Attenuated familial adenomatous polyposis (AFAP) in a patient associated with a novel mutation in APC.

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome associated with mutation in the adenomatous polyposis coli (APC) gene, a tumour suppressor located on chromosome 5q21. Attenuated familial adenomatous polyposis (AFAP) is a variant associated with fewer and later onset of colon polyps. AFAP-associated APC mutations have largely been found before codon 157, in exon 9 or after codon 1595. We present the case of a 44-year-old man incidentally found to have numerous gastric polyps during bariatric surgery, with innumerable polyps in the remaining part of the stomach and the entire colon, with rectal sparing, consistent with AFAP phenotype. Genetic testing demonstrated the c.7682dup (p.Ser2562Lysfs*21) variant in exon 15 of APC. This represents a previously undescribed APC mutation. This mutation likely yields end-binding protein 1 and human disc large binding protein inactivation, causing cell cycle microtubule dysregulation and tumour suppressor inactivation. Through loss of these regulatory mechanisms, this mutation is associated with AFAP phenotype. The patient was treated surgically and is doing well.

Ovarian cancer in BRCA mutation carriers: improved outcome after intraperitoneal (IP) cisplatin.

BACKGROUND: Ovarian cancer arising in women with BRCA mutations is known to have a more favorable outcome and to be more responsive to platinum-based regimens than in those without a hereditary background. We analyze our previously published intraperitoneal (IP) studies in relation to BRCA mutation status and update their outcomes. METHODS: Among 62 patients with ovarian cancer enrolled in IP platinum doublet studies in clinical trials (with etoposide (n = 18), with floxuridine (n = 30), and with topotecan (n = 14)), a deleterious BRCA mutation was eventually identified in 10 patients. The outcomes in these BRCA mutation carriers are described and compared with survival of others in respective trials. RESULTS: Ten patients that were confirmed to have BRCA mutations-all with high-grade and stages IIC to IV disease-survived a median of 10 years (range: 4-18+) after receiving IP cisplatin-based regimens. Two continue with no evidence of disease since their IP treatment, while four others remain alive with recurrences after 8, 9, 10, and 11 years, respectively. CONCLUSIONS: This experience suggests that IP cisplatin leads to favorable long term outcomes in advanced ovarian cancer in women with defective homologous recombination (i.e., with deleterious BRCA mutations). Whether such cisplatin dose-intensification from IP relative to (intravenous) IV drug administration leads to superior results in these mutation carriers requires further study.

A pilot study of letrozole for one year in women at enhanced risk of developing breast cancer: effects on mammographic density.

BACKGROUND: Tamoxifen or raloxifen for 5 years reduces the risk of developing invasive breast cancer by 40%. To address safety concerns and seek enhanced efficacy, studies of new chemopreventive agents using mammographic density as a surrogate end point are attractive. PATIENTS AND METHODS: Postmenopausal women with risk factors for developing breast cancer were given letrozole 2.5 mg daily for one year, and mammographic density was the biomarker of breast cancer risk modification. It was assessed (blinded to the reader) at baseline, 6, and 12 months in 16 evaluable women among 20 enrolled. RESULTS: Eight patients exhibited decreased mammographic density at six months, and eleven at 12 months. Toxicities included joint aches not precluding continued treatment. CONCLUSION: This pilot study supports the use of letrozole for reducing breast cancer risk. In addition, it encourages prospective studies of serial changes in mammographic density as a biomarker of risk modification within a selected high-risk population.

Expression of cancer testis antigens in human BRCA-associated breast cancers: potential targets for immunoprevention?

INTRODUCTION: Novel breast cancer risk-reducing strategies for individuals with germline mutations of the BRCA1 and/or BRCA2 genes are urgently needed. Identification of antigenic targets that are expressed in early cancers, but absent in normal breast epithelium of these high-risk individuals, could provide the basis for the development of effective immunoprophylactic strategies. Cancer testis (CT) antigens are potential candidates because their expression is restricted to tumors, and accumulating data suggest that they play important roles in cellular proliferation, stem cell function, and carcinogenesis. The objective of this study was to examine the expression of CT antigens and their frequency in BRCA-associated breast cancers. METHODS: Archived breast cancer tissues (n = 26) as well as morphologically normal breast tissues (n = 7) from women carrying deleterious BRCA 1 and/or 2 mutations were obtained for antigen expression analysis by immunohistochemistry. Expression of the following CT antigens was examined: MAGE-A1, MAGE-A3, MAGE-A4, MAGE-C1.CT7, NY-ESO-1, MAGE-C2/CT10, and GAGE. RESULTS: CT antigens were expressed in 16/26 (61.5%, 95% CI 43-80%) of BRCA-associated cancers, including in situ tumors. Thirteen of twenty-six (50%) breast cancers expressed two or more CT antigens; three cancers expressed all seven CT antigens. MAGE-A was expressed in 13/26 (50%) of cancers, NY-ESO-1 was expressed in 10/26 (38%) of tumors. In contrast, none of the CT antigens were expressed in adjacent or contralateral normal breast epithelium (P = 0.003). CONCLUSIONS: We report a high CT antigen expression rate in BRCA-associated breast cancer as well as the lack of expression of these antigens in benign breast tissue of carriers, identifying CT antigens as potential vaccine targets for breast cancer prevention in these high-risk individuals.

Three synchronous primary carcinomas in a patient with HNPCC associated with a novel germline mutation in MLH1: Case report.

BACKGROUND: MLH1 is one of six known genes responsible for DNA mismatch repair (MMR), whose inactivation leads to HNPCC. It is important to develop genotype-phenotype correlations for HNPCC, as is being done for other hereditary cancer syndromes, in order to guide surveillance and treatment strategies in the future. CASE PRESENTATION: We report a 47 year-old male with hereditary nonpolyposis colorectal cancer (HNPCC) associated with a novel germline mutation in MLH1. This patient expressed a rare and severe phenotype characterized by three synchronous primary carcinomas: ascending and splenic flexure colon adenocarcinomas, and ureteral carcinoma. Ureteral neoplasms in HNPCC are most often associated with mutations in MSH2 and rarely with mutations in MLH1. The reported mutation is a two base pair insertion into exon 10 (c.866_867insCA), which results in a premature stop codon. CONCLUSION: Our case demonstrates that HNPCC patients with MLH1 mutations are also at risk for ureteral neoplasms, and therefore urological surveillance is essential. This case adds to the growing list of disease-causing MMR mutations, and contributes to the development of genotype-phenotype correlations essential for assessing individual cancer risk and tailoring of optimal surveillance strategies. Additionally, our case draws attention to limitations of the Amsterdam Criteria and the need to maintain a high index of suspicion when newly diagnosed colorectal cancer meets the Bethesda Criteria. Establishment of the diagnosis is the crucial first step in initiating appropriate surveillance for colorectal cancer and other HNPCC-associated tumors in at-risk individuals.

T-cell clonality and myelodysplasia without chromosomal fragility in a patient with features of Seckel syndrome.

Seckel syndrome is a rare autosomal recessive disorder with characteristic craniofacial dysmorphism, skeletal defects, mental and prenatal growth retardation. About 50 cases have been reported in the literature. Hematologic abnormalities with associated chromosomal fragility have been noted in about 15% of the reported cases. We report a patient with Seckel syndrome with myelodysplastic features and clonal T-cells in the bone marrow but no evidence of chromosomal fragility. After 5 years of follow-up, this patient remains asymptomatic without any treatment and with stable peripheral blood counts.

Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis.

It has been known for several years that heterozygous mutations of three members of the fibroblast growth-factor-receptor family of signal-transduction molecules-namely, FGFR1, FGFR2, and FGFR3-contribute significantly to disorders of bone patterning and growth. FGFR3 mutations, which predominantly cause short-limbed bone dysplasia, occur in all three major regions (i.e., extracellular, transmembrane, and intracellular) of the protein. By contrast, most mutations described in FGFR2 localize to just two exons (IIIa and IIIc), encoding the IgIII domain in the extracellular region, resulting in syndromic craniosynostosis including Apert, Crouzon, or Pfeiffer syndromes. Interpretation of this apparent clustering of mutations in FGFR2 has been hampered by the absence of any complete FGFR2-mutation screen. We have now undertaken such a screen in 259 patients with craniosynostosis in whom mutations in other genes (e.g., FGFR1, FGFR3, and TWIST) had been excluded; part of this screen was a cohort-based study, enabling unbiased estimates of the mutation distribution to be obtained. Although the majority (61/62 in the cohort sample) of FGFR2 mutations localized to the IIIa and IIIc exons, we identified mutations in seven additional exons-including six distinct mutations of the tyrosine kinase region and a single mutation of the IgII domain. The majority of patients with atypical mutations had diagnoses of Pfeiffer syndrome or Crouzon syndrome. Overall, FGFR2 mutations were present in 9.8% of patients with craniosynostosis who were included in a prospectively ascertained sample, but no mutations were found in association with isolated fusion of the metopic or sagittal sutures. We conclude that the spectrum of FGFR2 mutations causing craniosynostosis is wider than previously recognized but that, nevertheless, the IgIIIa/IIIc region represents a genuine mutation hotspot.