Is there a link between ovarian cancer and tooth agenesis?

An epidemiologic study from the year 2008 found a highly significant increase of congenital tooth agenesis in women with ovarian cancer suggesting that a common genetic etiology may predispose women to both conditions. The finding was reminiscent of a previously described family harboring an AXIN2 mutation which could be shown to segregate with both the tooth agenesis and the predisposition to colon cancer transmitted in this family. Since tooth agenesis as a marker for susceptibility to ovarian cancer would be of great relevance to both oncologists and women with inborn missing teeth, the relationship between the two disorders requires a thorough assessment. We examined DNA samples from the ovarian cancer patients who participated in the original study, to look for a possible genetic connection between their ovarian malignancies and tooth agenesis. MSX1, PAX9, AXIN2, EDA, WNT10A, BARX and BRCA1 genes were selected for sequence analysis as they may cause tooth agenesis, are expressed in the female reproductive system, and/or are involved in tumorigenesis in general or specifically in the ovary.Our study revealed evidence that one half of the dually affected patients had an independent causation of the two conditions, thus reducing the previously estimated ovarian cancer risk for women with congenital tooth agenesis quite significantly.     

Are videoconferenced consultations as effective as face-to-face consultations for hereditary breast and ovarian cancer genetic counseling?

PurposeVideoconferencing is increasingly used to deliver family cancer services for hereditary breast and ovarian cancer to outreach areas. This study compared the effectiveness and acceptability of genetic counseling for hereditary breast and ovarian cancer through videoconferencing (hereafter referred to as “telegenetics”).MethodsOne hundred six women seen by telegenetics and 89 women seen face-to-face completed self-administered questionnaires before, and 1 month after, genetic counseling. Telegenetics consultations involved a genetic clinician via telegenetics in addition to a local genetic counselor present with the patient.ResultsNo significant differences were found between telegenetics and face-to-face genetic counseling in terms of knowledge gained (P = 0.55), satisfaction with the genetic counseling service (P = 0.76), cancer-specific anxiety (P = 0.13), generalized anxiety (P = 0.42), depression (P = 0.96), perceived empathy of the genetic clinician (P = 0.13), and perceived empathy of the genetic counselor (P = 0.12). Telegenetics performed significantly better than face-to-face counseling in meeting patients' expectations (P = 0.009) and promoting perceived personal control (P = 0.031).ConclusionTelegenetics seems to be an acceptable and effective method of delivering genetic counseling services for hereditary breast and ovarian cancer to underserved areas.     

Ask Rosa – The making of a digital genetic conversation tool,a chatbot,about hereditary breast and ovarian cancer

ObjectiveWe aimed at developing a pilot version of an app (Rosa) that can perform digital conversations with breast or ovarian cancer patients about genetic BRCA testing, using chatbot technology, to identify best practices for future patient-focused chatbots.MethodsWe chose a commercial chatbot platform and participatory methodology with a team of patient representatives, IT engineers, genetic counselors and clinical geneticists, within a nationwide collaboration. An iterative approach ensured extensive user and formal usability testing during the development process.ResultsThe development phase lasted for two years until the pilot version was completed in December 2019. The iteration steps disclosed major challenges in the artificial intelligence (AI)-based matching of user provided questions with predefined information in the database, leading initially to high level of fallback answers. We therefore developed strategies to reduce potential language ambiguities (e.g. BRCA1 vs BRCA2) and overcome dialogue confusion. The first prototype contained a database with 500 predefined questions and 67 corresponding predefined answers, while the final version included 2257 predefined questions and 144 predefined answers. Despite the limited AI functionality of the chatbot, the testing revealed that the users liked the layout and found the chatbot trustworthy and reader friendly.ConclusionsBuilding a health chatbot is challenging, expensive and time consuming with today’s technology. The users had a positive attitude to the chatbot, and would use it in a real life setting, if given to them by health care personnel.Practice implicationsWe here present a framework for future health chatbot initiatives. The participatory methodology in combination with an iterative approach ensured that the patient perspective was incorporated at every level of the development process. We strongly recommend this approach in patient-centered health innovations.     

Is postpartum depression a distinct diagnosis?

Controversy exists about the relationship between postpartum and nonpostpartum depression in both research and practice. While some researchers argue that these diagnoses cannot be differentiated, others insist that postpartum depression is distinct. The construct validity of the diagnosis “postpartum depression” is evaluated by critically reviewing the empirical evidence regarding prevalence, symptomatology, course, duration, relapse, and etiology. The literature suggests that women are at elevated risk for depression in the postpartum period. However, postpartum depressive episodes tend to be mild and to resolve quickly, which suggests that postpartum depression is best conceptualized as an adjustment disorder. Etiologically, postpartum depression is related to the same variables that predict nonpostpartum depression. These findings suggest that postpartum depression does not differ qualitatively from nonpostpartum depression. The implications of this conclusion for research and treatment are considered.     

Marker segregation information in breast/ovarian cancer genetic counseling: Is it still useful?

The use of mutation screening of BRCA1 and BRCA2 genes as a genetic test is still to a certain extent limited and the oncogeneticist may want to use complementary approaches to identify at-risk individuals. In a series of 23 families with at least three breast or ovarian cancer cases, screened for mutations at BRCA1 and BRCA2 and typed for markers at both loci, we investigated the usefulness of marker segregation information at two levels: 1) to what extent can the indirect approach identify the mutation carrier status of screened cases and their first-degree relatives, and 2) in what way does it help to identify the gene implicated in a family in which neither BRCA1 nor BRCA2 mutation has been detected? Using the indirect approach, the carrier status of the screened case could be determined with quasi certainty in three families and with a high probability in eight families. This status could be inferred in unaffected first-degree relatives as almost certain in one family and as highly probable in six families. Fourteen mutations were found concurrently in our series. Among the nine mutation-negative families, we were able to conclude that a BRCA1 mutation most probably segregated in one and that a mutation other than BRCA1 and BRCA2 was probably involved in two families. Our results show that, in small families, little help is to be expected from linkage data and mutation screening is the only way of identifying the origin of a genetic predisposition in a family. Marker segregation information may be useful in some large breast/ovarian cancer families in which no BRCA1 or BRCA2 mutation has been detected. Am. J. Med. Genet. 79: 175–183, 1998. © 1998 Wiley-Liss, Inc.     

Is cancer a transmittable disease?

A direct, horizontal and natural transmission of neoplasic cells has only recently been accepted by the biomedical community. There are three known examples in mammals: the Tasmanian Devil Tumor Disease, the Canine Transmissible Venereal Tumor and a similar disease in Sirian Hamsters. These diseases are not anecdotic cases only, but provide support for the cancer clonal evolution hypothesis.     

Is Chlamydia-infected tubal fimbria the origin of ovarian cancer?

Ovarian cancer is a highly lethal disease and its underlying biology is poorly understood. Prophylactic salpingo-oophorectomies in BRCA + women have recently implicated the fimbria as a site of origin for high-grade serous carcinoma and its intraepithelial precursors. This suggests that at least some ovarian cancers, probably the most aggressive ones, may not originate in the ovary itself, but rather may arise in the uterine tubes. Chronic inflammation is associated with carcinogenesis in several tissues, including liver, esophagogastric junction (cardia), and the uterine cervix. The mechanisms underlying the relationship between inflammation and cancer are complex and involve common pathways, in addition to DNA damage. A critical source of uterine tube inflammation is infection with Chlamydia trachomatis. We hypothesize that C.trachomatis infection may be involved in chronic tubal inflammation and subsequent fimbrial carcinogenesis. Fimbrial intraepithelial precursors can evolve into high grade serous carcinomas that spread rapidly to the ovarian surface and peritoneum; such tumors may appear to be primary ovarian neoplasia, though in reality being a secondary malignancy. This hypothesis must be further investigated to understand the intracellular signaling pathways involved in Chlamydia infection and its healing, and their relationship to carcinogenesis in order to discover potential therapeutic molecular targets. If our hypothesis were confirmed, salpingectomy instead of ovariectomy may also become the recommended surgery for high risk women.     

Assessing relatives’ readiness for hereditary cancer cascade genetic testing

PurposeTo explore the readiness of living, untested first-degree relatives (FDRs) to have cascade genetic testing (CGT) for a hereditary predisposition to cancer.MethodsAdults with a hereditary predisposition to cancer completed an anonymous, online survey about their genetic testing and their FDRs’ vital status, awareness of the variant, uptake of CGT, and readiness for CGT among living, untested FDRs using transtheoretical model stages of change.ResultsOne hundred fifty participants completed the survey and reported 825 FDRs. Overall, 70.3% of FDRs were reportedly aware of the variant and 30.5% had completed CGT. Siblings had higher rates of awareness and CGT than parents or children (p < 0.001). Relatives’ sex was associated with awareness and CGT; mothers were aware and had CGT at higher rates than fathers (p = 0.049 and p < 0.001), sisters were aware and had CGT at higher rates than brothers (p = 0.041 and p = 0.002), and daughters had higher rates of awareness than sons (p = 0.038). Of 340 living, untested FDRs, 79.4% were in the precontemplation stage of change, with no difference by relatives’ sex or relationship to the participant.ConclusionsMost living, untested FDRs were in precontemplation stage, indicating they are not ready or planning to have CGT within the next six months.     

Autosomal dominant optic atrophy with unilateral facial palsy: a new hereditary condition?

A mother and daughter are reported with bilateral optic atrophy with onset in infancy and unilateral facial palsy. This appears to be a novel autosomal dominant disorder.     

What's new in hereditary colorectal cancer?

Precancerous polyposes other than classic familial adenomatous polyposis and the condition hereditary nonpolyposis colorectal cancer, or Lynch syndrome, continue to present major diagnostic challenges for the anatomic pathologist. This editorial highlights the practical significance of novel insights and clinical guidelines in the recent literature, as well as in 4 contributions to this edition of the Archives of Pathology & Laboratory Medicine. The first section will address attenuated familial adenomatous polyposis and a newly recognized type of autosomal-recessive adenomatous polyposis associated with the DNA repair gene MYH. The remainder of the editorial discusses the role of the revised Bethesda guidelines in the diagnosis of hereditary nonpolyposis colorectal cancer and concludes with the recently identified serrated pathway syndrome.     

Human papillomavirus infection: Is it associated with epithelial ovarian cancer?

PurposeHuman papillomavirus (HPV), the causative agent of cervical cancer, is associated with several other epithelial malignancies. Previous reports on HPV infection and its association with ovarian cancer are highly contradicting. Reports on HPV association with ovarian cancer in Indian women are also rare. Hence, the purpose of this study was to screen women with serous epithelial ovarian cancer for possible HPV infection.MethodsTumor samples, collected at the time of surgery from 88 women with serous epithelial ovarian cancer were screened using a specific and sensitive PCR. The PCR results were confirmed with Southern blotting using HPV genome-specific probes, both of high-risk HPV type 16 and 18 and low-risk HPV type 6 and 11. All the samples were again tested for another 14 high-risk HPV genotypes with a commercially available qRT-PCR.ResultsAll the samples screened and confirmed by various tests did not show presence of either low-risk or high-risk HPV DNA, indicating the absence of HPV infections in these ovarian cancer tissues.ConclusionsThe present study shows that HPV infection may not be associated with epithelial ovarian cancer. The result of the current investigation strongly supports the results of earlier research that, HPV is not associated with ovarian cancer.     

Is there a common genetic basis for autoimmune diseases?

Autoimmune diseases (ADs) represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. The commonality between them however, is the damage to tissues and organs that arises from the response to self-antigens. The presence of shared pathophysiological mechanisms within ADs has stimulated searches for common genetic roots to these diseases. Two approaches have been undertaken to sustain the "common genetic origin" theory of ADs. Firstly, a clinical genetic analysis showed that autoimmunity aggregates within families of probands diagnosed with primary Sj?gren's (pSS) syndrome or type 1 diabetes mellitus (T1D). A literature review supported the establishment of a familiar cluster of ADs depending upon the proband's disease phenotype. Secondly, in a same and well-defined population, a large genetic association study indicated that a number of polymorphic genes (i.e. HLA-DRB1, TNF and PTPN22) influence the susceptibility for acquiring different ADs. Likewise, association and linkage studies in different populations have revealed that several susceptibility loci overlap in ADs, and clinical studies have shown that frequent clustering of several ADs occurs. Thus, the genetic factors for ADs consist of two types: those which are common to many ADs (acting in epistatic pleitropy) and those that are specific to a given disorder. Their identification and functional characterization will allow us to predict their effect as well as to indicate potential new therapeutic interventions. Both autoimmunity family history and the co-occurrence of ADs in affected probands should be considered when performing genetic association and linkage studies.     

Is cancer really a 'local' cellular clonal disease?

Cancer is not simply the result of specific genetic alterations in key regulatory genes, but rather a complex multistep process involving selection of a clonal population of cells. To accumulate three, or often as many as seven, specific mutations in a single cell without incurring a significant number of additional mutations that might lead to cell lethality requires a large number of target cells, some mutagenic activity acting on those target cells for a variable period of time, and efficient selection strategies, which may be to some extent tissue-specific. A number of 'protective' intracellular regulatory circuits might be present in proliferating cells deliberately to protect against carcinogenesis. If it does require some seven sequential carcinogenic 'genetic hits' in a single cellular clone for a malignant tumor to develop, it is mathematically more likely to occur in a tissue with a high background of genetic alterations in neighboring cellular clones, than in a tissue with a low background of such alterations, or with no detectable carcinogenic mutations at all. In this context, the old 'field cancerization' theory by Slaughter and the more recent 'multistep carcinogenesis' model by Fearon and Vogelstein can come together in a single model: 'multistep field cancerization'. This simple conclusion, and our ability to measure 'background carcinogenesis' in different parts of the body, might allow early detection of cancer risk, and eventually help us to develop suitable therapeutic strategies to delay or suppress the carcinogenic process. Molecular technologies are just beginning to be sufficiently sensitive to start testing the hypothesis.     

Is trisomy 5 a distinct cytogenetic subgroup in acute lymphoblastic leukemia?

Acute lymphoblastic leukemia (ALL) is characterized by recurrent clonal chromosomal abnormalities, with numerical abnormalities being a common feature especially among children. Case reports in the literature suggest that one such recurrent numerical abnormality is the gain of chromosome 5 (trisomy 5) as the sole abnormality; due to the rarity of these cases, however, little is known about their incidence, clinical features, and prognosis. We have identified seven cases with trisomy 5 as the sole or primary chromosomal abnormality from a total of 3,400 karyotypes collected in the Leukaemia Research Fund UK Cancer Cytogenetics Group Karyotype Database. All cases had a precursor B-cell immunophenotype and there was a male predominance. Five patients were children aged between 7 and 14 years old. Four of the six patients with a reasonable follow-up period had relapsed, indicating a poor prognosis. We conclude that trisomy 5 as the sole numerical abnormality occurs predominantly in older children, may be associated with a poor outcome, and may represent a distinct, albeit rare, cytogenetic subgroup in ALL.     

When brachytherapy met genetic oncology. Can radiation oncologists improve the detection of hereditary non-polyposis colorectal cancer?

Between January 1994 and December 2004, 696 patients with localized endometrial carcinoma have been treated at the Institute Jean-Godinot. Patients were selected on the following criteria: histologically proven adenocarcinoma of the endometrium; age at onset under 60 years; patient not deceased at the time of the study. One hundred twelve patients met these criteria and received a mailed specific questionnaire to establish their pedigree. Thirty-one patients (35.5%) were eventually found eligible for a genetic counselling but only 13 patients agreed to be informed later on. According to the obtained pedigrees and MSI test results, 7 genetic tests have been carried out and so far, 3 MMR mutations were detected. This study suggested the feasibility of a step by step screening of endometrial cancers to select patients at risk for Lynch syndrome and for whom a genetic test would be recommended. Authors suggest that either Amsterdam or Bethesda criteria should be systematically used prospectively in every newly diagnosed endometrial cancer and retrospectively using clinical databases available on endometrial cancers.     

Is there a link between an extremely poor response to ovarian hyperstimulation and early ovarian failure?

BACKGROUND: It has been previously reported that a group of 12 infertile women, who had a normal baseline hormonal profile and did not respond to repeated ovarian stimulation with gonadotrophins, developed ovarian failure within a few months. Based on this observation, we carried out a controlled retrospective cohort study to examine whether non-response to ovarian stimulation is linked to early ovarian failure. METHODS: All patients aged 35-40 years who had cancelled IVF cycles for non-response between 1991 and 1993 in our centre were asked to report on the subsequent development of menopausal symptoms, menopause or commencement of hormone replacement therapy. A control group consisted of patients with the same age and similar medical history, who had IVF the same year and responded well. RESULTS: Eleven out of the 12 patients of the non-response group developed menopausal symptoms within 7 years, compared with only four out of 24 in the control group. Similarly, eight out of 12 non-responders either went into menopause or started using hormone replacement therapy compared with one out of 24 in the control group. Using Fisher's exact test, the differences were highly significant (P < 0.0001). The median age at development of menopausal symptoms in the study group was 40 years (range 38-45). The median time between non-response and development of menopausal symptoms was 4 years (range 1-7). CONCLUSION: We carried out a controlled retrospective cohort study that showed a strong association between an extremely poor response to ovarian hyperstimulation and early ovarian failure.