Can risk of radiotherapy-induced normal tissue complications be predicted from genetic profiles?

Figures & data

Tables I and Table II. Overview of studies addressing associations between genetic alterations and clinical normal tissue radiosensitivity. Table I provides a list of studies with a particular focus on single nucleotide polymorphisms. The studies listed in Table II investigated other types of genetic variants or screened the genes for various sequence alterations. Table I. 

Author, year [ref. #]	Gene(s) investigated	N	Conclusion
Angele S, et al. 2003 [13]	ATM	254	Significant association between the codon 1853 Asn/Asn genotype and risk of various acute and late adverse normal tissue reactions, intronic IVS22-77 CC genotype associated with reduced risk
Andreassen CN, et al. (in press) [32]	ATM	41	Risk of subcutaneous fibrosis significantly associated with the codon 1853 Asp/Asn and Asn/Asn genotypes
Moullan N, et al. 2003 [43]	XRCC1	254	Codon 399 Gln allele in combination with the codon 194 Trp allele associated with increased risk of various acute and late adverse normal tissue reactions
De Ruyck K, et al. 2005 [42]	XRCC1, XRCC3, OGG1	62	XRCC3 IVS5-14 G allele significantly associated with increased risk of late gastro-intestinal damage, XRCC1 194 Trp allele with reduced risk
Chang-Claude J, et al. 2005 [41]	XRCC1, APEX, XPD	446	XRCC1 codon 399 Gln allele in combination with APEX codon 148 Glu allele significantly associated with reduced risk of acute skin reactions in a sub group of 104 patients (8 cases and 96 controls)
Quarmby S, et al. 2003 [58]	TGFB1	103	Risk of subcutaneous fibrosis significantly associated with the position −509 T and codon 10 Pro allele in 15 breast cancer patients with severe subcutaneous fibrosis compared to 88 controls
Andreassen CN, et al. 2003 [40]	TGFB1, SOD2, XRCC1, XRCC3, APEX	41	Risk of subcutaneous fibrosis significantly associated with the TGFB1 position −509 T and codon 10 Pro alleles, SOD2 codon 16 Ala and XRCC1 codon 399 Arg alleles. XRCC3 codon 241 Thr allele associated with risk of subcutaneous fibrosis and telangiectasia
Andreassen CN, et al. 2004 [33]	TGFB1, SOD2, XRCC1, XRCC3, APEX, ATM	52*	Risk of altered breast appearance significantly associated with the position −509 T and codon 10 Pro alleles in 26 matched case-control pairs
Andreassen CN, et al. (unpublished data)	TGFB1, SOD2, XRCC1, XRCC3, APEX, ATM	120	No significant associations between the investigated SNPs and risk of radiation-induced subcutaneous fibrosis
De Ruyck K, et al. (abstract) [11]	TGFB1	62	Non-significant association between possession of the −509 TT and codon 10 Pro/Pro genotypes and risk of late gastro-intestinal damage
Green H, et al. 2002 [50]	SOD2	80*	No association between the SOD2 codon 16 Val/Ala SNP and radiation-induced alteration of breast appearance in 41 cases and 39 matched controls
Kornguth DG, et al. 2005 [44]	ERCC4	130	Risk of need for long-term feeding tube after radiotherapy significantly reduced in patients with the T2505C (codon 835 Ser/Ser (silent)) SNP

Note: *The studies were based on patient cohorts that were partially identical, and the results for the SOD2 codon 16 SNP can therefore not be considered as independent.

Table II.  

Author, year [ref. #]	Gene(s) investigated	N	Conclusion
Appleby JM, et al. 1997 [15]	ATM	23	No ATM mutations detected in 23 patients with severe acute or late toxicity
Clarke RA, et al. 1998 [16]	ATM	9	No ATM truncations detected in neither five patients with severe acute toxicity nor in four controls
Ramsay J, et al. 1998 [14]	ATM	15	No ATM truncations detected in 15 patients with severe late toxicity
Weissberg JB, et al. 1998 [17]	ATM	13	No evidence of excessive acute or late toxicity in 13 ataxia-telangiectasia heterozygotes
Shayeghi M, et al. 1998 [18]	ATM	80	One ATM truncation in 41 patients with radiation induced breast shrinkage, none in 39 matched controls, difference not statistically significant
Hall EJ, et al. 1998 [19]	ATM	17	Three patients with ‘significant’ ATM mutations in 17 severe late reactors, no mutations in four controls, difference not statistically significant
Oppitz U, et al. 1999 [20]	ATM	20	No ‘unequivocal’ ATM mutations in 20 patients with severe acute or late toxicity
Iannuzzi CM, et al. 2002 [23]	ATM	46	Significant association between single base mutations and severe subcutaneous late damage.
Cesaretti JA, et al. 2005 [24]	ATM	37	Possession of missense mutations significantly associated with radiation-induced rectal bleeding and erectile dysfunction.
Bremer M, et al. 2003 [21]	ATM	10	No indications of increased acute or late radio-sensitivity in 10 patients being heterozygous for pathogenic ATM mutations
Borgmann K, et al. 2002 [22]	ATM, NBS, MRE11, RAD50, DNA ligase IV	5	No mutations detected in five patients with severe late toxicity, possible DNA ligase IV polymorphism detected in one patient
Gaffney DK, et al. 1998 [34]	BRCA1, BRCA2	21	No evidence of excessive acute toxicity in 21 patients with BRCA1 or BRCA2 mutations
Pierce LJ, et al. 2000 [35]	BRCA1, BRCA2	284	No exacerbation of acute or late toxicity in 71 patients with BRCA1 or BRCA2 mutations compared to 213 matched controls
Leong T, et al. 2000 [36]	BRCA1, BRCA2	22	No BRCA1 or BRCA2 mutations detected in 22 patients with severe acute or late toxicity
Severin DM 2001 [37]	hHR21	19	Non-conservative G1441A transition found in 1/19 and a T1440C substitution found in 6/19 radiosensitive patients. No control group to compare with
Price EA, et al. 1997 [38]	XRCC1, XRCC3, XRCC5	18	Significant associations between microsatellite polymorphisms in XRCC3/XRCC5 and severe acute or late toxicity in 8 radiosensitive patients and 11 ‘normal reactors’

Figure 1.  Curves illustrating the concept of estimating differences in radiosensitivity by analysis of dose-response relationships in patients scored for normal tissue morbidity in multiple treatment fields. Based on ED₅₀ values (indicated by grey arrows), enhancement ratios can be calculated. Data from the study investigating the influence of the TGFB1 codon 10 SNP on risk of radiation-induced fibrosis in 41 patients. Modified from ref. [40].

Figure 2.  A hypothetical and presumably very simplified model illustrating how different genetic alterations may influence clinical normal tissue radiosensitivity. The underlying assumption is that normal tissue complication risk is determined by the cumulative effect of a number of sequence variants (boxes A-I) that inflict a suboptimal function of gene products involved in the biological response to ionising radiation. Some of these alterations (boxes C-I) are expressed selectively through certain types of normal tissue reactions, whereas others (boxes A and B) affect radiosensitivity in a generalised way. Patient 1 exhibits a selectively increased susceptibility to normal tissue reaction Z due to the variants H and I. In contrast patient 2 exhibit a severe ‘global’ enhancement of radiosensitivity due to a highly penetrant sequence alteration (box A). Modified from ref. [10].

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