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- Antoniou, A, et al.
(författare)
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Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies
- 2003
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 72:5, s. 1117-1130
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers ( P trend .0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.
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| 2. |
- Threadgold, J, et al.
(författare)
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The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease
- 2002
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 50:5, s. 675-681
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mutations in the PRSS1 gene explain most occurrences of hereditary pancreatitis (HP) but many HP families have no PRSS1 mutation. Recently, an association between the mutation N34S in the pancreatic secretary trypsin inhibitor (SPINK1 or PSTI) gene and idiopathic chronic pancreatitis (ICP) was reported. It is unclear whether the N34S mutation is a cause of pancreatitis per se, whether it modifies the disease, or whether it is a marker of the disease. Patients and methods: A total of 327 individuals from 217 families affected by pancreatitis were tested: 152 from families with HP, 108 from families with ICP, and 67 with alcohol related CP (ACP). Seven patients with ICP had a family history of pancreatitis but no evidence of autosomal dominant disease (f-ICP) compared with 87 patients with true ICP (t-ICP). Two hundred controls were also tested for the N34S mutation. The findings were related to clinical outcome. Results: The N34S mutation was carried by five controls (2.5%; allele frequency 1.25%), 11/87 (13%) t-ICP patients (p=0.0013 v controls), and 6/7 (86%) affected (p<0.0001 v controls) and 1/9 (11%) unaffected f-ICP cases. N34S was found in 4/108 affected HP patients (p=0.724 v controls), in, 3/27 (11%) with wild-type and in 1/81 (1%) with mutant PRSS1, and 4/67 ACP patients (all p>0.05 v controls). The presence of the N34S mutation was not associated with early disease onset or disease severity. Conclusions: The prevalence of the N34S mutation was increased in patients with ICP and was greatest in f-ICP cases. Segregation of the N34S mutation in families with pancreatitis is unexplained and points to a complex association between N34S and another putative pancreatitis related gene.
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