Hereditary Cancer Susceptibility Syndromes Research Articles

Experiences and intentions of patients undergoing medically indicated oocyte or embryo cryopreservation: a qualitative study.

What structural (logistical) and psychological challenges do patients who cryopreserve oocytes or embryos for medical reasons face, including possible barriers to using their frozen materials? The majority of women who underwent oocyte or embryo cryopreservation for medical reasons reported a desire to use their frozen oocytes or embryos but had been impeded by ongoing medical issues, the need for a gestational carrier, or the lack of a partner. Current data suggest that many women who have frozen oocytes or embryos for medical indications are concerned about the prospect of infertility and have unique emotional and financial needs that differ from patients with infertility. Further, most patients have not returned to use their cryopreserved materials. This is a qualitative interview study of 42 people who cryopreserved between January 2012 and December 2021. Interviews were conducted between March 2021 and March 2022. All participants were cisgender women who had undergone oocyte or embryo cryopreservation for medical indications at an academic fertility center. Participants were invited to interview by email if they were younger than 40 years old when their oocytes or embryos were cryopreserved. Interviews were conducted over the internet and transcribed verbatim. Data were analyzed using thematic analysis with the constant comparison method. Saturation was reached at 42 interviews. The median age of participants was 35 years old (range 28-43) at interview and 31 years old (range 25-39) at cryopreservation. Of the 42 women, 30 had a cancer diagnosis, while 7 had non-cancer chronic medical conditions, and 5 had hereditary cancer susceptibility syndromes. There were 12 women who banked embryos and 30 who banked oocytes. The majority of women indicated a desire to use their cryopreserved materials, but many were unsure about how or when. Four had already used their frozen oocytes or embryos, while another four had conceived without assisted reproduction. The cryopreservation experience was described by the majority as highly emotionally challenging because they felt out of place among couples receiving infertility treatment and, for cancer patients, overwhelmed by the complex decisions to be made in a short time period. Common reported barriers to using frozen materials included ongoing medical issues preventing pregnancy, the need for a gestational carrier, the lack of a partner, and the desire for unassisted conception. Some were glad to have frozen oocytes or embryos to allow more time to meet a partner or if they were considering becoming single parents. The majority of participants had their oocytes or embryos frozen at a single, urban, academic fertility center, which may limit generalizability. We also could not calculate a response rate because the snowball technique was used to identify additional participants, so did not know the total number of people invited to participate. Like other interview studies, our study may be subject to response bias because those who agreed to participate may have particularly positive or negative views about their experiences. Furthermore, the mean follow-up time since freezing was relatively short (3.3 years, median 2.7 years), which may not have been enough time for some patients to use their frozen materials. Learning about the experiences of patients undergoing medically indicated oocyte and embryo cryopreservation can help clinicians better counsel these patients regarding decisions and hurdles they may encounter. We found that most patients had not returned to use their frozen materials because of ongoing medical issues, the need for a gestational carrier, lack of a partner, or the desire to attempt unassisted reproduction. This study did not receive any funding. The authors of this study have no conflicts of interest to declare. N/A.

Cancer genetics and breast cancer.

The risk of developing breast cancer is multifactorial and, at times, modifiable. However, the risk imposed by family history and hereditary pathogenic variants in a person's genetic code is, at present, an important fixed variable. Therefore, it is imperative to identify patients at risk for hereditary breast cancer and to understand the current evidence-based approach to the management of that risk. This chapter focuses on how genes play a role in breast cancer risk, why certain genes are commonly involved in hereditary breast cancer, and what are the specific genes and genetic syndromes that put patients at risk for breast cancer. Hereditary cancer susceptibility syndromes, including Hereditary Breast and Ovarian Cancer Syndrome (HBOC - BRCA1/2), Cowden Syndrome (CS - PTEN), Li-Fraumeni Syndrome (LFS - TP53), Peutz-Jegher Syndrome (PJS - STK11), Neurofibromatosis Type 1 (NF1), and Diffuse Hereditary Gastric Cancer Syndrome (CDH1) will be discussed along with individual genes not associated with a particular syndrome (ATM, BARD1, CHEK2, and PALB2).

Implications of ACMG guidelines to identify high-risk acute lymphoblastic leukemia patients with hereditary cancer susceptibility syndromes (HCSS) in a highly consanguineous population

BackgroundHereditary cancer susceptibility syndrome (HCSS) contributes to the cancer predisposition at an early age, therefore, identification of HCSS has found to be crucial for surveillance, managing therapeutic interventions and refer the patients and their families for genetic counselling. The study aimed to identify ALL patients who meet the American College of Medical Genetics (ACMG) criteria and refer them for the genetic testing for HCSS as hereditary leukemia and hematologic malignancy syndrome, and to elucidate the significance of high consanguinity with the prevalence of inherited leukemia in Pakistani population.MethodsA total of 300 acute lymphoblastic leukemia patients were recruited from the Children’s Hospital, Lahore, Pakistan from December 2018 to September 2019. A structured self-reporting questionnaire based on family and medical history of the disease was utilized for the data collection.ResultsIn our cohort, 60.40% of ALL patients were identified to meet ACMG criteria. Among them, a large number of patients (40.65%) solely fulfil the criteria due to the presence of parental consanguinity. However, parental consanguinity showed protective impact on the onset at early age of disease [OD = 0.44 (0.25–0.77), p-value = 0.00] while, a family history of cancer increased the risk of cardiotoxicity [OD = 2.46 (1.15–5.24), p-value = 0.02]. Parental consanguinity shows no significant impact on the family history of cancer and the number of relatives with cancer.ConclusionsMore than 50% of the ALL patients were considered the strong candidates’ for genetic testing of HCSS in the Pakistani population, and parental consanguinity was the leading criteria fulfilled by the individuals when assessed through ACMG guidelines. Our study suggests revisiting ACMG guidelines, especially for the criterion of parental consanguinity, and formulating the score based criteria based on; genetic research, the toxicology profile, physical features, personal and family history of cancer for the identification of patients for the genetic testing.

Transfer of embryos with positive results following preimplantation genetic testing for monogenic disorders (PGT-M): experience of two high-volume fertility clinics

To assess the experiences of two large fertility clinics in which embryos with positive results following preimplantation genetic testing for monogenic disorders (PGT-M) were transferred upon patient request, in order to explore the nature of the conditions for which these requests have been made and review ethical considerations. Retrospective review of previous embryo transfers at the NYU Langone Fertility Center and ORM Fertility was performed. Embryo transfers prior to May 2019 in which embryo biopsy and PGT-M occurred were reviewed, and transferred embryos that were positive for a monogenic disorder (excluding autosomal recessive carriers) were identified. Seventeen patients were identified who elected to transfer 23 embryos that tested positive for nine different monogenic disorders. Most of the embryos transferred were positive for disorders that are autosomal dominant (15/23), are adult-onset (14/23), are associated with reduced penetrance (16/23), and have available management to lessen symptom severity (22/23). Transfer of positive embryos most commonly occurred for hereditary cancer susceptibility syndromes (9/23 embryos), particularly hereditary breast and ovarian cancer syndrome. When unaffected embryos are not produced following in vitro fertilization with PGT-M, some patients request to transfer embryos with positive test results. The majority of transfers were for embryos positive for adult-onset, reduced penetrance diseases. As these requests will likely increase over time, it is essential to consider the practical and ethical implications.

Prevalence of hereditary cancer susceptibility syndromes in children with cancer in a highly consanguineous population

Background & aimHereditary cancer susceptibility syndromes (HCSS) are reported in up to one-third of children with cancer. Diagnosis of HCSS is crucial for implementation of surveillance protocols. We identified children who fulfilled criteria for HCSS in Saudi Arabia using the American College of Medical Genetics and Genomics (ACMG) guidelines, addressing the utility of these guidelines in a highly consanguineous population. MethodsThis multi-center cross-sectional study recruited 1858 children with cancer between January 2011 and December 2014. HCSS criteria were based on the ACMG guidelines. ResultsSeven hundred and four (40.4%) out of 1742 eligible patients fulfilled criteria for HCSS. Consanguinity was reported in 629 (38%) patients, with 50 (2.9%) first-degree, 535 (30.7%) second-degree, and 272 (15.6%) third-degree relatives affected with cancer. Two hundred and eighty eight (17.4%) leukemia and 87 (5.3%) brain tumour patients fulfilled HCSS criteria, with parental consanguinity being the most frequent criterion in both (leukemia 85.4%, brain tumors 83.9%). However, leukemia was less frequent in patients of consanguineous parents (p = 0.023). ConclusionFour out of 10 children with cancer fulfilled criteria for HCSS, most often due to consanguinity. This higher than expected prevalence suggests the need to validate consanguinity as a criterion for HCSS in highly consanguineous populations.

Blocking protein quality control to counter hereditary cancers.

Inhibitors of molecular chaperones and the ubiquitin-proteasome system have already been clinically implemented to counter certain cancers, including multiple myeloma and mantle cell lymphoma. The efficacy of this treatment relies on genomic alterations in cancer cells causing a proteostatic imbalance, which makes them more dependent on protein quality control (PQC) mechanisms than normal cells. Accordingly, blocking PQC, e.g. by proteasome inhibitors, may cause a lethal proteotoxic crisis in cancer cells, while leaving normal cells unaffected. Evidence, however, suggests that the PQC system operates by following a better-safe-than-sorry principle and is thus prone to target proteins that are only slightly structurally perturbed, but still functional. Accordingly, implementing PQC inhibitors may also, through an entirely different mechanism, hold potential for other cancers. Several inherited cancer susceptibility syndromes, such as Lynch syndrome and von Hippel-Lindau disease, are caused by missense mutations in tumor suppressor genes, and in some cases, the resulting amino acid substitutions in the encoded proteins cause the cellular PQC system to target them for degradation, although they may still retain function. As a consequence of this over-meticulous PQC mechanism, the cell may end up with an insufficient amount of the abnormal, but functional, protein, which in turn leads to a loss-of-function phenotype and manifestation of the disease. Increasing the amounts of such proteins by stabilizing with chemical chaperones, or by targeting molecular chaperones or the ubiquitin-proteasome system, may thus avert or delay the disease onset. Here, we review the potential of targeting the PQC system in hereditary cancer susceptibility syndromes.

Significance of defining a pathogenic variant in hereditary cancer syndrome

<p>With the advances in cancer genetics, over 200 hereditary cancer susceptibility syndromes have been described. About 5%–10% of all cancers are caused by hereditary mutations. The most common syndromes are those associated with breast, ovarian and gastrointestinal cancers. The hereditary pattern of stomach and endometrial cancer was first reported by Warthin in 1931. In 1966, Lynch and colleagues reported studies of two extended pedigrees with a similar hereditary pattern of multiple carcinomas and this was designated a cancer family syndrome. This condition was subsequently called hereditary nonpolyposis colorectal cancer (HNPCC). However, the term “Lynch syndrome” has been commonly used to describe this condition since 1984.</p>

Prevalence of hereditary cancer susceptibility syndromes in children: A report from the Saudi Arabian Pediatric Hematology Oncology Society.

e13086Background: Hereditary cancer susceptibility syndromes (HCSS) contribute to the cause of up to 29% of childhood cancer. The Saudi population has high rate of consanguineous marriages and this...

Functional in silico analysis of missense mutations in the MSH6 gene

Missense mutations of mismatch repair (MMR) genes – MLH1, MSH2, MSH6 and PMS2 – may (but do not necessarily) play a role in the etiology of the Lynch syndrome (LS) which is one of the hereditary cancer susceptibility syndromes. Pathogenic mutations in one of those genes result in a higher risk of developing cancer in colon, endometrium, small intestine, ovary, urinary tract, stomach or breast. One in ten patients with LS have a germline mutation in MSH6, and 40% of all mutations in that gene are single amino acid substitutions. One of the elements taking part in the MMR process is the MSH6 protein which, along with MSH2, is a component of a protein dimer – MutSα. MMR function is critical in maintaining cellular DNA integrity. Loss of that function results in increased number of uncorrected mutations which may lead to malignant tissue transformation. This is why it is crucial to determine whether the detected change is located in a DNA sequence coding the MMR protein and if it impairs the repair function. Alas, the consequences of single amino acid substitution are often harder to evaluate than outcomes of deletions, insertions or nonsense mutations. Moreover, performing a functional and molecular analysis for each detected alteration would be too expensive and unrealistic. This is where the use of prediction software would be of assistance. The intent of this thesis was to determine the pathogenic significance of a set of missense mutations using selected in silico analysis tools and to evaluate their utility in everyday use. Twenty-one MSH6 missense mutations were analyzed, three of them already classified as non-pathogenic polymorphisms, and two had confirmed pathogenic status. They were used accordingly as negative and positive controls. Three online programs were used for the analysis of those mutations, which allowed to evaluate each substitution from a different angle. SIFT utilizes alignment of homologous sequences from variety of organisms to determine the conservation of the substitution site and thereby estimates the potential pathogenicity of a mutation. PolyPhen-2 prediction is based on the sequence, protein structure and position of each mutation. The last of the used programs was ESEfinder which tested the impact of a mutation on the presence of ESEs (Exonic Splicing Enhancers) in the examined sequence. After performing the in silico analysis and confronting the results with data available in literature and the Internet databases, it was established that next to one of the changes confirmed as non-pathogenic polymorphisms, there are probably eight further non-pathogenic ones. Likewise, beside the two confirmed pathogenic alterations, in the analyzed set there were probably five additional pathogenic mutations. The last group is formed by substitutions that remain uncertain because of their ambiguous results. Following the analysis of the results and available data, a conclusion was reached that the sole use of in silico prediction is not sufficient for a complete classification of the mutations, but they may be helpful for decision making in choosing or prioritizing the variants worth further analysis.

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.

The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each practice guideline focuses on a clinical or practice-based issue and is the result of a review and analysis of current professional literature believed to be reliable. As such, information and recommendations within the ACMG and NSGC joint practice guidelines reflect the current scientific and clinical knowledge at the time of publication, are current only as of their publication date, and are subject to change without notice as advances emerge. In addition, variations in practice, which take into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant approaches, treatments, and/or procedures that differ from the recommendations outlined in this guideline. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. Genetic counseling practice guidelines are never intended to displace a health-care provider's best medical judgment based on the clinical circumstances of a particular patient or patient population. Practice guidelines are published by the ACMG or the NSGC for educational and informational purposes only, and neither the ACMG nor the NSGC "approve" or "endorse" any specific methods, practices, or sources of information.Cancer genetic consultation is an important aspect of the care of individuals at increased risk of a hereditary cancer syndrome. Yet several patient, clinician, and system-level barriers hinder identification of individuals appropriate for cancer genetics referral. Thus, the purpose of this practice guideline is to present a single set of comprehensive personal and family history criteria to facilitate identification and maximize appropriate referral of at-risk individuals for cancer genetic consultation. To develop this guideline, a literature search for hereditary cancer susceptibility syndromes was conducted using PubMed. In addition, GeneReviews and the National Comprehensive Cancer Network guidelines were reviewed when applicable. When conflicting guidelines were identified, the evidence was ranked as follows: position papers from national and professional organizations ranked highest, followed by consortium guidelines, and then peer-reviewed publications from single institutions. The criteria for cancer genetic consultation referral are provided in two formats: (i) tables that list the tumor type along with the criteria that, if met, would warrant a referral for a cancer genetic consultation and (ii) an alphabetical list of the syndromes, including a brief summary of each and the rationale for the referral criteria that were selected. Consider referral for a cancer genetic consultation if your patient or any of their first-degree relatives meet any of these referral criteria.

Exploring psychological responses to genetic testing for Lynch Syndrome within the family context.

Genetic testing for hereditary cancer susceptibility syndromes is a family-centered process. Nonetheless, little research has explored how the family context affects psychological responses to genetic testing. We examine how personal test results and the test results of immediate and extended family members shape responses to genetic testing. Individuals at risk of carrying a mutation associated with an inherited cancer susceptibility syndrome (Lynch syndrome) received genetic testing. Six months after receiving their results, participants reported on cancer distress, cancer worry, and depressive symptoms. Among mutation carriers for Lynch syndrome, the higher the proportion of carriers in their immediate family, the less cancer worry and distress they reported. In contrast, mutation carriers and non-carriers with a high proportion of carriers in their immediate family and mutation carriers with a high proportion of carriers in their extended family were at elevated risk for clinically significant levels of depressive symptoms. Personal test results alone are not highly predictive of psychological outcomes. Instead, the interaction between personal and family test results, or in some cases, family test results alone, predict key psychological outcomes. The current research has important implications for genetic counseling and intervention efforts. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.

Approximately 5% to 10% of cancers are attributable to a hereditary cancer predisposition syndrome. Identifying those patients with cancer who have an inherited cancer predisposition syndrome has significant benefit both to the patient and to at-risk relatives. In addition, oncology patients' short- and long-term management can be personalized based on their genetic status. For example, in the short term, BRCA1/BRCA2-positive genetic test results can affect surgical decisions and may soon have an impact on systemic treatment options. In the long term, oncology patients' survivorship plans can be tailored to incorporate surveillance and prevention for their increased risk of second malignancies. Furthermore, the ability to perform predictive genetic testing on patients' family members results in a more precise risk assessment and initiation of appropriate screening and prevention strategies. Family history is key to the identification of those individuals who have an inherited predisposition to malignancy or who are at increased risk for additional primary cancers. The goals of any cancer family history should be to provide enough information to make a preliminary determination of the risk of a familial predisposition and to develop a preliminary management plan. A cancer family history taken at the first visit with the oncology provider can raise the suspicion of a hereditary cancer syndrome and prompt further investigation. After the initial visit, the ongoing relationship between the oncologist and the patient provides multiple opportunities for reassessment and updating of family history. This can prompt changes in recommended cancer screening. Additionally, the field of hereditary cancer predisposition is advancing rapidly. The long-term relationship between the oncologist and cancer survivor affords repeated opportunities for reassessment and recognition of newly defined cancer susceptibility genes and new opportunities for more advanced genetic testing that may apply to patients who have previously undergone genetic testing.1 Not only is hereditary risk assessment part of good oncology care, but there is also an increasing focus on the area of quality improvement with regard to the provision of genetic testing and counseling services. For example, the American College of Surgeons Commission on Cancer (CoC) grants accreditation only to facilities that are committed to excellence in cancer care and are able to comply with established CoC standards. The 2012 CoC program standards require that cancer risk assessment, genetic counseling, and testing services be provided to patients either on site or by referral by a qualified genetics professional. Furthermore, the American Society of Clinical Oncology (ASCO) Quality Oncology Practice Initiative (QOPI) includes measures regarding the collection and interpretation of cancer family histories and whether appropriate testing was ordered. ASCO has taken a lead in providing guidance and education regarding identification and management of individuals with inherited predisposition to malignancy. In 1996, ASCO published a policy statement on genetic testing for cancer susceptibility to foster expanded access to medical care for at-risk patients and their families, as well as to enhance continued advances in the quality of that care.2 This statement was updated in 2003 and again in 2010.3,4 Over the last two decades, ASCO has developed two editions of an educational syllabus (ASCO Curriculum: Cancer Genetics and Cancer Susceptibility Testing), has held numerous workshops and symposia, and has fostered a growing number of online education modules at ASCO University (http://university.asco.org/). Over the last several years, ASCO has assisted oncology professionals in responsibly integrating genetic testing into clinical oncology practice. A primary objective of this work has been to increase oncologists' core knowledge about hereditary cancer susceptibility syndromes, methods of cancer risk assessment and risk management, and risks and benefits of genetic testing. A challenge in developing guidance for practicing oncologists in this area is that there is no clear evidence base from which to define how a family history should be taken or what constitutes the right amount of information for an initial cancer screening family history. To address this need, the ASCO Cancer Genetics Subcommittee, under the auspices of the Cancer Prevention Committee, has developed this statement for oncology providers to Define a minimum cancer family history Provide guidance regarding interpretation and next steps Identify current barriers to accurate family history taking and interpretation To be clear, this consensus statement does not formulate specific guidelines for referral but seeks to provide clarification to the practicing oncology provider and other specialists on how and what to collect for a cancer family history and how to interpret the family history in the context of other information. To develop this statement, the Cancer Genetics Subcommittee convened a group of 15 experts in the areas of oncology, cancer genetics, and genetic counseling. A consensus conference was held in February 2012, and the deliberations from this meeting were used by the Cancer Genetics Subcommittee to generate this statement.

Indications et efficacité de la chirurgie prophylactique des cancers gynécologiques et digestifs avec prédisposition génétique

Preventive surgery is a mainstay of treatment for persons with genetic risk factors for cancer The indications of preventive surgery are based on a thorough risk assessment, clinical characteristics of the different hereditary cancer susceptibility syndromes, the types of mutation, and the possibility of watchful waiting for early cancer detection. Preventive surgery may either be recommended or represent one possible option. Bilateral prophylactic mastectomy can reduce the risk of breast cancer by up to 95% in BRCA1/BRCA2 mutation carriers. Bilateral prophylactic salpingo-oophorectomy is recommended for BRCA1/ BRCA2 carriers: women who undergo this preventive surgery have a reduced risk of ovarian cancer but also of breast cancer (around 50% for breast cancer). Patients with Lynch syndrome are at high risk of endometrial cancer, and prophylactic hysterectomy may be proposed to women for whom surgery is indicated for a uterine disorder (fibroma). Prophylactic surgery may be proposed to patients at risk of hereditary gastrointestinal malignancies, either on a case-by-case basis (Lynch syndrome) or more systematically for patients with the familial adenomatous polyposis syndrome or hereditary difuse gastric cancer Despite its efficacy, prophylactic surgery in a healthy individual, albeit at high risk of cancer, remains a difficult, multidisciplinary decision. Psychological support is needed to anticipate the possible physical psychological and social complications--and benefits.

BRCA1/2-Associated and Sporadic Breast Cancers: Fellow Travelers or Not?

How useful are hereditary cancer susceptibility syndromes for modeling sporadic cancers? If the biology of cancers developing within hereditary syndromes follows the same pathways to malignancy as does a substantial proportion of sporadic cancers, then prevention trials focused on hereditary high-

Genetics of Gastroesophageal Cancer: Paradigms, Paradoxes, and Prognostic Utility

Hereditary diffuse gastric cancer and tylosis are autosomal dominant cancer susceptibility syndromes. Accumulating evidence also suggests a genetic contribution to Barrett's esophagus and adenocarcinoma, traditionally considered acquired disorders. In this article we review the current knowledge on the genetic mechanisms underlying hereditary diffuse gastric cancer, tylosis, and Barrett's esophagus. Hereditary diffuse gastric cancer is a paradigm for hereditary cancer susceptibility syndromes with E-cadherin implicated as the dominant oncogene in up to one-third of cases. Tylosis in contrast remains the paradox as whilst the putative abnormality has been localized to the long arm of chromosome 17, sequencing of this region has failed to reveal a disease causing mutation. In the case of Barrett's esophagus and adenocarcinoma, although a validated specific disease-associated gene is yet to be identified, the increasing body of evidence of a possible genetic link is paving the way for subsequent prognostic studies such as AspECT (Aspirin Esomeprazole Chemoprevention Trial). For the clinician these advances in understanding are already having implications for practice in terms of improved screening and the stratification of management strategies. As the mechanisms continue to be defined, there is the real possibility that these mechanisms could be exploited or subverted in the design of new therapies. In the meantime, however, clinicians should undertake rigorous biopsy programs to ensure early invasive lesions are detected.

DNA repair pathways and hereditary cancer susceptibility syndromes

Every living organism is exposed to numerous genomic insults on a daily basis as a consequence of cellular metabolism and exposure to environmental agents capable of interacting with the genome (e.g. chemicals, toxins, pollutants, UV and ionizing radiation) (1). Maintenance of the integrity of the genome is paramount to the survival and propagation of a species and involves the continuous activity of a variety of DNA repair pathways. Inherited mutations in genes involved in DNA damage recognition and repair lead to disease by destabilization of the genome and increased mutagenesis. In fact, it is common for cancer cells to exhibit loss of genomic stability presumably as a result of clonally acquired mutations in DNA repair genes (2). Currently, roughly 150 DNA repair genes have been identified in humans (3) and a variety of familial cancer predisposition and/or premature aging syndromes are now linked to various loss-of-function mutations in these genes (4). Genetic interaction between DNA repair pathways and global cell differentiation pathways is supported by phenotypic similarities between inactivating mutations in a DNA repair, cell cycle arrest and apoptosis proteins. Though there is clearly some degree of functional redundancy between DNA repair pathways for correction of specific DNA lesions, the particular clinical characteristics of a repair defect can be predicted by the specific repair pathway affected (5). Patients with cancer predisposition syndromes often have multiple family members affected by cancer, develop cancer at an early age, and are at risk for developing multiple primary tumors over time (6, 7). Though patients with identifiable cancer predisposition syndromes are rare, defining their molecular defects has led to widespread applicability by uncovering relevant molecular pathways that are perturbed via somatic (non-inherited) mutations in the majority of sporadic cancers. In this review, we describe general molecular mechanisms of major forms of DNA repair and illustrate clinical consequences of deficiencies in these pathways. For more in depth detail, the reader is referred to several recent reviews and texts (2, 8-13).

New Insights in the Genetics of Adrenocortical Tumors, Pheochromocytomas and Paragangliomas

Recent advances in the molecular genetic of adrenal tumors give new insights in the pathophysiology of these neoplasms in both hereditary and sporadic cases. The practice of genetic counselling in patients with adrenal tumors have been recently changed by the identification and the understanding of new specific hereditary cancer susceptibility syndromes. In the case of sporadic adrenocortical tumors these progress also offer new prognosis predictors. The genetic predisposition to adrenocortical cancer in children has been well established in the Li-Fraumeni and Beckewith-Wiedeman syndromes due to germline p53 mutation located at 17p13 and dysregulation of the imprinted IGF-2 locus at 11p15, respectively. Adrenocortical tumors are also observed in Multiple Endocrine Neoplasia type I syndrome. Cushing's syndrome due to primary pigmented nodular adrenocortical disease have been observed in patients with germline PRKAR1A inactivating mutations. Interestingly allelic loss at 17p13 and 11p15 have been observed in sporadic adrenocortical cancer and somatic PRKAR1A mutations in secreting adrenocortical adenomas. The potential interest of these finding for the diagnosis of these tumors will be discussed. In the case of pheochromocytoma and paraganglioma, the demonstration that three genes encoding three succinate dehydrogenase subunits (SDHD, SDHB, SDHC), belonging to the complex II of the respiratory chain in the mitochondria, are involved in the genetics of familial and especially in apparently sporadic phaeochromocytomas have dramatically modified our practice. Up to date, four diagnosis of familal disease (multiple endocrine neoplasia type II, von Hippel Lindau disease, neurofibromatosis type 1 and hereditary paraganglioma) should be discussed and causative mutations in six different phaechomocytoma susceptibility genes (RET, VHL, NF1, SDHB, SDHD, SDHC) could be identified. In this review, we will perform an update compiling these new clinical, genetic and functional data recently published. We will suggest guidelines for the practice of the phaeochomocytoma genetic testing in the patients and their families, and for an early detection of tumors in the patients or in individuals determined to be at-risk of disease by the presymptomatic genetic testing.

Ten novel MSH2 and MLH1 germline mutations in families with HNPCC.

Hereditary nonpolyposis colorectal cancer (HNPCC) is one of the most common hereditary cancer-susceptibility syndromes. Germline mutations in mismatch repair genes are associated with the clinical phenotype of HNPCC. We report ten novel germline mutations, three in MSH2 and seven in MLH1. All but one mutation have been found in families fulfilling criteria of the Bethesda guidelines; four of them additionally fulfilled the Amsterdam criteria I or II. Eight mutations were considered pathogenic and predictive diagnostics in healthy family members at risk shall be undertaken; these include five frameshift mutations leading to premature stop codons, in MSH2: c.1672delT (p.S558Xfs) and c.2466_2467delTG (p.C822X) and in MLH1: c.1023delG (p.R341Xfs), c.1127_1128dupAT (p.K377Xfs) and c.1310delC (p.P437Xfs); three mutations leading to splice aberrations, in MSH2: c.1661G>C (r.1511_1661del) and in MLH1: c.677+3A>C (r.589_677del) and c.1990-2A>G predicted to result in a splice site defect. The remaining two mutations are unclassified variants with assumed pathogenicity: one missense mutation in the highly conserved ATPase domain of MLH1 (c.122A>G [p.D41G]) and one in-frame insertion of twelve nucleotides in MLH1 (c.2155_2156insATGTGTTCCACA [p.I719delinsNVFHI]). These two mutations were not found in 102 alleles of healthy control individuals. The corresponding tumors from all patients showed a high level of microsatellite instability (MSI-H). Immunohistochemistry (IHC) revealed complete loss of expression of the affected protein in the tumor cells from all but three patients. The tumors from the patients with the mutations c.1127_1128dupAT and c.1990-2A>G showed a reduction of expression of the MLH1-protein, rather than complete loss. In the tumor from the patient with the missense mutation c.122A>G [p.D41G] a normal expression of the proteins coded by MLH1 and MSH2 was noticed.

American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.

American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.

Homologous repair of DNA damage and tumorigenesis: the BRCA connection.

Homologous recombination has been recognized in recent years to be an important DNA repair pathway in mammalian cells, for such damage as chromosomal double-strand breaks. Cells mutated for the genes involved in the hereditary breast and ovarian cancer susceptibility syndromes, i.e. BRCA1 and BRCA2, show defects in DNA repair by homologous recombination, implicating this repair pathway in protecting individuals against tumorigenesis. This review summarizes recent advances in our understanding of BRCA1 and BRCA2 in DNA repair, as well as insight into these proteins gleaned from structure determination of domains of these proteins and the broader evolutionary conservation than previously appreciated.