Cancer Susceptibility Mutations Research Articles

Inherited Susceptibility for Pediatric Cancer

The percentage of childhood cancers that are caused by a clearly inherited predisposition varies significantly from only a few percent to more than 50% with individual tumor types. Recent advances in genetic testing and studies of cohorts of cancer patients have demonstrated the likelihood of identifying a cancer susceptibility mutation for numerous childhood cancers. Inherited predisposition to cancer is frequently the result of dominant constitutional mutations in tumor suppressor genes, which can be inherited from an affected parent or occur de novo during gametogenesis. In this article, we review the childhood malignancies that are associated with at least a 10% likelihood of being caused by a genetic susceptibility to cancer and therefore warrant consideration for a genetic evaluation; these malignancies include retinoblastoma, adrenocortical carcinoma, atypical teratoid and malignant rhabdoid tumors, optic pathway tumors, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, vestibular schwannomas, endolymphatic sac tumors, hemangioblastomas, medullary thyroid cancer, pheochromocytomas, and paragangliomas. Children with other malignancies may also warrant genetic evaluation if there is the co-occurrence of malignancy and two or more congenital anomalies, or malignancy and a significant family history of related cancers. We also review the importance of the correct genetic diagnosis in order to ensure appropriate treatment and ongoing cancer surveillance for the child with cancer and closely related family members (e.g., parents and siblings).

Intra-abdominal carcinomatosis after prophylactic oophorectomy in women of hereditary breast ovarian cancer syndrome kindreds associated with BRCA1 and BRCA2 mutations

Objective Prophylactic surgical removal of the ovaries has been offered for many years as a potential preventative of ovarian cancer in women deemed to be at increased hereditary risk for this disease. Now, it is possible to test for specific mutations of the BRCA1 and BRCA2 genes that render members of hereditary breast ovarian cancer (HBOC) syndrome families susceptible to cancer. Widespread intra-abdominal carcinomatosis, which mimics metastatic ovarian serous carcinoma, has been reported following oophorectomy in individuals at increased hereditary risk. This study was undertaken to examine and report particularly the occurrence of intra-abdominal carcinomatosis, as well as other cancers, following prophylactic oophorectomy in patients who carry cancer susceptibility mutations of BRCA1 and BRCA2 and to assess the cumulative risks for this disease in order to assist in developing appropriate surgical interventions, based on currently available information, and to counsel patients who choose prophylactic surgery, concerning the potential prognosis, thereafter. Methods The Creighton University Hereditary Cancer Institute registry was searched for members of HBOC syndrome families who had undergone prophylactic oophorectomy. The histories and results of DNA testing for the BRCA1 and BRCA2 mutations carried in their families were recorded, tabulated and examined, and the aggregate data are reported along with pertinent details of those individuals who developed neoplastic diseases after prophylactic oophorectomy. All available histologic and cytologic materials of patients who were diagnosed with intra-abdominal carcinomatosis were reviewed, and life-table calculations were performed to assess cumulative risks for this disease following prophylactic oophorectomy. Results From 72 HBOC syndrome families that carried either BRCA1 or BRCA2 cancer-associated mutations, 238 individuals who had undergone prophylactic oophorectomy were recorded in our registry between January 1985 and December 2002. During a mean follow-up of 9.3 years, cancers were diagnosed in 27 subjects, including 16 individuals with breast cancer and five patients with intra-abdominal carcinomatosis. Breast cancers were stage I in 10 of 12 proven carriers of cancer-associated mutations. All five cases of intra-abdominal carcinomatosis were serous carcinomas, and all occurred in BRCA1 mutation carriers. Histologic review of the prophylactically removed ovaries found borderline lesions in two cases, one with possible early stromal invasion. Two of the five patients who developed intra-abdominal carcinomatosis were among 78 patients in this series who were diagnosed and treated for breast cancer before prophylactic oophorectomy. A 3.5% cumulative risk for all mutation carriers and a 3.9% cumulative risk for BRCA1 mutation carriers were calculated through 20 years of follow-up after prophylactic oophorectomy. Conclusions Intra-abdominal carcinomatosis in our series was diagnosed only in BRCA1 mutation carriers. The calculated cumulative risks of developing intra-abdominal carcinomatosis after prophylactic oophorectomy in members of HBOC syndrome families, specifically those who carry deleterious mutations, are well below the estimated risks of ovarian cancer published in the literature for similar patients. Breast cancers, which tended to be small and localized, were the most common malignancy in BRCA1 and BRCA2 mutation carriers after prophylactic oophorectomy.

Basic concepts for genetic testing in common hereditary colorectal cancer syndromes.

Approximately 5% of colorectal cancers are associated with one of the autosomal dominant hereditary cancer syndromes. The two most common familial colon cancer syndromes are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). The causative mutation can be identified in many families with these syndromes by genetic testing of an affected individual. If an affected individual tests positive for a disease-causing mutation, genetic testing of unaffected, at-risk family members can be performed to determine whether they have inherited the cancer-susceptibility mutation, and a personalized cancer surveillance strategy can be devised. Genetic testing significantly enhances cancer risk assessment in these families. However, the complicated nature of result interpretation and the emotional impact of the result necessitate that testing be carried out in conjunction with patient education and informed consent by a physician who has a keen appreciation for the inherent challenges. This article describes the genetic testing strategy in HNPCC and FAP.

Should women at increased risk for breast and ovarian cancer be randomized to prophylactic surgery? An ethical and empirical assessment.

More information is needed about the relative effectiveness of prophylactic surgery, chemoprevention, and surveillance in reducing breast and ovarian cancer risk in women with an inherited susceptibility mutation. We assessed practical and ethical barriers to conducting randomized clinical trials (RCTs) to compare preventive interventions for breast and ovarian cancer. Eighty-seven at-risk women who attended an education and counseling session about BRCA1/2 testing were asked about their willingness to participate in hypothetical research studies for breast and ovarian cancer risk reduction. In addition, 247 Maryland physicians from five specialties completed a mail survey including a question about their likelihood of recommending RCT participation to an at-risk woman. Nineteen percent of at-risk women reported willingness to participate in a hypothetical RCT for breast cancer risk reduction and 17% for ovarian cancer risk reduction. Women with children and women likely to have a prophylactic mastectomy if found to have a susceptibility mutation were significantly more willing to participate in an RCT. A majority of women would be willing to participate in nonrandomized trials or registries. Fifty-two percent of physicians responded that they would be likely to recommend RCT participation to a woman carrying a breast cancer susceptibility mutation. Oncologists were the most likely to recommend an RCT. Although the results of nonrandomized trials may be difficult to interpret because of such issues as selection bias. Greater feasibility combined with fewer ethical concerns make nonrandomized trials a more viable alternative to randomized trials for evaluation of preventive interventions for breast and ovarian cancer when prophylactic surgery is one of the treatments being evaluated.