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Genetic predisposition in breast cancer
Genetic
predisposition in
breast
cancer
SiR-Mutations in either of two recently identified (BRCA I) or localised (BRCA2) genes (see Sept 24, p 877) probably account for most of the 5% of breast cancer patients who show a clear dominantly inherited predisposition.’‘ In addition, about 4% (up to 13%) of cases with no obvious family history could be carriers (heterozygotes) of the recessively inherited gene for ataxia-telangiectasia (A-T), which confers a very high cancer risk in affected cases and a 4-fold (range 2-7 fold) increase in relative risk of breast cancer in heterozygotes.2 Direct investigation of the frequency of A-T gene carriers in breast cancer patients is not yet possible because the gene has not been cloned. An alternative approach is to use a cellular marker for the gene. Sanford and Parshad3 reported good discrimination between A-T heterozygotes and controls with an assay that detects defects in processing of DNA damage, manifested as structural chromosome aberrations in cells X-irradiated in the G2 phase of the cell cycle. Although we could not confirm these findings4 with the Sanford/Parshad method, we have obtained good discrimination with our own G2 assay on peripheral blood
lymphocytes; only 9% (7/74) of control donors overlapped the A-T heterozygote range (figure). We have therefore used our assays in an attempt to identify A-T heterozygotes in women
with breast
cancer.
21 of
an
unselected series of 50
patients, tested before treatment, had a chromosomal radiosensitivity within the A-T heterozygote range (figure). This frequency (42%, 95% CI 28-57%) is much higher than the highest estimate of A-T heterozygosity (13%) in breast cancer cases. Sensitivity to radiation-induced chromosome damage in G2 cells is strongly associated with inherited cancer predisposition. Sanford and Parshad3have shown sensitivity apparently sporadic breast
cancer
2
in fifteen cancer-prone conditions, many of which we have confirmed with our own assay and to which we have added others-for example, basal cell naevus syndrome and hereditary non-polyposis colon cancer (unpublished results). We suggest that predisposition to breast cancer is not confined to those kindreds with a strong family history or to A-T heterozygotes, but is present in a much higher proportion of cases that carry predisposing genes of low penetrance. Our results also suggest that these predisposing genes are involved in the processing of DNA damage. David Scott, Ann Spreadborough, Edward Levine, Stephen A Roberts Cancer Research Campaign Department of Cancer Genetics, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester M20 9BX, UK
1 2 3
4
5
Ponder B. Breast cancer genes: searches begin and end. Nature 1994; 371: 279. Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol 1994; 66 (suppl): S177-82. Sanford KK, Parshad R. Detection of cancer-prone individuals using cytogenetic response to X-rays. In: Obe G, Natarajan AT, eds. Chromosomal aberrations: basic and applied aspects. Berlin: SpringerVerlag, 1990: 113-20. Scott D, Jones LA, Elyan SAG, Spreadborough A, Cowan R, Ribiero G. Identification of A-T heterozygotes. In: Gatti RA, Painter RB, eds. Ataxia-telangiectasia. Berlin: Springer-Verlag 1992: 101-16. Skolnick MH, Cannon-Albright LA, Goldgar DE, et al. Inheritance of proliferative breast disease in breast cancer kindreds. Science 1990; 250: 1715-20.
Breast
Aberrations per 100 cells
Figure: Chromosome damage In lymphocytes exposed to 0-5 Gy X-rays In G2 phase of cell cycle4 Top panel-healthy controls, 74 donors (111 samples), 39 male and 35 female (no sex effect), aged 5-68 (no age effect), mean=93-8 (SD 13-6) (coefficient of variation 14%), differences between donors p<0091; middle panel-obligate A-T heterozygotes, 28 donors (30 samples), aged 27-67 (no age effect), mean=145 (40-4) (28%); bottom panel-breast cancer patients, 50 donors, aged 35-73 (no age effect), mean=109 (26-8) (25%). Vertical line gives maximum discrimination between controls and A-T heterozygotes. Both A-T heterozygote and breast cancer groups are significantly more sensitive than controls (Mann-Whitney test, p<0001). 1444
cancer
SIR-In his provocative overview (Sept 10, p 734) of The Lancet conference on breast cancer Devitt makes a strong plea for oncologists to devote more efforts to analysis of host factors (the "forest") and less to the local breast cancer itself (the "tree"). He cites individual cases showing the vast heterogeneity of the disease and the inability to predict or to understand why some individuals show long survival and others quick fatal dissemination. For high-risk breast cancer patients, adverse pathological and histochemical tumour characteristics and clinical staging may be relevant for short-term (5-year) survival prediction, but they show poor correlation with long-term survival. Although host resistance obviously plays a part, it has been of little interest to the oncologist because even crude simple methods of determining delayed immune competence have scarcely been used. It is noteworthy that survival in stage III after aggressive polychemotherapy now approaches survival in stage IIB and IIC.’ The conventional view had been that stage III, being more advanced than stage II, must have an associated weaker immune system, yet delayed immune competence in stage III to tuberculin was better than in stage II in New York in Krown’s study at Sloan-Kettering.2 The more indolent course of stage II, III, and IV cancers in Japanese women could be a function of their almost universal exposure to tuberculosis. Survival in Israel is better
predisposition in
breast
cancer
SiR-Mutations in either of two recently identified (BRCA I) or localised (BRCA2) genes (see Sept 24, p 877) probably account for most of the 5% of breast cancer patients who show a clear dominantly inherited predisposition.’‘ In addition, about 4% (up to 13%) of cases with no obvious family history could be carriers (heterozygotes) of the recessively inherited gene for ataxia-telangiectasia (A-T), which confers a very high cancer risk in affected cases and a 4-fold (range 2-7 fold) increase in relative risk of breast cancer in heterozygotes.2 Direct investigation of the frequency of A-T gene carriers in breast cancer patients is not yet possible because the gene has not been cloned. An alternative approach is to use a cellular marker for the gene. Sanford and Parshad3 reported good discrimination between A-T heterozygotes and controls with an assay that detects defects in processing of DNA damage, manifested as structural chromosome aberrations in cells X-irradiated in the G2 phase of the cell cycle. Although we could not confirm these findings4 with the Sanford/Parshad method, we have obtained good discrimination with our own G2 assay on peripheral blood
lymphocytes; only 9% (7/74) of control donors overlapped the A-T heterozygote range (figure). We have therefore used our assays in an attempt to identify A-T heterozygotes in women
with breast
cancer.
21 of
an
unselected series of 50
patients, tested before treatment, had a chromosomal radiosensitivity within the A-T heterozygote range (figure). This frequency (42%, 95% CI 28-57%) is much higher than the highest estimate of A-T heterozygosity (13%) in breast cancer cases. Sensitivity to radiation-induced chromosome damage in G2 cells is strongly associated with inherited cancer predisposition. Sanford and Parshad3have shown sensitivity apparently sporadic breast
cancer
2
in fifteen cancer-prone conditions, many of which we have confirmed with our own assay and to which we have added others-for example, basal cell naevus syndrome and hereditary non-polyposis colon cancer (unpublished results). We suggest that predisposition to breast cancer is not confined to those kindreds with a strong family history or to A-T heterozygotes, but is present in a much higher proportion of cases that carry predisposing genes of low penetrance. Our results also suggest that these predisposing genes are involved in the processing of DNA damage. David Scott, Ann Spreadborough, Edward Levine, Stephen A Roberts Cancer Research Campaign Department of Cancer Genetics, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester M20 9BX, UK
1 2 3
4
5
Ponder B. Breast cancer genes: searches begin and end. Nature 1994; 371: 279. Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol 1994; 66 (suppl): S177-82. Sanford KK, Parshad R. Detection of cancer-prone individuals using cytogenetic response to X-rays. In: Obe G, Natarajan AT, eds. Chromosomal aberrations: basic and applied aspects. Berlin: SpringerVerlag, 1990: 113-20. Scott D, Jones LA, Elyan SAG, Spreadborough A, Cowan R, Ribiero G. Identification of A-T heterozygotes. In: Gatti RA, Painter RB, eds. Ataxia-telangiectasia. Berlin: Springer-Verlag 1992: 101-16. Skolnick MH, Cannon-Albright LA, Goldgar DE, et al. Inheritance of proliferative breast disease in breast cancer kindreds. Science 1990; 250: 1715-20.
Breast
Aberrations per 100 cells
Figure: Chromosome damage In lymphocytes exposed to 0-5 Gy X-rays In G2 phase of cell cycle4 Top panel-healthy controls, 74 donors (111 samples), 39 male and 35 female (no sex effect), aged 5-68 (no age effect), mean=93-8 (SD 13-6) (coefficient of variation 14%), differences between donors p<0091; middle panel-obligate A-T heterozygotes, 28 donors (30 samples), aged 27-67 (no age effect), mean=145 (40-4) (28%); bottom panel-breast cancer patients, 50 donors, aged 35-73 (no age effect), mean=109 (26-8) (25%). Vertical line gives maximum discrimination between controls and A-T heterozygotes. Both A-T heterozygote and breast cancer groups are significantly more sensitive than controls (Mann-Whitney test, p<0001). 1444
cancer
SIR-In his provocative overview (Sept 10, p 734) of The Lancet conference on breast cancer Devitt makes a strong plea for oncologists to devote more efforts to analysis of host factors (the "forest") and less to the local breast cancer itself (the "tree"). He cites individual cases showing the vast heterogeneity of the disease and the inability to predict or to understand why some individuals show long survival and others quick fatal dissemination. For high-risk breast cancer patients, adverse pathological and histochemical tumour characteristics and clinical staging may be relevant for short-term (5-year) survival prediction, but they show poor correlation with long-term survival. Although host resistance obviously plays a part, it has been of little interest to the oncologist because even crude simple methods of determining delayed immune competence have scarcely been used. It is noteworthy that survival in stage III after aggressive polychemotherapy now approaches survival in stage IIB and IIC.’ The conventional view had been that stage III, being more advanced than stage II, must have an associated weaker immune system, yet delayed immune competence in stage III to tuberculin was better than in stage II in New York in Krown’s study at Sloan-Kettering.2 The more indolent course of stage II, III, and IV cancers in Japanese women could be a function of their almost universal exposure to tuberculosis. Survival in Israel is better