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It is often said that cancer is genetic. What exactly does that mean? This article is our answer to that question at the turn of the millennium. We present models of carcinogenesis, review basic cancer genetics terminology, and explain some of the fundamental genetic changes common to all types of cancer. These are organized into 6 sections of (1) self-sufficiency in growth signals, (2) insensitivity to growth-inhibitory signals, (3) evasion of programmed cell death, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) tissue invasion and metastases. Underlying all of these changes are the even more fundamental enabling factors of genetic instability on both the chromosomal and the gene level. Finally, we look toward the future in a field where the future is now!

Because of wide publicity, many oncologists are aware of the availability of genetic susceptibility testing to detect mutations in cancer susceptibility genes such as BRCA1. One might innocently assume that the genetic test is as easy to order as filling out your standard requisition form for a blood count. This is not consistent with current practices. The daunting ethical, medical, legal, social, and technological challenges must be addressed. In order for a genetic test to benefit your patients, it should best be undertaken in the context of a well-organized, comprehensive Familial Cancer Risk Counseling program. Establishing such a program is the focus of this chapter.

Purpose: To help oncology nurses to appreciate genetic contributions to carcinogenesis; to learn how genetic changes are connected to biological mechanisms underlying cancer initiation, promotion, and progression; and to become familiar with new genetic technologies being incorporated into clinical oncology practice. Data sources: Review of published professional journals and oncology textbooks. Conclusions: Molecular genetic approaches with high sensitivity and specificity offer new hope for the improved evaluation of potential carcinogens, cancer prevention, early and accurate diagnosis, more reliable prognosis, and effective treatment and monitoring of cancer. Effective translation of molecular technologies will require development of improved methods, clinical validation studies, high-quality control, multisite clinical outcome studies, and development of multidisciplinary collaborations. Implications for nursing practice: Oncology nurses are incorporating new genetic technologies into the following areas of practice: patient education, cancer prevention and control, diagnostic and prognostic testing, and treatment.

Introduction: Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome causing a range of cancers across the lifespan. About 70% of families meeting classical LFS criteria have detectable germline mutations in the TP53 gene, vs 40% of those classified as Li-Fraumeni-like (LFL). The psychological, social, and behavioral issues faced by individuals with LFS/LFL and their relatives comprise an important, but under-studied, topic. Methods: Ours is a prospective, cohort study of LFS/LFL. Enrollees are invited to participate in epidemiologic and lifestyle questionnaires, clinical evaluations, genetic counseling and testing if indicated, molecular research, cancer screening and psychosocial assessments, and, of adults, standardized, self-report, psychological assessments. Those attending clinic also have in-person interview and social assessments. Results: Two of the first five families we saw illustrate a wide range of psychosocial issues, which emerged during the social assessment and family interview.Family 1 included two adolescents with histories of osteosarcoma, and their unaffected father. Their biological mother had died a decade earlier from a different type of cancer and their father had remarried. The adolescent female proband was struggling with internal conflict, overwhelmed with trying to balance pleasing her family with the developmentally appropriate task of gaining independence. The younger male proband focused on short-term goals, seemingly finding the cancer risk personally irrelevant. The father worried about raising his children in a highly secular environment, and about how to manage their medical needs. The proband of Family 2 is a 37-year-old woman who had already survived 4 primary cancers, seen with her 2 unaffected, mutation-positive children and her mother. She was divorced from the children's father and raised them as a single mom for several years with the help of her mother until re-marrying. Pertinent psychosocial issues included an emotional and practical cut-off between the biological parents, resulting in the mother's struggle to manage her children's healthcare needs and communicate with them about their risk independent of their father, who preferred not to be involved in the medical system. Additionally, the mother's strong sense of independence created a communication barrier between her and her own mother, who felt shut out of her daughter's emotional experience despite wanting to provide support. Conclusions: There is great breadth of needs in families with LFS/LFL. Understanding the psychological, social, and behavioral issues as they are manifest in the context of LFS will help guide our efforts aimed at alleviating the psychosocial morbidity associated with this syndrome. We recommend that families receive ongoing psychosocial evaluation as an integral part of their medical management, preferable by multi-disciplinary teams. Citation Format: June A. Peters, Lindsey M. Hoskins, Phuong L. Mai, Farzana Walcott, Renee Bremer, Sharon A. Savage. Li-Fraumeni syndrome: Clinical experience with family psycho-social issues. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1383. doi:10.1158/1538-7445.AM2013-1383

This study was designed to evaluate the utility of flow-FISH telomere length measurement in white blood cells (WBC) as a screening test for Dyskeratosis congenita (DC). We studied 26 patients: 17 with DC, 1 silent carrier (clinically normal; mutation in TERC), 4 with the Hoyeraal-Hreidarsson variant (HH), and 4 with Revesz Syndrome. Five had mutations in DKC1, 5 in TERC, and 2 in TERT. 23 had hematologic abnormalities, 19 had 2 or 3 of the DC diagnostic triad (lacey pigmentation, dyskeratotic nails, and leukoplakia), and 4 had soft signs of DC. We evaluated 54 first-degree relatives of DC patients, 16 Fanconi Anemia patients (FA), 14 with Diamond-Blackfan Anemia (DBA), 5 with Shwachman Diamond Syndrome (SDS), and 10 with other possibly inherited cytopenias (Other). Telomere length was measured in granulocytes and lymphocyte subsets by automated multicolor flow-FISH; results were compared with age-matched values from 400 normal controls. “Very low (VL)” telomere length was defined as a mean telomere length below the normal first percentile for age and specific WBC type. We observed VL telomeres in all subsets in the silent carrier, all HH and Revesz patients, and 15/17 with DC. Eight of 51 DC relatives had VL telomeres in granulocytes versus 2/54 with VL telomeres in lymphocytes. The sensitivities for distinguishing a DC patient from an unaffected relative were 92% in lymphocytes and 96% in granulocytes; the specificities were 96% and 98%, respectively; the sensitivity and specificity for VL telomeres in both cell types were 96% and 96%. The silent carrier with a TERC mutation developed thrombocytopenia, hypocellular marrow, and a cytogenetic clone during follow-up. The 2 DC relatives with VL telomeres in lymphocytes were from a family without a known mutant gene; they may also be silent carriers. The latter possibility disqualified an HLA-matched sibling as a donor for DC-related aplastic anemia, because of engraftment concerns; another sibling donor with normal telomere length was selected. VL granulocyte telomeres were observed in 5/16 FA, 3/14 DBA, 1/5 SDS, and 1/10 Other patients, versus 2/16 FA, 1/14 DBA, 1/5 SDS, and 0/10 Other in lymphocytes, and in both lineages in only 1 each of FA, DBA, and SDS. The sensitivity and specificity for distinguishing DC from non-DC patients using VL telomeres in both lineages were 96% and 93%, respectively. Only DC patients had consistently VL telomeres in all cell subsets. Flow-FISH telomere length measurement provides a sensitive and specific method for identifying patients with DC among families, regardless of mutation status, and distinguishes patients with DC from those with other inherited or acquired marrow failure syndromes. It may also help to detect silent carriers, and facilitate identification of mutations in other telomere biology genes. Our data suggest that the diagnostic triad, soft physical findings and/or bone marrow failure may not be required for the diagnosis of DC. Correct diagnosis of DC will enhance genetic counseling and hematologic management.

Margaret W, now forty-one, has had regular mammograms since she was in her mid-thirties, when she discovered a small lump in her left breast. Although the lump proved to be a benign cyst, on the basis of her family history her physician had strongly recommended that she continue routine annual mammograms. Two of her mother's three sisters had been treated for breast cancer (one at age 45, the other at 48) and her maternal grandmother was diagnosed with breast cancer at age sixty-seven. The grandmother's sister had died of ovarian cancer at fifty-three. Cancer has now appeared in Margaret's own generation: not long ago her thirty-seven-year-old cousin Emily underwent a bilateral total mastectomy for infiltrating adenocarcinoma. Emily's oncologist, aware of the family's history would like to refer her - and her relatives - to a geneticist colleague studying inherited susceptibility to breast and ovarian cancer. There is evidence, the oncologist told Emily, that about one in 200 women have inherited such susceptibility. The colleague he would like her to see is studying BRCA1, a newly identified gene associated with both breast and ovarian cancer. While researchers haven't yet isolated the precise sequence of BRCA1 (and so can't screen for it directly), he noted, linkage analysis in extended families with unusual cancer histories can reveal familial markers associated with, the gene. Since Dr. Ayers, the geneticist, is willing to provide families with information about any markers such analysis uncovers, in participating in die research Emily, Margaret, and their relatives could not only provide data that might someday help other women avoid breast cancer, but could benefit directly themselves in being able to plan their care more thoughtfully with their physicians. Her cousin came to Margaret to talk over the idea of participating in linkage studies. It would involve all members of their extended family in one way or another, and Margaret isn't sure they would want to or should take part. On die other hand, joining the research and being counseled about their individual risks might mean better health for each of them - Margaret is especially concerned about what the family history suggests for her two daughters, aged twenty and seventeen. In talking together Margaret and Emily realize they don't know all the questions they should ask to make a wise decision. What does being "genetically susceptible" to breast cancer really mean? What other implications might taking part in this research hold for them and their families? Who will give them the best counsel in making a decision? This case foretells an imminent shift of emphasis in medical genetics. In marked contrast to the traditional focus of genetic counseling n providing diagnosis and reproductive risks for rare genetic conditions, the identification of genes associated with susceptibility to common disorders, such as breast cancer, will propel this specialty into the area of preventive health care. But due to the significance of factors other than genetics in disease etiology, genetic susceptibility information - in the form of genes or DNA sequences associated with common diseases - will be inherently limited in predictive value. Individuals who are carriers of a genetic susceptibility trait might never experience the condition with which the trait has been associated. While there may seem to be little appreciable difference, testing for genetic susceptibility is unlike testing for other types of susceptibility. An important difference is that instead of measuring the end result of combined environmental and/or genetic factors at a particular moment in time, such as with cholesterol testing, only genetic material, immutable and unchangeable over time, is assessed. Unlike cholesterol tests, which generate a course of action (such as diet and exercise recommendations or drug therapies), genetic information itself is resistant to human intervention. …

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.

Subjective user responses were obtained for a test earmuff exhibiting approximately flat attenuation of about 25 dB from 500–8000 Hz for SPLs less than 115 dB, with attenuation increasing nonlinearly up to about 10 dB at higher SPLs. The study population consisted of police officers performing annual gunfire requalification, in which officers execute required target shots during two sequential relay exercises. In the first phase of the study, subjects wore either their regular hearing protector or the test muff during the first relay, then the alternate protector for the second relay (with order counterbalanced). In the second phase, additional subjects wore either a control earmuff that was identical to the test earmuff except for the nonlinear mechanism (also eliminating the flat response characteristics) or the test earmuff. Subjects completed questionnaires concerning their opinions of the hearing protectors worn during both phases. Preliminary results indicate a significant difference in favor of the test earmuff in three areas: speech understanding, perceived level of protection, and comfort.