is feasible and may even be desirable in endometrial cancer, especially when offered during routine follow up. Full article
(This article belongs to the Special Issue Genetic Epidemiology of Inherited Cancers)
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16 pages, 1514 KiB  
Article
Cost-Effectiveness of the Manchester Approach to Identifying Lynch Syndrome in Women with Endometrial Cancer
by Tristan M. Snowsill, Neil A. J. Ryan and Emma J. Crosbie
J. Clin. Med. 2020, 9(6), 1664; https://doi.org/10.3390/jcm9061664 - 1 Jun 2020
Cited by 18 | Viewed by 3778
Abstract
Lynch syndrome (LS) is a hereditary cancer syndrome responsible for 3% of all endometrial cancer and 5% in those aged under 70 years. It is unclear whether universal testing for LS in endometrial cancer patients would be cost-effective. The Manchester approach to identifying [...] Read more.
Lynch syndrome (LS) is a hereditary cancer syndrome responsible for 3% of all endometrial cancer and 5% in those aged under 70 years. It is unclear whether universal testing for LS in endometrial cancer patients would be cost-effective. The Manchester approach to identifying LS in endometrial cancer patients uses immunohistochemistry (IHC) to detect mismatch repair (MMR) deficiency, incorporates testing for MLH1 promoter hypermethylation, and incorporates genetic testing for pathogenic MMR variants. We aimed to assess the cost-effectiveness of the Manchester approach on the basis of primary research data from clinical practice in Manchester. The Proportion of Endometrial Tumours Associated with Lynch Syndrome (PETALS) study informed estimates of diagnostic performances for a number of different strategies. A recent microcosting study was adapted and was used to estimate diagnostic costs. A Markov model was used to predict long-term costs and health outcomes (measured in quality-adjusted life years, QALYs) for individuals and their relatives. Bootstrapping and probabilistic sensitivity analysis were used to estimate the uncertainty in cost-effectiveness. The Manchester approach dominated other reflex testing strategies when considering diagnostic costs and Lynch syndrome cases identified. When considering long-term costs and QALYs the Manchester approach was the optimal strategy, costing £5459 per QALY gained (compared to thresholds of £20,000 to £30,000 per QALY commonly used in the National Health Service (NHS)). Cost-effectiveness is not an argument for restricting testing to younger patients or those with a strong family history. Universal testing for Lynch syndrome in endometrial cancer patients is expected to be cost-effective in the U.K. (NHS), and the Manchester approach is expected to be the optimal testing strategy. Full article
(This article belongs to the Special Issue Genetic Epidemiology of Inherited Cancers)
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Review

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18 pages, 758 KiB  
Review
The Management of Peutz–Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline
by Anja Wagner, Stefan Aretz, Annika Auranen, Marco J. Bruno, Giulia M. Cavestro, Emma J. Crosbie, Anne Goverde, Anne Marie Jelsig, Andrew R. Latchford, Monique E. van Leerdam, Anna H. Lepisto, Marta Puzzono, Ingrid Winship, Veronica Zuber and Gabriela Möslein
J. Clin. Med. 2021, 10(3), 473; https://doi.org/10.3390/jcm10030473 - 27 Jan 2021
Cited by 69 | Viewed by 9327
Abstract
The scientific data to guide the management of Peutz–Jeghers syndrome (PJS) are sparse. The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline [...] Read more.
The scientific data to guide the management of Peutz–Jeghers syndrome (PJS) are sparse. The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients. Methods: Literature searches were performed using MEDLINE, Embase, and Cochrane. Evidence levels and recommendation strengths were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A Delphi process was followed, with consensus being reached when ≥80% of the voting guideline committee members agreed. Recommendations and statements: The only recent guidelines available were for gastrointestinal and pancreatic management. These were reviewed and endorsed after confirming that no more recent relevant papers had been published. Literature searches were performed for additional questions and yielded a variable number of relevant papers depending on the subject addressed. Additional recommendations and statements were formulated. Conclusions: A decade on, the evidence base for recommendations remains poor, and collaborative studies are required to provide better data about this rare condition. Within these restrictions, multisystem, clinical management recommendations for PJS have been formulated. Full article
(This article belongs to the Special Issue Genetic Epidemiology of Inherited Cancers)
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19 pages, 956 KiB  
Review
Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes
by Mariona Terradas, Gabriel Capellá and Laura Valle
J. Clin. Med. 2020, 9(6), 1954; https://doi.org/10.3390/jcm9061954 - 23 Jun 2020
Cited by 14 | Viewed by 4460
Abstract
In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in [...] Read more.
In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the involvement in the CRC predisposition of other genes, including MRE11, BARD1, POT1, BUB1B, POLE2, BRF1, IL12RB1, PTPN12, or the epigenetic alteration of PTPRJ. The contribution of the identified candidate genes to familial/early onset MMR-proficient nonpolyposis CRC, if any, is extremely small, suggesting that other factors, such as the accumulation of low risk CRC alleles, shared environmental exposures, and/or gene–environmental interactions, may explain the missing heritability in CRC. Full article
(This article belongs to the Special Issue Genetic Epidemiology of Inherited Cancers)
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21 pages, 1953 KiB  
Review
Implications of Hereditary Origin on the Immune Phenotype of Mismatch Repair-Deficient Cancers: Systematic Literature Review
by Lena Bohaumilitzky, Magnus von Knebel Doeberitz, Matthias Kloor and Aysel Ahadova
J. Clin. Med. 2020, 9(6), 1741; https://doi.org/10.3390/jcm9061741 - 4 Jun 2020
Cited by 24 | Viewed by 3227
Abstract
Microsatellite instability (MSI) represents one of the major types of genomic instability in human cancers and is most common in colorectal cancer (CRC) and endometrial cancer (EC). MSI develops as a consequence of DNA mismatch repair (MMR) deficiency, which can occur sporadically or [...] Read more.
Microsatellite instability (MSI) represents one of the major types of genomic instability in human cancers and is most common in colorectal cancer (CRC) and endometrial cancer (EC). MSI develops as a consequence of DNA mismatch repair (MMR) deficiency, which can occur sporadically or in the context of Lynch syndrome (LS), the most common inherited tumor syndrome. MMR deficiency triggers the accumulation of high numbers of somatic mutations in the affected cells, mostly indel mutations at microsatellite sequences. MSI tumors are among the most immunogenic human tumors and are often characterized by pronounced local immune responses. However, so far, little is known about immunological differences between sporadic and hereditary MSI tumors. Therefore, a systematic literature search was conducted to comprehensively collect data on the differences in local T cell infiltration and immune evasion mechanisms between sporadic and LS-associated MSI tumors. The vast majority of collected studies were focusing on CRC and EC. Generally, more pronounced T cell infiltration and a higher frequency of B2M mutations were reported for LS-associated compared to sporadic MSI tumors. In addition, phenotypic features associated with enhanced lymphocyte recruitment were reported to be specifically associated with hereditary MSI CRCs. The quantitative and qualitative differences clearly indicate a distinct biology of sporadic and hereditary MSI tumors. Clinically, these findings underline the need for differentiating sporadic and hereditary tumors in basic science studies and clinical trials, including trials evaluating immune checkpoint blockade therapy in MSI tumors. Full article
(This article belongs to the Special Issue Genetic Epidemiology of Inherited Cancers)
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Other

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8 pages, 253 KiB  
Brief Report
Risk-Reducing Gynecological Surgery in Lynch Syndrome: Results of an International Survey from the Prospective Lynch Syndrome Database
by Mev Dominguez-Valentin, Toni T. Seppälä, Christoph Engel, Stefan Aretz, Finlay Macrae, Ingrid Winship, Gabriel Capella, Huw Thomas, Eivind Hovig, Maartje Nielsen, Rolf H Sijmons, Lucio Bertario, Bernardo Bonanni, Maria Grazia Tibiletti, Giulia Martina Cavestro, Miriam Mints, Nathan Gluck, Lior Katz, Karl Heinimann, Carlos A. Vaccaro, Kate Green, Fiona Lalloo, James Hill, Wolff Schmiegel, Deepak Vangala, Claudia Perne, Hans-Georg Strauß, Johanna Tecklenburg, Elke Holinski-Feder, Verena Steinke-Lange, Jukka-Pekka Mecklin, John-Paul Plazzer, Marta Pineda, Matilde Navarro, Joan Brunet Vidal, Revital Kariv, Guy Rosner, Tamara Alejandra Piñero, María Laura Gonzalez, Pablo Kalfayan, Julian R. Sampson, Neil A. J. Ryan, D. Gareth Evans, Pål Møller and Emma J. Crosbieadd Show full author list remove Hide full author list
J. Clin. Med. 2020, 9(7), 2290; https://doi.org/10.3390/jcm9072290 - 18 Jul 2020
Cited by 12 | Viewed by 4378
Abstract
Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. [...] Read more.
Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT. Results: Risk-reducing hysterectomy and BSO are offered to path_MLH1 and path_MSH2 carriers in 20/21 (95%) contributing centers, to path_MSH6 carriers in 19/21 (91%) and to path_PMS2 carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (~90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35–55 years). Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of path_MLH1, path_MSH2 and path_MSH6 variants but less so for path_PMS2 carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research. Full article
(This article belongs to the Special Issue Genetic Epidemiology of Inherited Cancers)
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