We present the first characterisation of the mutational spectrum of the entire coding sequences and exon-intron boundaries of the BRCA1 and BRCA2 genes as well as large BRCA1 rearrangements in Portuguese families with inherited predisposition to breast/ovarian cancer. Of the 100 probands studied, pathogenic mutations were identified in 22 (24.7%) of 89 breast and/or ovarian cancer families with more than one affected member (15 in BRCA1 and seven in BRCA2), but in none of the 11 patients without family history of cancer. One (6.7%) of the BRCA1 mutations is a large deletion involving exons 11-15. Seven pathogenic point mutations are novel: 2088C>T, 2156delinsCC, and 4255_4256delCT in BRCA1 and 4608_4609delTT, 5036delA, 5583_5584insT, and 8923C>T in BRCA2. The novel 2156delinsCC was identified in three probands from different families and probably represents a founder mutation in our population. We also found a previously reported 3450_3453del4 mutation in three unrelated patients. In addition to the 22 pathogenic mutations, we identified 19 missense mutations of uncertain pathogenic significance, three of them (5241G>C in BRCA1 and IVS6+13C>T and 3731T>C in BRCA2) previously undescribed. The percentage of cases with truncating mutations in BRCA1 and BRCA2 was higher in breast/ovarian cancer (37.0%, mostly BRCA1) and male breast cancer (40%, all BRCA2) families than in families with only female breast cancer (17.5%). Interestingly, we found evidence for genetic anticipation regarding age at diagnosis of both breast and ovarian cancer in those families presenting affected members in more than one generation. These findings should be taken into consideration while planning screening and prophylactic measures in families with inherited predisposition to breast and ovarian cancer.

Purpose: Dihydropyrimidine dehydrogenase is a critical enzyme in the catabolism of 5-Fluorouracil, a drug frequently used in cancer therapy. Patients with deficient dihydropyrimidine dehydrogenase activity are at risk of developing severe 5-Fluorouracil-associated toxicity. Genetic analysis of the gene coding for dihydropyrimidine dehydrogenase has shown that mutations in exon 14, especially the splice-site mutation IVS14ϩ1G3 A, were associated with dihydropyrimidine dehydrogenase enzymatic deficiency. Methods: We evaluated the frequency of mutations in exon 14 of dihydropyrimidine dehydrogenase (DPYD) gene in 73 unselected colorectal cancer patients treated with 5-Fluorouracil after surgery at a Portuguese Cancer Institute. Results: Sequencing the entire exon 14 allowed the detection of mutations in two of the 73 patients (2.7%), namely two of the eight (25%) patients who presented grade 3-4 toxicity after 5-Fluorouracil chemotherapy. One patient was heterozygous for the splice-site mutation IVS14ϩ1G3 A, whereas the second patient was heterozygous for a novel missense mutation 1845G3 T (E615D) in exon 14 of DPYD gene. Conclusion: We conclude that mutations in exon 14 of DPYD gene are responsible for a significant proportion of life-threatening toxicity to 5-Fluorouracil, and should therefore be excluded before its administration to cancer patients. Genet Med 2004:6(2):102-107. Key Words: DPYD mutations, dihydropyrimidine dehydrogenase, 5-FU toxicity, 5-FU catabolism, chemotherapy5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic drugs for the treatment of malignant neoplasms, namely colorectal cancer. 5-FU is a pyrimidine analogue, giving rise to cytotoxic metabolites after metabolization by the pyrimidine pathways. One of them, the 5-fluorodUMP, inhibits thymidylate synthase, thus impairing DNA synthesis. Additional cytotoxic effects arise from 5-FU metabolites being incorporated into RNA and DNA. 1 Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. It has been reported that more than 80% of the administered 5-FU is catabolized by DPD, 2-4 so the activity of this enzyme may be of paramount importance to predict the efficacy and toxicity of this drug. Deficiency in DPD enzyme activity has been correlated with considerable delay in 5-FU clearance from plasma. 4,5 The important role of DPD in 5-FU-based chemotherapy has been demonstrated in cancer patients with major deficiency of this enzyme's activity. These patients may present severe toxicity after the administration of 5-FU, including diarrhea, neutropenia, and neurotoxicity, and death may occasionally occur. 6 -9 Population studies suggested that, although total deficiency is rare, as many as 3% to 5% of the population may have low enzyme levels and thus be at increased risk of severe toxicity if treated with 5-FU. 10 Several of these patients are genotypically heterozygous for a mutant DPYD allele. [11][12][13][14][15][16] To date, more than 30 variant DPYD alleles have been identi...

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