BRCA1 and BRCA2 mutation testing in Cyprus; a population based study.

This paper presents the largest study in Cyprus evaluating the frequency and distribution of BRCA1/2 mutations in a high risk patient cohort. Deleterious mutations in the BRCA1/2 genes were identified in 68 of the 527 patients tested (13%). It is of interest that a quarter of those tested positive, did not have an extensive family history of breast/ovarian cancer but were diagnosed with early onset breast cancer, ovarian cancer under the age of 60 or triple negative breast cancer. The spectrum of mutations identified in our patient cohort is different compared to other Mediterranean countries. Furthermore, several of the mutations detected are novel and have not been identified in other ethnic populations. This highlights the importance of operating a national reference center for cancer genetic diagnosis which offers services tailored to the needs of the Cypriot population.

Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early-onset breast cancer in Cyprus.

In Cyprus, the prevalence of breast cancer associated with BRCA1 and BRCA2 mutations in young women is unknown. In this study, we present the results of mutational analysis of the BRCA1 and BRCA2 genes in 26 Cypriot women diagnosed with breast cancer by the age of 40. The entire coding regions, including splice sites, of the BRCA1 and BRCA2 genes were sequenced using cycle sequencing. We identified four pathogenic mutations: two in BRCA1 [c.1840A>T (K614X), c.5310delG (5429delG)] and two in BRCA2 [c.3531-3534delCAGC (3758del4), c.8755delG (8984delG)] in six of 26 unrelated patients. The BRCA2 mutation c.3531-3534delCAGC (3758del4) is novel and the BRCA1 mutation c.1840A>T (K614X) is reported for the first time in Cypriot patients. The BRCA2 Cypriot founder mutation c.8755delG (8984delG) was detected in three unrelated patients. Additionally, we identified one novel BRCA1 missense mutation, two novel polymorphisms and three novel intronic variants of which BRCA1 c.4185+3A>G (IVS12+3A>G) may be pathogenic. Of the six BRCA1/2 mutation carriers, only four had a family history. These results show that the prevalence of BRCA1 and BRCA2 mutations in Cypriot women diagnosed with early-onset breast cancer is high. We conclude that Cypriot women with early-onset breast cancer should be offered BRCA1/2 testing irrespective of their family history.

Normal cellular radiosensitivity in an adult Fanconi anaemia patient with marked clinical radiosensitivity.

BACKGROUND: Fanconi anaemia is a rare disease associated with cellular sensitivity to chemicals (e.g. mitomycin C and diepoxybutane); variable but mild cellular radiosensitivity has also been reported. MATERIALS AND METHODS: A 32-year-old patient with Fanconi anaemia and tonsillar carcinoma, treated by radiotherapy, was found to exhibit profound clinical radiosensitivity. Confluent, ulcerating oropharyngeal mucositis developed after a conventionally fractionated dose of 34Gy and healing was incomplete by 2 months after cessation of therapy. RESULTS: Cellular radiosensitivity assays and RPLD studies from this patient did not suggest any major detectable radiosensitivity. CONCLUSION: There is a discrepancy between the observed clinical radiosensitivity and the usual "predictive" radiosensitivity assays in this patient with Fanconi anaemia.

What is the optimal therapy of brain metastases?

The conclusions of a symposium held in London in October 1999 and devoted to the optimal management of brain metastatic disease were: 1. Prognostic factors are: size and number of metastases (and the presence of mass effect); the status of the systemic cancer outside the central nervous system; performance/neurological status; the age of the patient; and the type of cancer. 2. Surgical management of the single, superficially located brain metastasis with symptomatic mass effect is recommended in good performance status patients. Many would follow this routinely by whole brain radiotherapy. 3. Whole brain radiotherapy is often not followed by durable control of the disease and carries morbidity; better management plans are required. In poor prognosis patients the delivery of radiotherapy may not always be indicated. 4. The current literature demonstrates that stereotactic radiosurgery can enhance the likelihood of sterilizing individual brain metastases compared with whole brain radiotherapy alone. 5. The results of questionnaire showed that the histological diagnosis and latency to onset made little difference to the opinion of neuroscience clinicians, who generally favoured stereotactic radiation therapy over whole brain radiotherapy (with or without a conventionally delivered boost) for all patients with less than four metastases. The opinions of oncologists differed. For bronchial and breast cancer patients, whole brain radiotherapy, with or without a boost, was favoured by the majority, particularly in oat cell cancer. However, with a long latency to 'isolated' brain metastasis, oncologists favoured focal radiation therapy. There was a strong preference amongst oncology experts to reserve stereotactic radiation therapy for apparently isolated brain metastasis; this opinion applied to bronchus and breast cancer, and also to melanoma. 6. Whole brain radiotherapy followed by positron emission tomography scanning to determine what viable metastatic disease remained (and potentially treatable by stereotactic/focal technology) was favoured by most of delegates who answered this question.

Stereotactic radiosurgery for pituitary adenomas.

Pituitary adenoma is a radiosensitive disease and postoperative radiotherapy reduces the chance of relapse. Non-irradiated patients, followed in the modern era, suffer up to 20% five-year and up to 44% ten-year relapse. To some extent, predictors of relapse are available at the time of presentation or after surgery. Although conventionally fractionated radiotherapy has a very good track record with regard to controlling disease and safety in the modern age, there is considerable contemporary interest in the technique of radiosurgery (highly concentrated radiation therapy using stereotactic mapping). The usefulness of this technique in the treatment of pituitary adenoma is discussed in this review.