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19 pages, 3080 KiB

Open AccessArticle

A Previously Unrecognized Molecular Landscape of Lynch Syndrome in the Mexican Population

by Alejandra Padua-Bracho, José A. Velázquez-Aragón, Verónica Fragoso-Ontiveros, Paulina María Nuñez-Martínez, María de la Luz Mejía Aguayo, Yuliana Sánchez-Contreras, Miguel Angel Ramirez-Otero, Marcela Angélica De la Fuente-Hernández, Silvia Vidal-Millán, Talia Wegman-Ostrosky, Abraham Pedroza-Torres, Cristian Arriaga-Canon, Luis A. Herrera-Montalvo and Rosa Maria Alvarez-Gómez

Int. J. Mol. Sci. 2022, 23(19), 11549; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911549 - 30 Sep 2022

Cited by 1 | Viewed by 1823

Abstract

Lynch syndrome (LS) is the main hereditary colorectal cancer syndrome. There have been few reports regarding the clinical and molecular characteristics of LS patients in Latin America; this is particularly true in the Mexican population, where no information is available. The present study [...] Read more.

Lynch syndrome (LS) is the main hereditary colorectal cancer syndrome. There have been few reports regarding the clinical and molecular characteristics of LS patients in Latin America; this is particularly true in the Mexican population, where no information is available. The present study aims to describe the clinical and molecular spectrum of variants in a cohort of patients diagnosed with LS in Mexico. We present a retrospective analysis of 412 patients with suspected LS, whose main site of cancer diagnosis was the colon (58.25%), followed by the endometrium (18.93%). Next-generation sequencing analysis, with an extensive multigene panel, showed that 27.1% (112/414) had a variant in one of the genes of the mismatch repair pathway (MMR); 30.4% (126/414) had a variant in non-MMR genes such as CHEK2, APC, MUTYH, BRCA1, and BRCA2; and 42.5% (176/414) had no genetic variants. Most of the variants were found in MLH1. Pathogenic variants (PVs) in MMR genes were identified in 65.7% (96/146) of the total PVs, and 34.24% (45/146) were in non-MMR genes. Molecular and clinical characterization of patients with LS in specific populations allowed personalized follow-up, with the option for targeted treatment with immune checkpoint inhibitors and the development of public health policies. Moreover, such characterization allows for family cascade testing and consequent prevention strategies. Full article

(This article belongs to the Special Issue Molecular Biology of Hereditary Tumors)

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Review

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14 pages, 9379 KiB

Open AccessReview

Moderate-Risk Genes for Hereditary Ovarian Cancers Involved in the Homologous Recombination Repair Pathway

by Akiko Abe, Issei Imoto, Arisa Ueki, Hidetaka Nomura and Hiroyuki Kanao

Int. J. Mol. Sci. 2022, 23(19), 11790; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911790 - 04 Oct 2022

Cited by 2 | Viewed by 1722

Abstract

Approximately 20% of cases of epithelial ovarian cancer (EOC) are hereditary, sharing many causative genes with breast cancer. The lower frequency of EOC compared to breast cancer makes it challenging to estimate absolute or relative risk and verify the efficacy of risk-reducing surgery [...] Read more.

Approximately 20% of cases of epithelial ovarian cancer (EOC) are hereditary, sharing many causative genes with breast cancer. The lower frequency of EOC compared to breast cancer makes it challenging to estimate absolute or relative risk and verify the efficacy of risk-reducing surgery in individuals harboring germline pathogenic variants (GPV) in EOC predisposition genes, particularly those with relatively low penetrance. Here, we review the molecular features and hereditary tumor risk associated with several moderate-penetrance genes in EOC that are involved in the homologous recombination repair pathway, i.e., ATM, BRIP1, NBN, PALB2, and RAD51C/D. Understanding the molecular mechanisms underlying the expression and function of these genes may elucidate trends in the development and progression of hereditary tumors, including EOC. A fundamental understanding of the genes driving EOC can help us accurately estimate the genetic risk of developing EOC and select appropriate prevention and treatment strategies for hereditary EOC. Therefore, we summarize the functions of the candidate predisposition genes for EOC and discuss the clinical management of individuals carrying GPV in these genes. Full article

(This article belongs to the Special Issue Molecular Biology of Hereditary Tumors)

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27 pages, 3195 KiB

Open AccessReview

Functions of Breast Cancer Predisposition Genes: Implications for Clinical Management

by Akiyo Yoshimura, Issei Imoto and Hiroji Iwata

Int. J. Mol. Sci. 2022, 23(13), 7481; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137481 - 05 Jul 2022

Cited by 12 | Viewed by 3526

Abstract

Approximately 5–10% of all breast cancer (BC) cases are caused by germline pathogenic variants (GPVs) in various cancer predisposition genes (CPGs). The most common contributors to hereditary BC are BRCA1 and BRCA2, which are associated with hereditary breast and ovarian cancer (HBOC). [...] Read more.

Approximately 5–10% of all breast cancer (BC) cases are caused by germline pathogenic variants (GPVs) in various cancer predisposition genes (CPGs). The most common contributors to hereditary BC are BRCA1 and BRCA2, which are associated with hereditary breast and ovarian cancer (HBOC). ATM, BARD1, CHEK2, PALB2, RAD51C, and RAD51D have also been recognized as CPGs with a high to moderate risk of BC. Primary and secondary cancer prevention strategies have been established for HBOC patients; however, optimal preventive strategies for most hereditary BCs have not yet been established. Most BC-associated CPGs participate in DNA damage repair pathways and cell cycle checkpoint mechanisms, and function jointly in such cascades; therefore, a fundamental understanding of the disease drivers in such cascades can facilitate the accurate estimation of the genetic risk of developing BC and the selection of appropriate preventive and therapeutic strategies to manage hereditary BCs. Herein, we review the functions of key BC-associated CPGs and strategies for the clinical management in individuals harboring the GPVs of such genes. Full article

(This article belongs to the Special Issue Molecular Biology of Hereditary Tumors)

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17 pages, 482 KiB

Open AccessReview

Rare Hereditary Gynecological Cancer Syndromes

by Takafumi Watanabe, Shu Soeda, Yuta Endo, Chikako Okabe, Tetsu Sato, Norihito Kamo, Makiko Ueda, Manabu Kojima, Shigenori Furukawa, Hidekazu Nishigori, Toshifumi Takahashi and Keiya Fujimori

Int. J. Mol. Sci. 2022, 23(3), 1563; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031563 - 29 Jan 2022

Cited by 4 | Viewed by 4567

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Molecular Biology of Hereditary Tumors)

17 pages, 902 KiB

Open AccessReview

Genetics of Pheochromocytomas and Paragangliomas Determine the Therapeutical Approach

by Balazs Sarkadi, Eva Saskoi, Henriett Butz and Attila Patocs

Int. J. Mol. Sci. 2022, 23(3), 1450; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031450 - 27 Jan 2022

Cited by 14 | Viewed by 4889

Abstract

Pheochromocytomas and paragangliomas are the most heritable endocrine tumors. In addition to the inherited mutation other driver mutations have also been identified in tumor tissues. All these genetic alterations are clustered in distinct groups which determine the pathomechanisms. Most of these tumors are [...] Read more.

Pheochromocytomas and paragangliomas are the most heritable endocrine tumors. In addition to the inherited mutation other driver mutations have also been identified in tumor tissues. All these genetic alterations are clustered in distinct groups which determine the pathomechanisms. Most of these tumors are benign and their surgical removal will resolve patient management. However, 5–15% of them are malignant and therapeutical possibilities for them are limited. This review provides a brief insight about the tumorigenesis associated with pheochromocytomas/paragangliomas in order to present them as potential therapeutical targets. Full article

(This article belongs to the Special Issue Molecular Biology of Hereditary Tumors)

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19 pages, 361 KiB

Open AccessReview

Molecular Features and Clinical Management of Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer

by Akiyoshi Kasuga, Takeshi Okamoto, Shohei Udagawa, Chinatsu Mori, Takafumi Mie, Takaaki Furukawa, Yuto Yamada, Tsuyoshi Takeda, Masato Matsuyama, Takashi Sasaki, Masato Ozaka, Arisa Ueki and Naoki Sasahira

Int. J. Mol. Sci. 2022, 23(3), 1205; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031205 - 21 Jan 2022

Cited by 12 | Viewed by 3922

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Molecular Biology of Hereditary Tumors)

17 pages, 2483 KiB

Open AccessReview

ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors

by Sayaka Ueno, Tamotsu Sudo and Akira Hirasawa

Int. J. Mol. Sci. 2022, 23(1), 523; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010523 - 04 Jan 2022

Cited by 19 | Viewed by 3676

Abstract

Ataxia–telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over [...] Read more.

Ataxia–telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients. Full article

(This article belongs to the Special Issue Molecular Biology of Hereditary Tumors)

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18 pages, 964 KiB

Open AccessReview

Homologous Recombination Deficiencies and Hereditary Tumors

by Hideki Yamamoto and Akira Hirasawa

Int. J. Mol. Sci. 2022, 23(1), 348; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010348 - 29 Dec 2021

Cited by 26 | Viewed by 4679

Abstract

Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, [...] Read more.

Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. The penetrance of germline pathogenic variants of each gene varies, whereas all their associated protein products are indispensable for maintaining a high-fidelity DNA repair system by HR. The present review summarizes the basic molecular mechanisms and components that collectively play a role in maintaining genomic integrity against DNA double-strand damage and their clinical implications on each type of hereditary tumor. Full article

(This article belongs to the Special Issue Molecular Biology of Hereditary Tumors)

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