Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations.
ABSTRACT A clinical testing cohort was used to gain a broader understanding of the spectrum of tumors associated with germline p53 mutations to aid clinicians in identifying high-risk families.
Full sequencing of the coding exons (2 to 11) and associated splice junctions of the p53 gene was performed on 525 consecutive patients whose blood samples were submitted for diagnostic testing. Clinical features of p53 germline carriers in this cohort were characterized, clinical referral schemes based on reported p53-associated family phenotypes were evaluated, and practical mutation prevalence tables were generated.
Mutations were identified in 91 (17%) of 525 patients submitted for testing. All families with a p53 mutation had at least one family member with a sarcoma, breast, brain, or adrenocortical carcinoma (ACC). Every individual with a choroid plexus tumor (eight of eight) and 14 of 21 individuals with a childhood ACC had a mutation regardless of family history. Based on reported personal and family history, 95% of patients (71 of 75) with a mutation met either classic Li Fraumeni syndrome (LFS) or Chompret criteria. A simplified prevalence table provides a concise summary of individual and family characteristics associated with p53 mutations.
This is, to our knowledge, the largest single report of diagnostic testing for germline p53 mutations, yielding practical mutation prevalence tables and suggesting clinical utility of classic LFS and Chompret criteria for identifying a subset of cancer-prone families with p53 germline mutations, with important implications for diagnosis and management.
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ABSTRACT: Tumor suppressor genes BRCA1 and BRCA2 are the two main breast and ovarian cancer susceptibility genes, and their genetic testing has been used to evaluate the risk of hereditary breast and ovarian cancer (HBOC). While several studies have reported the prevalence of BRCA1 and BRCA2 mutations in Japanese populations, there is insufficient information about deleterious mutations compared with western countries. Moreover, because many rare variants are found in BRCA1 and BRCA2, both of which encode large proteins, it is difficult to sequence all coding regions using the Sanger method for mutation detection. In this study, therefore, we performed next-generation sequencing (NGS) analysis of the entire coding regions of BRCA1 and BRCA2 in 135 breast and/or ovarian cancer patients. Deleterious BRCA1 and BRCA2 mutations were detected in 10 patients (7.4%) by NGS analysis. Of these, one mutation in BRCA1 and two in BRCA2 had not been reported previously. Furthermore, a BRCA2 mutation found in a proband was also identified in two unaffected relatives. These data suggest the utility of screening BRCA1 and BRCA2 mutations by NGS in clinical diagnosis.Molecular Genetics & Genomic Medicine. 10/2014;
Article: Beyond BRCA1 and BRCA2.Current Problems in Cancer 11/2014; 38(6):235-248. · 1.00 Impact Factor
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ABSTRACT: As more women with an inherited increased risk of gynecologic cancer are identified, the clinician will be challenged to counsel these women on risk-reducing strategies. Although there are some recent studies that show potential for ovarian cancer surveillance strategies, there remains no definitive evidence that surveillance leads to a stage shift or a reduction in mortality. Recent studies support the following conclusions: first, oral contraceptive use reduces ovarian cancer risk without significantly increasing breast cancer risk, second, salpingo-oophorectomy leads to a reduction in ovarian cancer, breast cancer, and overall mortality for women who are carriers of BRCA1 and BRCA2 mutations, and third, the 'ovarian cancers' associated with BRCA mutations actually include fallopian tube and peritoneal cancer and may have a precursor lesion in the fallopian tube; this observation has prompted the provocative suggestion of removing the fallopian tube to reduce ovarian cancer risk. Because of the interplay between the hormonal impact of ovarian function on breast cancer risk, the risk reduction associated with oophorectomy, and the impact of early menopause on other health outcomes, an integrated multidisciplinary approach is required to aid in the increasingly complex decisions faced by women with high inherited risk of developing gynecologic cancers.Current Opinion in Obstetrics and Gynecology 12/2014; 27(1). · 2.37 Impact Factor