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- Yang, Xin, et al.
(author)
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Cancer risks associated with germline PALB2 pathogenic variants : An international study of 524 families
- 2020
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In: Journal of Clinical Oncology. - 0732-183X. ; 38:7, s. 674-685
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Journal article (peer-reviewed)abstract
- PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 3 1022). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.
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- Djursby, Malene, et al.
(author)
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Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer
- 2022
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In: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 141:12, s. 1925-1933
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Journal article (peer-reviewed)abstract
- The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch syndrome-associated mismatch repair (MMR) gene MSH6 (n = 6). In conclusion, screening using a comprehensive cancer gene panel in families with accumulation of late-onset CRC appears not to have a significant clinical value due to the low level of high-risk pathogenic variants detected. Our data suggest that only patients with abnormal MMR immunohistochemistry (IHC) or microsatellite instability (MSI) analyses, suggestive of Lynch syndrome, or a family history indicating another cancer predisposition syndrome should be prioritized for such genetic evaluations. Variants in MSH6 and MUTYH have previously been proposed to be involved in digenic or oligogenic hereditary predisposition to CRC. Accumulation of variants in MSH6 and monoallelic, pathogenic variants in MUTYH in our study indicates that digenic or oligogenic inheritance might be involved in late-onset CRC and warrants further studies of complex types of inheritance.
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- Olafsdottir, Elinborg J., et al.
(author)
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Breast cancer survival in Nordic BRCA2 mutation carriers—unconventional association with oestrogen receptor status
- 2020
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 123:11, s. 1608-1615
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Journal article (peer-reviewed)abstract
- Background: The natural history of breast cancer among BRCA2 carriers has not been clearly established. In a previous study from Iceland, positive ER status was a negative prognostic factor. We sought to identify factors that predicted survival after invasive breast cancer in an expanded cohort of BRCA2 carriers. Methods: We studied 608 women with invasive breast cancer and a pathogenic BRCA2 mutation (variant) from four Nordic countries. Information on prognostic factors and treatment was retrieved from health records and by analysis of archived tissue specimens. Hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression. Results: About 77% of cancers were ER-positive, with the highest proportion (83%) in patients under 40 years. ER-positive breast cancers were more likely to be node-positive (59%) than ER-negative cancers (34%) (P < 0.001). The survival analysis included 584 patients. Positive ER status was protective in the first 5 years from diagnosis (multivariate HR = 0.49; 95% CI 0.26–0.93, P = 0.03); thereafter, the effect was adverse (HR = 1.91; 95% CI 1.07–3.39, P = 0.03). The adverse effect of positive ER status was limited to women who did not undergo endocrine treatment (HR = 2.36; 95% CI 1.26–4.44, P = 0.01) and patients with intact ovaries (HR = 1.99; 95% CI 1.11–3.59, P = 0.02). Conclusions: The adverse effect of a positive ER status in BRCA2 carriers with breast cancer may be contingent on exposure to ovarian hormones.
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