Chromosomal radiosensitivity and low penetrance predisposition to cancer.
AffiliationPaterson Institute for Cancer Research, Christie Hospital NHS Trust, Withington, Manchester, UK. firstname.lastname@example.org
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AbstractThis mini-review summarises studies in this Institute on the sensitivity of cells of patients with common cancers to the chromosome-damaging effects of ionising radiation, in the context of related studies. Using the 90th percentile of healthy controls (n >200) as the cut-off point between a normal and a sensitive response, 40% of patients with breast cancer (n = 166) were sensitive when cells were irradiated in the G2 phase of the cell cycle. Smaller studies showed that patients with colorectal, head and neck (at < 45 years) and childhood cancers also exhibited degrees of enhanced sensitivity, whereas cervical and lung cancer cases did not. Cells from breast and head and neck cases irradiated in G(0) also showed increased sensitivity. We propose that such elevated sensitivity is a marker of low penetrance predisposition to cancer. The strongest support for this hypothesis was our demonstration of the Mendelian heritability of chromosomal radiosensitivity in 95 family members of breast cancer cases. Challenges for the future include more heritability studies, identification of the underlying genetic determinants, assessment of the associated cancer risk (spontaneous and radiogenic) and population screening for cancer prevention strategies.
CitationChromosomal radiosensitivity and low penetrance predisposition to cancer. 2004, 104 (1-4):365-70 Cytogenet. Genome Res.
JournalCytogenetic and Genome Research
- Chromosomal radiosensitivity as a marker of predisposition to common cancers?
- Authors: Baria K, Warren C, Roberts SA, West CM, Scott D
- Issue date: 2001 Apr 6
- Chromosomal radiosensitivity in young cancer patients: possible evidence of genetic predisposition.
- Authors: Baria K, Warren C, Eden OB, Roberts SA, West CM, Scott D
- Issue date: 2002 May
- Chromosomal radiosensitivity, cancer predisposition and response to radiotherapy.
- Authors: Scott D
- Issue date: 2000 May
- Chromosomal mutagen sensitivity associated with mutations in BRCA genes.
- Authors: Speit G, Trenz K
- Issue date: 2004
- Heritability of cellular radiosensitivity: a marker of low-penetrance predisposition genes in breast cancer?
- Authors: Roberts SA, Spreadborough AR, Bulman B, Barber JB, Evans DG, Scott D
- Issue date: 1999 Sep
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Ovarian cancer among 8,005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2.Ingham, S; Warwick, J; Buchan, I; Sahin, S; O'Hara, Catherine; Moran, Anthony; Howell, Anthony; Evans, D; Centre for Health Informatics, Institute of Population Health, The University of Manchester, Manchester, UK. (2013-06)Mutations in BRCA1/2 genes confer ovarian, alongside breast, cancer risk. We examined the risk of developing ovarian cancer in BRCA1/2-positive families and if this risk is extended to BRCA negative families.
Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council.De Wit, Ronald; Roberts, J Trevor; Wilkinson, Peter M; De Mulder, Pieter H M; Mead, Graham M; Fosså, S D; Cook, P; De Prijck, Linda; Stenning, S; Collette, L; Rotterdam Cancer Institute and University Hospital, Rotterdam, The Netherlands. email@example.com (2001-03-15)PURPOSE: To test the equivalence of three versus four cycles of bleomycin, etoposide, and cisplatin (BEP) and of the 5-day schedule versus 3 days per cycle in good-prognosis germ cell cancer. PATIENTS AND METHODS: The study was designed as a 2 x 2 factorial trial. The aim was to rule out a 5% decrease in the 2-year progression-free survival (PFS) rate. The study included the assessment of patient quality of life. A cycle of BEP consisted of etoposide 500 mg/m(2), administered at either 100 mg/m(2) days 1 through 5 or 165 mg/m(2) days 1 through 3, cisplatin 100 mg/m(2), administered at either 20 mg/m(2) days 1 through 5 or 50 mg/m(2) days 1 and 2. Bleomycin 30 mg was administered on days 1, 8, and 15 during cycles 1 through 3. The randomization procedure allowed some investigators to participate only in the comparison of three versus four cycles. RESULTS: From March 1995 until April 1998, 812 patients were randomly assigned to receive three or four cycles: of these, 681 were also randomly assigned to the 5-day or the 3-day schedule. Histology, marker values, and disease extent are well balanced in the treatment arms of the two comparisons. The projected 2-year PFS is 90.4% on three cycles and 89.4% on four cycles. The difference in PFS between three and four cycles is -1.0% (80% confidence limit [CL], -3.8%, +1.8%). Equivalence for three versus four cycles is claimed because both the upper and lower bounds of the 80% CL are less than 5%. In the 5- versus 3-day comparison, the projected 2-year PFS is 88.8% and 89.7%, respectively (difference, -0.9%, (80% CL, -4.1%, +2.2%). Hence, equivalence is claimed in this comparison also. Frequencies of hematologic and nonhematologic toxicities were essentially similar. Quality of life was maintained better in patients receiving three cycles; no differences were detected between 3 and 5 days of treatment. CONCLUSION: We conclude that three cycles of BEP, with etoposide at 500 mg/m(2), is sufficient therapy in good-prognosis germ cell cancer and that the administration of the chemotherapy in 3 days has no detrimental effect on the effectiveness of the BEP regimen.
Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a Clinical Cancer Genetics service setting: risks of breast/ovarian cancer quoted should reflect the cancer burden in the family.Evans, D Gareth R; Shenton, Andrew; Woodward, Emma; Lalloo, Fiona; Howell, Anthony; Maher, Eamonn R; Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital Manchester M13 0JH, UK. firstname.lastname@example.org (2008)BACKGROUND: The identification of a BRCA1 or BRCA2 mutation in familial breast cancer kindreds allows genetic testing of at risk relatives. However, considerable controversy exists regarding the cancer risks in women who test positive for the family mutation. METHODS: We reviewed 385 unrelated families (223 with BRCA1 and 162 with BRCA2 mutations) ascertained through two regional cancer genetics services. We estimated the penetrance for both breast and ovarian cancer in female mutation carriers (904 proven mutation carriers - 1442 females in total assumed to carry the mutation) and also assessed the effect on penetrance of mutation position and birth cohort. RESULTS: Breast cancer penetrance to 70 and to 80 years was 68% (95%CI 64.7-71.3%) and 79.5% (95%CI 75.5-83.5%) respectively for BRCA1 and 75% (95%CI 71.7-78.3%) and 88% (95%CI 85.3-91.7%) for BRCA2. Ovarian cancer risk to 70 and to 80 years was 60% (95%CI 65-71%) and 65% (95%CI 75-84%) for BRCA1 and 30% (95%CI 25.5-34.5%) and 37% (95%CI 31.5-42.5%) for BRCA2. These risks were borne out by a prospective study of cancer in the families and genetic testing of unaffected relatives. We also found evidence of a strong cohort effect with women born after 1940 having a cumulative risk of 22% for breast cancer by 40 years of age compared to 8% in women born before 1930 (p = 0.0005). CONCLUSION: In high-risk families, selected in a genetics service setting, women who test positive for the familial BRCA1/BRCA2 mutation are likely to have cumulative breast cancer risks in keeping with the estimates obtained originally from large families. This is particularly true for women born after 1940.