Familial myeloma.

We describe a family with five cases of multiple myeloma, three cases of monoclonal gammopathy of undetermined significance (MGUS), and five cases of prostate cancer in two generations. The putative progenitor had progeny with two female partners. The progeny had prostate cancer, multiple myeloma, and MGUS.

Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion.

OBJECTIVES: The Lynch syndrome (LS) is an inherited cancer syndrome showing a preponderance of colorectal cancer (CRC) in context with endometrial cancer and several other extracolonic cancers, which is due to pathogenic mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Some families were found to show a LS phenotype without an identified MMR mutation, although there was microsatellite instability and absence of MSH2 expression by immunohistochemistry. Studies of a subset of these families found a deletion at the 3' end of the epithelial cell adhesion molecule (EPCAM) gene, causing transcription read-through resulting in silencing of MSH2 through hypermethylation of its promoter. The tumor spectrum of such families appears to differ from classical LS. METHODS: Our study of two large families (USA Family R and Dutch Family A) with an EPCAM deletion was carried out using each institution's standard family study protocol. DNA was extracted from peripheral blood and EPCAM deletion analysis was performed. RESULTS: Both families were found to harbor the same deletion at the 3' end of EPCAM. Analysis showed that the deletion originated from a common ancestor. Family R and Family A members showed segregation of CRC with the presence of this EPCAM mutation. Compared with classic LS, there were almost no extracolonic cancers. CONCLUSIONS: Members of Family R and Family A, all with the same EPCAM deletion, predominantly presented with CRC but no LS-associated endometrial cancer, confirming findings seen in other, smaller, LS families with EPCAM mutations. In these EPCAM mutation carriers, cancer surveillance should be focused on CRC.

Genetic counseling and the advanced practice oncology nursing role in a hereditary cancer prevention clinic: hereditary breast cancer focus (part I).

Interest in hereditary breast cancer has increased rapidly among all health care providers as well as the laity. A major problem for health care providers, however, is the time and skill required for gathering family history, interpreting the pedigree, and providing genetic counseling for the high-risk patient so that BRCA testing, when indicated, can be pursued and screening and prevention strategies employed by the patient. The fields of hereditary cancer and molecular biology have developed at a rate that makes it difficult for physicians to keep up with this explosive knowledge. Therefore, "Who is going to take care of all of these crucial matters for patient benefit?" is a germane question. Our experience has confirmed that the advanced practice oncology nurse who is interested in cancer genetics can become skilled at providing this service to the patient and his/her family. This study portrays the role of such an oncology nurse in meeting this important public health challenge, with special attention devoted to the logistics of this role in the rapidly emerging field of hereditary breast cancer.

Genetic counseling and the advanced practice oncology nursing role in a hereditary cancer prevention clinic: hereditary breast cancer focus (part II).

Hereditary breast cancer (BC) is heterogeneous to the extent that no two high-risk patients can be considered as being the same. These individual differences are magnified further when patients' emotional response to all facets of hereditary BC are considered, particularly issues surrounding gene testing. A series of case histories have been provided that illustrate the wide range of attitudes, feelings, and emotional responses explained by patients when learning of their hereditary cancer risk status. The role of the oncology nurse-genetic counselor has been described in each of these family reports.

Family information service participation increases the rates of mutation testing among members of families with BRCA1/2 mutations.

Some members of hereditary breast-ovarian cancer (HBOC) families may not participate in BRCA testing to determine their mutation status in part because they are unaware of their cancer risk and the availability of BRCA testing. Participation in a family information service (FIS), of which we have provided more than 100 sessions during the past 30 years, has been seen to effectively allow family members to be educated regarding their cancer genetic risk and potential benefits from cancer control measures such as mutation testing. However, the effect of the FIS on the rate of mutation testing has not been studied. One thousand five hundred seventy-four eligible (>18-year old, at a 25% or higher pedigree risk) members from 60 extended HBOC families with BRCA1/2 mutations were invited to attend a FIS to learn about their risk and undergo genetic testing. The rates of mutation testing were compared between those who had attended an FIS, and those who had not with chi-squared test and logistic regression analysis. Seventy five percent (334/444) of FIS attendees had undergone mutation testing following or during an FIS which was significantly higher than the 33.8% (382/1130) rate among nonattendees (p < 0.0001). Logistic regression analysis showed that FIS attendance, breast-ovarian cancer history, gender, and age were significant variables for undertaking a mutation test. FIS attendance significantly increased the rate of mutation testing among high-risk family members.

Pancreatic cancer and the FAMMM syndrome.

Hereditary cancer syndromes provide excellent models for molecular genetic studies that may aid significantly in case detection, surveillance, and management. Ultimately, molecularly based designer pharmaceuticals may emerge from this research, such as the case of trastuzumab (Herceptin) in HER-2/neu positive breast cancer, and imatinib (Gleevec) in chronic myelocytic leukemia and gastrointestinal stromal tumors. Importantly, these molecular findings may fuel significant clues to cancer control. This background is mentioned since surveillance and management of pancreatic cancer, a major concern of this manuscript, has been uniformly unsuccessful as evidenced by the close correspondence between its incidence and its mortality. Yet knowledge about its genetic and molecular pathology will hopefully ameliorate this vexing problem. One molecular genetic clue is the recently identified palladin mutation in two pancreatic cancer prone families. However, caution must be used toward the palladin mutation, as several recent publications have questioned its significance as a pancreatic cancer causing mutation. We provide a concise description of pancreatic cancer in concert with malignant melanoma in the familial atypical multiple mole melanoma (FAMMM) syndrome as a potential preventive model. This knowledge should help clinicians and basic scientists seize on the opportunity to develop more sensitive and specific screening and management programs in this disease; while a relatively small subset of pancreatic cancer may be readily identifiable through its FAMMM phenotype, coupled with its CDKN2A mutation, this hereditary disorder, given a keen knowledge of its natural history and molecular genetics, may prove to be an effective clinical preventive model.

Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management.

Hereditary forms of colorectal cancer, as is the case with virtually all forms of hereditary cancer, show extensive phenotypic and genotypic heterogeneity, a phenomenon discussed throughout this special issue of Familial Cancer. Clearly, the family physician, oncology specialist, genetic counselor, and cancer geneticist must know fully the complexity of hereditary cancer syndromes, their differential diagnosis, in order to establish a diagnosis, direct highly-targeted surveillance and management, and then be able to communicate effectively with the molecular geneticist so that an at-risk patient's DNA can be tested in accord with the syndrome of concern. Thus, a family with features of the Lynch syndrome will merit microsatellite instability testing, consideration for immunohistochemistry evaluation, and mismatch repair gene testing, while, in contrast, a patient with FAP will require APC testing. However, other germline mutations, yet to be identified, may be important should testing for these mutations prove to be absent and, therein, unrewarding to the patient. Nevertheless, our position is that if the patient's family history is consistent with one of these syndromes, but a mutation is not found in the family, we still recommend the same surveillance and management strategies for patients from families with an established cancer-causing germline mutation. Our purpose in this paper is to provide a concise coverage of the major hereditary colorectal cancer syndromes, to discuss genetic counseling, molecular genetic evaluation, highly targeted surveillance and management, so that cancer control can be maximized for these high hereditary cancer risk patients.

Hereditary breast cancer: part I. Diagnosing hereditary breast cancer syndromes.

Hereditary breast cancer (HBC) accounts for as much as 10% of the total BC burden. Most of these cases will be found to be due to a BRCA germline mutation. An estimated additional 15-20% of those affected with BC will have one or more first- and/or second-degree relatives with BC. Therefore, when these numbers are combined, familial BC risk accounts for approximately 20-25% of the total BC burden. However, because of the often limited information on family history in the etiologic assessment of BC, this may be an underestimate. Confounding factors include its phenotypic and genotypic heterogeneity, given the association of HBC with a plethora of differing cancer syndromes. Its most common occurrence is its association with ovarian cancer in the so-called hereditary breast-ovarian cancer syndrome due to BRCA1 and BRCA2 mutations. More rarely, it occurs in the Li-Fraumeni syndrome, caused by a p53 germline mutation, in which markedly early-onset BC is found in association with brain tumors, sarcomas, leukemia, lymphoma, malignant melanoma, and adrenal cortical carcinoma. Importantly, the age-adjusted incidence of BC in women in the United States fell sharply, by 6.7%, in 2003, when compared with the rate identified in 2002. We postulate that increasing knowledge about the genetics of BC may have partially contributed to the identification of high-risk patients who thereby may have benefited significantly from early diagnosis.

Hereditary breast cancer: part II. Management of hereditary breast cancer: implications of molecular genetics and pathology.

Management of patients at high risk for hereditary breast cancer (HBC) must critically assess its phenotypic and genotypic heterogeneity, particularly evidenced by the varying spectra of cancer sites that are integral to the respective HBC syndromes. Targeted management must consider their biology, pathology, and molecular genetics, all in concert with their respective carcinogenic pathways, as they may differ significantly from one breast cancer syndrome to the next. A striking example of management differences pertains to BRCA1 and BRCA2 mutation-positive breast cancers wherein those with BRCA1 mutations are frequently estrogen receptor (ER)-negative in contrast to BRCA2 mutations which are more frequently ER-positive; therein, significant differences exist with respect to anti-estrogen therapy which will be more amenable to BRCA2 versus BRCA1 mutation carriers manifesting breast cancer. In turn, tumors that are negative for ER, PR, and Her2-neu, often referred to as "triple negative" tumors, may also harbor a unique basal-like gene expression profile and are characterized by poor prognosis wherein endocrine and/or Her2-neu-targeted therapies are not effective treatment options. A further confounder pertains to the lifetime risk for ovarian cancer, which differs strikingly between BRCA1 mutation carriers, who show a 40-60% lifetime risk, and their BRCA2 counterparts, who carry a lifetime risk of approximately 12-15% for ovarian cancer. It is clear that as we learn more about the biology and the molecular aspects of hereditary forms of breast cancer, it will be compelling for the clinician to integrate this knowledge with pharmacologic, radiologic, and surgical treatment options for these high-risk patients.

Familial B-cell chronic lymphocytic leukemia: analysis of cytogenetic abnormalities, immunophenotypic profiles, and immunoglobulin heavy chain gene usage.

B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease that may exhibit familial clustering. We examined the cytogenetic, immunophenotypic, and VH gene usage characteristics of a family with B-CLL affecting 7 members in 3 generations. Interphase fluorescence in situ hybridization studies identified an acquired deletion of chromosome 13q14 in the leukemic cells of 6 affected members, accompanied by deletion 14q32 or trisomy 12 in 2 cases. VH gene analysis demonstrated clonal rearrangements of the VH3 gene family in 5 cases and of VH2 genes in 1 case. All 6 cases were mutated in VH2 or VH3. Two cases had a second VH1 family gene rearrangement that was unmutated. Flow cytometry performed on 5 cases showed the typical B-CLL immunophenotype; all were CD38-, but 3 expressed ZAP-70. Our findings support previous observations that familial and sporadic B-CLL cases are biologically similar and suggest that familial clusters will be useful for studying pathogenetic events in B-CLL.

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications.

Lynch syndrome is the most common form of hereditary colorectal cancer (CRC). This review covers the cardinal features of Lynch syndrome with particular emphasis upon its diagnostic criteria, molecular genetics, natural history, genetic counseling, surveillance and management. Considerable attention has been given to the etiologic role of mismatch repair (MMR) genes as well as low penetrance alleles and modifier genes. The American founder mutation, a deletion of exons 1-6 of MSH2, is discussed in some detail, owing to its high frequency in the US (19 000-30 000 carriers). Genetic counseling is essential prior to patients' undergoing DNA testing and again when receiving their test results. Families with a lower incidence of CRC and extracolonic cancers, in the face of being positive for Amsterdam I criteria but who do not have MMR deficiency by tumor testing, are probably not Lynch syndrome, and thereby should preferably be designated as familial CRC of undetermined type. Patients who are either noncompliant or poorly compliant with colonoscopy, and who are MMR mutation positive, may be candidates for prophylactic colectomy, while MMR mutation-positive women who are noncompliant with gynecologic surveillance may be candidates for prophylactic hysterectomy and bilateral salpingo-oophorectomy.

Patient responses to the disclosure of BRCA mutation tests in hereditary breast-ovarian cancer families.

Limited attention has been given to the impact of BRCA mutation disclosure on participants' psychological reaction and cancer control compliance. We asked women (290 mutation-positive, 370 mutation-negative) from 84 hereditary breast-ovarian cancer (HBOC) families with known deleterious BRCA mutations to participate in an evaluation regarding cancer prevention recommendations before and after BRCA mutation disclosure. Both men and women (n = 780) were invited to complete a questionnaire to evaluate their psychological response to BRCA mutation disclosure. Before BRCA testing, 23.0% (152 of 660) of these women underwent prophylactic bilateral mastectomy, oophorectomy, or both; of these, 53% (80 of 152) were subsequently found to be mutation negative. After mutation disclosure, 52.9% (110 of 208) of mutation carriers and 0% (0 of 203) of noncarriers underwent prophylactic surgeries. These changes were statistically significant compared with before disclosure (P < 0.0001). The rate of transvaginal ovarian ultrasound screening was significantly increased in mutation carriers (P < 0.015) and marginally decreased in noncarriers (P = 0.063) post disclosure. Psychologically, compared with noncarriers without cancer, a significantly higher percentage of carriers, regardless of their cancer status, felt guilt about passing a mutation to their children, worried about developing additional cancer or their children developing cancer, and were concerned about health insurance discrimination. Despite these psychological consequences, carriers and noncarriers reported a positive attitude toward genetic testing.

Hereditary breast-ovarian cancer at the bedside: role of the medical oncologist.

PURPOSE: To provide practical considerations for diagnosing, counseling, and managing patients at high risk for hereditary breast cancer. DESIGN: We have studied 98 extended hereditary breast cancer (HBC)/hereditary breast-ovarian cancer (HBOC) families with BRCA1/2 germline mutations. From these families, 1,315 individuals were counseled and sampled for DNA testing. Herein, 716 of these individuals received their DNA test results in concert with genetic counseling. Several challenging pedigrees were selected from Creighton University's hereditary cancer family registry, as well as one family from Evanston/Northwestern Healthcare, to be discussed in this present report. RESULTS: Many obstacles were identified in diagnosis, counseling, and managing patients at high risk for HBC/HBOC. These obstacles were early noncancer death of key relatives, perception of insurance or employment discrimination, fear, anxiety, apprehension, reduced gene penetrance, and poor compliance. Other important issues such as physician culpability and malpractice implications for failure to collect or act on the cancer family history were identified. CONCLUSION: When clinical gene testing emerged for BRCA1 and BRCA2, little was known about the efficacy of medical interventions. Potential barriers to uptake of testing were largely unexplored. Identification and referral of high-risk patients and families to genetic counseling can greatly enhance the care of the population at the highest risk for cancer. However, because premonitory physical stigmata are absent in most of these syndromes, an HBOC diagnosis may be missed unless a careful family history of cancer of the breast, ovary, or several integrally associated cancers is obtained.

BRCA1 and pancreatic cancer: pedigree findings and their causal relationships.

Anecdotal reports and series studies indicate that 5-10% of pancreatic cancer (PC) cases are familial. In addition, PC is associated with a variety of hereditary cancer syndromes. PC appears to be an integral cancer in the hereditary breast-ovarian cancer (HBOC) syndrome, with most notice given to the role of BRCA2. Our purpose is to call attention to BRCA1, which also predisposes to PC. Using data from our familial breast cancer registry, we identified 19 BRCA1/2 families that contain PC affecteds in the pedigrees, 15 with BRCA1 mutations and 4 with BRCA2 mutations. The association between BRCA2 and pancreatic cancer is well established; however, a definite link with pancreatic cancer in families carrying a BRCA1 mutation has been far less studied. Thus, the focus of this report is on 9 of the 15 BRCA1 families, in which PC affecteds were either confirmed carriers of the BRCA1 mutation or were inferred as probable obligate BRCA1 mutation carriers. The numbers are small, but nevertheless illustrate the finding of others of an apparent association between PC and BRCA1-mutation-bearing families. Given the dismal prognosis of PC, with the only current hope for survival being through surgical extirpation of the pancreas prior to metastasis, it is prudent that we realize the potential predisposition toward PC via BRCA1, in the hope of early diagnosis and prevention.

What the physician needs to know about Lynch syndrome: an update.

The Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), is the most common form of hereditary colorectal cancer (CRC), accounting for 2% to 7% of all CRC cases. The next most common hereditary CRC syndrome is familial adenomatous polyposis (FAP), which accounts for less than 1% of all CRC. Lynch syndrome is of crucial clinical importance due to the fact that it predicts the lifetime risk for CRC and a litany of extra-CRC cancers (of the endometrium, ovary, stomach, small bowel, hepatobiliary tract, upper uroepithelial tract, and brain) through assessment of a well-orchestrated family history. A Lynch syndrome diagnosis is almost certain when a mutation in a mismatch repair gene--most commonly MSH2, MLHI, or, to a lesser degree, MSH6--is identified. Once diagnosed, the potential for significant reduction in cancer-related morbidity and mortality through highly targeted surveillance may be profound. Particularly important is colonoscopy initiated at an early age (ie, 25 years) and repeated annually due to accelerated carcinogenesis. In women, endometrial aspiration biopsy and transvaginal ultrasound are important given the extraordinarily high risk for endometrial and ovarian carcinoma. These cancer control strategies have a major impact on at-risk family members once they have been counseled and educated thoroughly about Lynch syndrome's natural history and their own hereditary cancer risk.

Hereditary cancer: family history, diagnosis, molecular genetics, ecogenetics, and management strategies.

The translation of knowledge about hereditary breast cancer and its improved control, as well as prevention through prophylactic surgery, has been significantly accelerated through the veritable explosive discoveries in molecular genetics inclusive of BRCA1 and BRCA2 germline mutations. Needed however, among the physician community, medical geneticists, and genetic counselors, is a raised level of knowledge about hereditary breast cancer syndromes. Particular attention needs to be given to their extant genotypic and phenotypic heterogeneity, their natural history, and foremost, the requirement of a sufficiently detailed family history, with knowledge as to how to interpret its significance so that hereditary cancer syndrome can be diagnosed, should it, in fact, exist in the particular family. Collectively, surveillance and management programs can then be developed for the patient and his or her high-risk relatives. We believe very firmly that this knowledge needs to be extended to the individual patient(s), first- and second-degree relatives so that they can benefit from this knowledge.

Hereditary chronic lymphocytic leukemia: an extended family study and literature review.

Leukemia is manifested in about 1-2% of people in Western industrialized nations. The most common form of leukemia is B-cell chronic lymphocytic leukemia (B-CLL), which accounts for approximately 30% of all cases. While CLL's etiology remains elusive, there is increasing evidence that substantially supports the role of hereditary factors in a subset of cases of this disease. Our purpose is to describe an extremely well documented CLL family wherein the disease has been verified in a father and his four sons; two of the sons are identical twins. The family history, including available medical records and pathology reports, was gathered and reviewed. Peripheral blood lymphocytes were used for cytogenetic and fluorescence in situ hybridization analyses. The family reported herein shows classic findings in support of an autosomal dominant mode of genetic transmission of CLL. Given the explosive developments in molecular genetics during the past decade, it is certain that families of this type will provide important clues to the etiology, pathogenesis, and ultimate prevention of CLL.

Familial pancreatic carcinoma in Jews.

Pancreatic cancer (PC) is the most fatal of all gastrointestinal cancers, wherein its mortality compares strikingly with its incidence. Unfortunately, 80-90% of PCs are diagnosed in the nonresectable stage. While the lifetime risk of PC in developed countries is approximately 1-3%, it is the fifth most common cause of cancer deaths among both males and females in Western countries. It occurs in excess in Jews. Approximately 5-10% of PC shows familial clustering. Examination of such familial clusters must take into consideration cancers of diverse anatomic sites, such as malignant melanoma in the familial atypical multiple melanoma (FAMMM) syndrome due to the CDKN2A (p16) germline mutation, and combinations of colorectal and endometrial carcinoma, ovarian carcinoma, and several other cancers in hereditary nonpolyposis colorectal cancer (HNPCC), which are due to mismatch repair germline mutations, the most common of which are MSH2 and MLH1 . Other hereditary disorders predisposing to PC include Peutz-Jeghers syndrome, due to the STK11 mutation, familial pancreatitis due to the cationic trypsinogen gene, site-specific familial pancreatic cancer which may be due to the 4q32-34 mutation, hereditary breast-ovarian cancer (HBOC) syndrome that is due to BRCA2 and possibly some families with HBOC that is due to BRCA1 , familial adenomatous polyposis due to the ATP gene, and ataxia telangiectasia due to the ATM germline mutation. This extant heterogeneity mandates that the physician be knowledgeable about these PC-prone syndromes which play such an important role when considering the differential diagnosis of hereditary PC. Unfortunately, there are no PC screening programs with acceptable sensitivity and specificity. However, the gold standard for screening at this time is endoscopic ultrasound. Clearly, there is a great need for the development of novel screening approaches with acceptable sensitivity and specificity. Further research is needed to elucidate those etiologic factors that contribute to the apparent excess of PC in Ashkenazi Jews. Attention should also be given to the search for mutations predisposing to PC in Jews so that opportunities to learn more about the disease's pathogenesis, as well as screening and control, may take place.