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ImportanceThere are limited guidelines for clinical management in Li-Fraumeni syndrome, a multi-organ cancer predisposition condition. Whole body magnetic resonance imaging may play a role in surveillance of this high risk population.ObjectiveTo assess the clinical utility of whole body magnetic resonance imaging in germline TP53 mutation carriers at baseline.Data SourcesClinical and research surveillance cohorts were identified through the Li-Fraumeni Exploration Research Consortium.Study selectionCohorts that incorporated whole body magnetic resonance imaging for individuals with germline TP53 mutations were included.Data extraction and synthesisData was extracted by investigators from each cohort independently and synthesized by two investigators. Random effects meta-analysis methods were used to estimate proportions. Main outcomes and measuresThe proportion of participants at baseline in whom a lesion was detected that required follow up and in whom a new primary malignancy was detected. ResultsA total 578 participants from 13 cohorts were included in the analysis. Two hundred twenty-five lesions requiring clinical follow up were detected by whole body magnetic resonance imaging in 173 participants. Sixty-one lesions were diagnosed in 54 individuals as either benign or malignant neoplasms. Overall, 42 cancers were identified in 39 individuals, with 35 new localized cancers treated with curative intent. The overall detection rate for new localized primary cancers was 7% (95% Confidence Interval 5-9%).Conclusions and relevanceThese data suggest clinical utility in baseline whole body magnetic resonance imaging in TP53 germline mutation carriers, and may form an integral part of baseline clinical risk management in this high-risk population.

Background Testicular cancer, while rare compared with other adult solid tumors, is the most common cancer in young men in northern Europe and North America. Risk factors include white race, positive family history, contralateral testicular cancer, cryptorchidism, infertility and testicular microlithiasis. As the genetic causes of familial clusters (Familial Testicular Cancer or FTC) are being sought, it is also important to understand the psycho-social experiences of members of FTC families. Methods This is a cross-sectional examination via the Colored Eco-Genetic Relationship Map (CEGRM) of social connections reported by 49 men in FTC families participating in NCI research study 02-C-178. Results The CEGRM was acceptable and feasible for use with men in FTC families, and valuable in understanding their social connections. These men have largely adjusted to the TC history in themselves and/or their relatives. They have considerable social and emotional support from family and friends, although there is wide variability in sources and types. Conclusions The CEGRM focuses on men's social connections and close emotional bonds in FTC families. This action-oriented process of placing colored symbols on significant relationships uncovered previously under-appreciated emotions accompanying men's social exchanges. Most men in FTC families succeed in re-establishing a sense of normalcy in their lives and social connections, in the aftermath of a testicular cancer diagnosis.

Familial aggregations of testicular germ cell tumor (FTGCT) have been well described, suggesting the existence of a hereditary TGCT subset. Approximately 1.4% of newly diagnosed TGCT patients report a positive family history of TGCT. Sons and siblings of TGCT patients have four- to sixfold and eight- to tenfold increases in TGCT risk respectively. Segregation analyses suggest an autosomal recessive mode of inheritance. Linkage analyses have identified several genomic regions of modest interest, although no high-penetrance cancer susceptibility gene has been mapped yet. These data suggest that the combined effects of multiple common alleles, each conferring modest risk, might underlie familial testicular cancer. Families display a mild phenotype: the most common number of affected families is 2. Age at diagnosis is 2–3 years younger for familial versus sporadic cases. The ratio of familial seminoma to nonseminoma is 1.0. FTGCT is more likely to be bilateral than sporadic TGCT. This syndrome is cancer site specific. Testicular microlithiasis is a newly recognized FTGCT component. Candidate gene-association studies have implicated the Y chromosome gr/gr deletion and PDE11A gene mutations as genetic modifiers of FTGCT risk. Two genomewide association studies of predominantly sporadic but also familial cases of TGCT have implicated the KIT-ligand, SPRY4, and BAK1 genes as TGCT risk modifiers. All five loci are involved in normal testicular development and/or male infertility. These genetic data provide a novel insight into the genetic basis of FTGCT, and an invaluable guide to future TGCT research.

Background Ductal lavage (DL) has been proposed as a minimally-invasive, well-tolerated tool for obtaining breast epithelial cells for cytological evaluation of breast cancer risk. We report DL tolerability in BRCA1/2 mutation-positive and -negative women from an IRB-approved research study. Methods 165 BRCA1/2 mutation-positive, 26 mutation-negative and 3 mutation unknown women underwent mammography, breast MRI and DL. Psychological well-being and perceptions of pain were obtained before and after DL, and compared with pain experienced during other screening procedures. Results The average anticipated and experienced discomfort rating for DL, 47 and 48 (0–100), were significantly higher (p < 0.01) than the anticipated and experienced discomfort of mammogram (38 and 34), MRI (36 and 25) or nipple aspiration (42 and 27). Women with greater pre-existing emotional distress experienced more DL-related discomfort than they anticipated. Women reporting DL-related pain as worse than expected were nearly three times more likely to refuse subsequent DL than those reporting it as the same or better than expected. Twenty-five percent of participants refused repeat DL at first annual follow-up. Conclusion DL was anticipated to be and experienced as more uncomfortable than other procedures used in breast cancer screening. Higher underlying psychological distress was associated with decreased DL tolerability.

Background When women from families with a known BRCA1 or BRCA2 mutation test negative for the family mutation, it is assumed that they will transition their personal cancer risk perception from high to average risk. However, there are scant data regarding the experience of mutation-negative women after genetic testing disclosure, particularly related to the shift of risk perception from assumed mutation-positive to actual mutation-negative. This study was designed to explore cancer risk perception and the experience of being a mutation-negative woman within a known BRCA1/2 mutation-positive family. Methods We employed a qualitative descriptive design and convened a sample of 13 women who contributed in-depth, semi-structured telephone interviews (audio-recorded and transcribed verbatim) and performed qualitative content analysis with NVivo 2.0 software. Results Six major content areas emerged from interview data: (i) rationale for initial involvement in the breast imaging study, (ii) rationale for continued participation, (iii) experience of living in a multiple-case family, (iv) risk perception: the personal meaning of mutation-negative status, (v) opinions regarding cancer aetiology and (vi) communication patterns between mutation-negative and mutation-positive family members. Conclusions Living in a hereditary breast and ovarian cancer family is a complex experience that affects cognitive, emotional and social functioning. Our findings indicate that mutation-negative women may have unmet psychosocial needs that must be addressed by health-care professionals, particularly in the primary-care setting following genetic disclosure of a potentially reassuring result regarding their lack of the very high cancer risks associated with BRCA1/2 mutations.

Objective: We investigated the association between psychological distress and indices of social integration and communal coping among sisters from hereditary breast and ovarian cancer (HBOC) families. Sample and methods: Sixty-five sisters from 31 HBOC families completed the Brief Symptom Inventory-18 and the Colored Eco-Genetic Relationship Map, which identified members of participants’ social support networks. Hierarchical linear models were used for all analyses to account for the clustering of sisters within families. Results: Intra-family correlation coefficients suggested that sisters shared perceptions of breast cancer risk and worry, but not ovarian cancer risk and worry. Further, sisters demonstrated shared levels of anxiety and somatization, but not depressive symptoms. Communal coping indices quantifying shared support resources were negatively related to anxiety and somatization. The number of persons with whom cancer risk information was shared exhibited a positive trend with somatization. Social integration, as measured by the size of participants’ emotional support network, was negatively associated with anxiety. Lower depression scores were observed among participants with more persons playing multiple support roles and fewer persons providing tangible assistance. Conclusion: Understanding how support relationships impact well-being among persons adjusting to HBOC risk, and the particular role of family in that process, will facilitate developing appropriate management approaches to help cancer-prone families adjust to their cancer risk. Published in 2008 by John Wiley & Sons Ltd.

BRCA1/2-positive women who learn their mutation status early in the life-course face unique challenges related to navigating the tasks of young adulthood. Using qualitative methods and grounded theory, the authors analyzed in-depth interviews with 11 women aged 26 to 35 who learned their mutation status before marriage. Their narratives illustrate the complexity of relationship formation, and highlight the potential for relationship-bonding and intimacy-building in the course of sharing mutation information. Disclosing BRCA mutation status to dating partners is often preceded by feelings of fear and anxiety, yet many participants reported that doing so has positive effects on relationships. Partners' abilities to respond with interest, empathy, and affection are associated with in creased future intimacy, consistent with generally accepted principles within the family/couple systems field. Individual cancer risk perception and familial cancer experiences may affect the disclosure experience, which can be understood via Attachment Theory. Our findings provide clinical insight, identify new areas for research, and suggest ways to assist this unique population in their adjustment to being BRCA mutation-positive.

Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with congenital genitourinary tract anomalies suggest an underlying genetic predisposition ([1][1

Background Germ-cell testicular cancer has not been definitively linked to any known hereditary cancer susceptibility disorder. Familial testicular cancer in the presence of other findings in affected and unaffected family members might indicate a previously-unidentified hereditary cancer syndrome. Case presentation The patient was diagnosed with a left testicular seminoma at age 28, and treated with left orchiectomy followed by adjuvant cobalt radiation. His family history is significant for testicular seminoma in his son, bladder cancer in his sister, and lipomatosis in his father. His evaluation as part of an etiologic study of familial testicular cancer revealed multiple colon polyps (adenomatous, hyperplastic, and hamartomatous) first found in his 50 s, multiple lipomas, multiple hyperpigmented skin lesions, left kidney cancer diagnosed at age 64, and a growth-hormone producing pituitary adenoma with associated acromegaly diagnosed at age 64. The patient underwent genetic testing for Cowden syndrome (PTEN gene), Carney complex (PRKAR1A gene), and multiple endocrine neoplasia syndrome type 1 (MEN1 gene); no deleterious mutations were identified. Discussion The constellation of benign and malignant neoplasms in the context of this patient's familial testicular cancer raised the possibility that these might be manifestations of a known hereditary susceptibility cancer syndrome; however, genetic testing for the three syndromes that were most likely to explain these findings did not show any mutation. Alternatively, this family's phenotype might represent a novel neoplasm susceptibility disorder. This possibility cannot be evaluated definitively on the basis of a single case report; additional observations and studies are necessary to investigate this hypothesis further.

BackgroundTesticular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with genitourinary (GU) tract anomalies have suggested an underlying genetic predisposition. Linkage data have not identified a rare, highly-penetrant, single gene in familial TGCT (FTGCT) cases. Based on its association with congenital GU tract anomalies and suggestions that there is an intrauterine origin to TGCT, we hypothesized the existence of unrecognized dysmorphic features in FTGCT.MethodsWe evaluated 38 FTGCT individuals and 41 first-degree relatives from 22 multiple-case families with detailed dysmorphology examinations, physician-based medical history and physical examination, laboratory testing, and genitourinary imaging studies.ResultsThe prevalence of major abnormalities and minor variants did not significantly differ between either FTGCT individuals or their first-degree relatives when compared with normal population controls, except for tall stature, macrocephaly, flat midface, and retro-/micrognathia. However, these four traits were not manifest as a constellation of features in any one individual or family. We did detect an excess prevalence of the genitourinary anomalies cryptorchidism and congenital inguinal hernia in our population, as previously described in sporadic TGCT, but no congenital renal, retroperitoneal or mediastinal anomalies were detected.ConclusionsOverall, our study did not identify a constellation of dysmorphic features in FTGCT individuals, which is consistent with results of genetic studies suggesting that multiple low-penetrance genes are likely responsible for FTGCT susceptibility.

Background Complementary and alternative medicine (CAM) use is well documented among breast cancer patients and survivors, but little evidence is available to describe rates and patterns of use among women at increased genetic risk of breast cancer. Methods A pre-visit telephone interview was conducted to ascertain CAM use among the BRCA mutation carriers enrolled in a high-risk breast cancer screening study. Participants were asked to report on their use of thirteen therapies within the year prior to enrollment into the study. Logistic regression was used to evaluate the association between various factors and CAM use in this population. Results Among the 164 BRCA1 or BRCA2 mutation-positive (BRCA+) women in this analysis, 78% reported CAM use, with prayer and lifestyle diet being the two most commonly reported modalities. Many subjects used multiple CAM therapies, with 34% reporting use of three or more modalities. The most commonly used modalities were mind-body therapies and biologically-based practices, 61.6% and 51.8%, respectively. High-risk women were more likely to use CAM if they were older, more educated, more worried about ovarian cancer risk, or had a previous cancer diagnosis. Conclusion This study suggests that the prevalence of CAM use is high among BRCA mutation carriers, with frequency of use comparable to that of breast cancer patients and survivors. Given the high prevalence of CAM use in our subjects, especially biologically-based therapies including herbal supplements, whose safety and efficacy in relation to cancer risk are unknown, our study suggests that future research is necessary to clarify these risks, and that it is important for providers to inquire about and to discuss the pros and cons of CAM use with their BRCA+ patients.