Cancer
Patients studied
Assay
Association
References
Breast cancer
Breast/various
23 (16 breast)
PTT
No
Appleby et al. (1997)
Breast
15
PTT
No
Ramsay et al. (1998)
Breast/various
5
PTT
No
Clarke et al. (1998)
Breast
80
PTT
No
Shayeghi et al. (1998)
Breast/various
20
SSCP
No
Oppitz et al. (1999)
Breast
46
DHPLC
Yes, late fibrosis
Lannuzzi et al. (2002)
Breast
1,100
SSCP
No
Bremer et al. (2003)
Breast
254
PTT, RFLP, DHPLC
Positive, acute and/or late reactions (Asn1853Asn), negative (intronic SNPs)
Angèle et al. (2003)
Breast
52
SNPE
No, cosmesis
Andreassen et al. (2005)
Breast
41
DHPLC
Yes, late fibrosis
Andreassen et al. (2006a)
Breast
120
DHPLC
No, late fibrosis
Andreassen et al. (2006b)
Breast
252
DHPLC
Yes, lung/pleural late effects (Leu1420Phe, others)
Edvardsen et al. (2007)
Breast
131
DHPLC
Yes, late fibrosis (1853Asn)
Ho et al. (2007)
Breast
399
MALDI-TOF
No, acute dermatitis
Suga et al. (2007)
Breast/various
34
DHPLC, RFLP
Yes, severe late (minor allele SNPs)
Azria et al. (2008)
Breast
69
RFLP, MALDI-TOF
Only in combination with risk alleles in other genes, fibrosis
Zschenker et al. (2010)
Prostate cancer
Prostate
17
DNA seq
Yes
Hall et al. (1998)
Prostate
37
DHPLC
Yes
Cesaretti et al. (2005)
Lung cancer
Lung
213
RFLP
Yes (−111 A and 126713 A), pneumonitis
Zhang et al. (2010)
Researchers persisted with more specific and sensitive methods to detect individuals who carry germline ATM mutations without the ataxia-telangiectasia syndrome, and the majority of modern studies from the last decade showed clinical evidence of greater radiotherapy toxicity or a positive association as part of a multi-gene profile (see Table 1). Others continued to yield negative results or were not reproducible. Studies in other diseases, including prostate cancer and lung cancer, also suggested that ATM polymorphisms have an impact on radiosensitivity in other sites of the body and thus support the potential importance of this gene in breast cancer patients. These studies are summarized, with references, in Table 1.
Considered as a body of evidence, these data suggest that one possible mechanism for heightened radiosensitivity outside of a major syndrome may be seen in carriers of mutations in proteins involved in the DNA damage response, particularly in ATM mutation carriers who do not have the clinical syndrome of ataxia-telangiectasia. The significance of ATM polymorphisms in clinical practice, together with all other polymorphisms that have been linked to radiosensitivity, was cast into doubt recently due to results of a British clinical trial (Barnett et al. 2012). The study was named the RAPPER (Radiogenomics: Assessment of Polymorphisms for Predicting the Effects of Radiotherapy) trial, and the size and scope was unprecedented in the field of radiogenomics. The details of the trial will be discussed later in this chapter, but the authors suggest that most studies in this field have yielded false-negative results due to smaller sample sizes or focused on rare variants that are too rare to be clinically significant, including studies of ATM. Thirteen ATM SNPS, including those SNPs that had been previously implicated in adverse reactions to breast radiotherapy and tag SNPS designed to represent all known variants of the gene, were studied in the RAPPER trial, and none was associated significantly with radiation toxicity. Nevertheless, the strongest association in the study of 92 SNPs was found between an ATM SNP (rs4988023, a surrogate for rs1801516) and acute bladder toxicity in prostate cancer. No SNP in ATM approached significance for late sequelae in breast cancer patients.
Of course, polygenic effects may be particularly relevant to clinical practice, possibly in combination with non-genetic factors contributing to normal tissue toxicity. Polymorphisms in many other genes involved in DNA double-strand break repair and in the radiation response have been hypothesized to be likely to play an important role in radiotherapy toxicity. SNP profiles or genotypes, including ATM together with multiple genes, have been associated with radiation toxicity in smaller studies of breast cancer, head and neck and other cancers (Alsbeih et al. 2010; Azria et al. 2008). These also yielded negative results in the RAPPER study (Barnett et al. 2012).
5 XRCC1 Variants
XRCC1 is a base excision repair gene that has been implicated in radiation toxicity by several studies. It has been linked to both acute reactions and late effects in breast cancer patients treated with radiation, although negative studies have also been reported (Table 2). Andreassen and team initially showed evidence correlating an XRCC1 variant to late fibrosis and to telangiectasia after post-mastectomy radiation in 75 patients from the Danish post-mastectomy study cohort (Andreassen et al. 2003). An Arg399Arg genotype in XRCC1 (the most common genotype, found in 51 % of patients) was associated with a higher risk of grade 3 fibrosis and a higher risk of telangiectasia. This effect was enhanced in combination with other candidate SNPs. The same team was unable to reproduce the finding of increased fibrosis risk in a larger study of 120 subjects from the same cohort (Andreassen et al. 2006a, b). Several other European studies also associated acute and late radiation reactions with specific XRCC1 polymorphisms in patient cohorts of substantial size (details and references in Table 2).
Table 2
Studies correlating XRCC1 variants with radiotherapy toxicity, specifically in breast cancer
Patients studied | Assay | Association of studied SNP(s) or genotypes with toxicity | References |
|---|---|---|---|
Significant associations | |||
41 | SNPE | Positive (Arg399Arg), late fibrosis (not telangiectasia) | Andreassen et al. (2003) |
254 | RT-PCR and VSRED | Positive (399Gln with 194Trp), acute and/or late | Moullan et al. (2003) |
247 | RFLP | Positive (399Gln with 194Cys and in a genotype with 2 others), acute and/or late | Brem et al. (2006) |
446 | MPA | Protective (399Gln) in normal BMI, acute | Chang-Claude et al. (2005) |
167 | RFLP | Positive (Arg399Gln), late telangiectasia | Giotopolous et al. (2007) |
399 | MALDI-TOF | Protective (genotype), acute | Suga et al. (2007) |
69 | RFLP and MALDI-TOF | Positive (399Arg) only in genotype of 6 genes, late | Zschenker et al. (2010) |
87 | SNPE and RT-PCR | Positive (Arg194Trp with Arg399Gln), acute | Mangoni et al. (2011) |
No significant associations | |||
52 | RT-PCR and SNPE | None, cosmesis | Andreassen et al. (2005) |
120 | RT-PCR | None, late fibrosis | |
409 | RT-PCR | None (includes 399 and 194 alone and in a genotype with 2 others), late | Chang-Claude et al. (2009) |
43 | RFLP | None, acute | Sterpone et al. (2010) |
57 | Pyro | None, late fibrosis or fat necrosis (single fraction PBI) | Falvo et al. (2012) |
The scientific investigations into this topic with the greatest numbers of patients have been conducted in Germany. Tan and colleagues in a team led by Chang-Claude conducted a study of 446 breast cancer patients, 77 of whom developed acute toxicity from radiation for breast-conserving treatment. They selected variants in 3 candidate genes and used melting point analysis to detect polymorphisms. There was no significant association overall, but a protective effect of the XRCC1 Arg399Gln allele against acute toxicity was shown only in breast cancer patients of normal weight (Tan et al. 2006). Chang-Claude and team focused on late toxicity in a subsequent study, in which they prospectively genotyped 409 breast cancer patients who received radiation after breast-conserving surgery (Chang-Claude et al. 2009). The primary technique for genotyping was real-time PCR. They selected six candidate genes with functional importance in DNA repair and two “damage response” genes and selected several candidate functional polymorphisms of these genes for genotyping, including four polymorphisms of XRCC1 (one of them was Arg399Gln). They then compared the proportion of patients with the polymorphism in the patients with telangiectasia or fibrosis versus the patients without these late effects at a median follow-up of 51 months. They did not offer a subgroup analysis based on patient weight, as in their previous study. The SNPs were not associated with late toxicity, whether alone or in combination.
Patients with cancer at other sites have been the subjects of similar studies of XRCC1 polymorphisms in recent years. For instance, XRCC1 SNPs have been correlated with radiation fibrosis after lung cancer treatment (Alsbeih et al. 2010) and with acute reactions in head and neck cancers, when two SNPs in XRCC1 are found in combination (Pratesi et al. 2011). Once again, the clinical significance of such studies is unclear in the light of the RAPPER study results. Twelve SNPs in XRCC1 were included in the trial. As with ATM, the researchers also selected tag SNPs representing all known variants in the gene and there were no statistically significant associations with radiation toxicity (Barnett et al. 2012). However, there were SNPs that came close to significance and the authors felt warranted further study in even larger patient cohorts: These included XRCC1 SNPs rs1799782 and rs25487. They were specifically associated with altered pigmentation and telangiectasia, respectively, after breast irradiation.
6 TGFB1
Another gene that has been widely implicated in radiation toxicity is TGFB1, encoding TGF-beta, a cytokine known to stimulate a strong inflammatory response and to be involved in late radiation toxicities such as pneumonitis and fibrosis (Hall and Giaccia 2011). SNPs in the gene have been linked to radiation toxicity in the treatment of breast cancer and in other sites. Alsbeih and colleagues in Saudi Arabia demonstrated a significant association of 10Leu with soft tissue fibrosis in head and neck cancers (Alsbeih et al. 2010). In prostate cancer, TGFB1 SNPs have been correlated with radiation toxicity in one study (Peters et al. 2008) but other reports have been negative (see Table 3). In lung cancer, TGFB1 SNPs have been associated with pneumonitis risk (Yuan et al. 2009) and esophagitis risk (Zhang et al. 2010).
Table 3
Studies correlating TGFB1 mutation status with radiotherapy toxicity in cancer
Cancer | Patients studied | Association | References |
|---|---|---|---|
Breast cancer | |||
Breast | 103 | Yes (10Pro and −509 T), fibrosis | Quarmby et al. (2003) |
Breast | 41 | Yes, fibrosis (10Pro and −509 T), not telangiectasia | Andreassen et al. (2003) |
Breast | 52 | Yes, breast appearance (10Pro and −509T) | Andreassen et al. (2005) |
Breast | 120 | No, late fibrosis | |
Breast | 167 | Positive (−509 T), late fibrosis, not telangiectasia | Giotopolous et al. (2007) |
Breast | 399 | No (position −509 and more), acute skin effects | Suga et al. (2007) |
Breast/various | 34 | Yes, severe late (minor allele SNPs) | Azria et al. (2008) |
Breast | 778 | No (codon 10 or −509) | RAPPER study early report (Barnett et al. 2010) |
Breast | 69 | Yes (only as part of a 6-gene genotype), late fibrosis | Zschenker et al. (2010) |
Prostate cancer | |||
Prostate | 141 | Yes (minor alleles in codons 10 and 25, position −509), E.D., not urinary QOL | Peters et al. (2008) |
Prostate | 445 | No (codon 10), late effects, E.D. and QOL | Meyer et al. (2009) |
Prostate | 197 | No (position −509), late effects | Suga et al. (2008) |
Other cancers | |||
Cervical/endometrial | 78 | No, late gastrointestinal | De Ruyck et al. (2006) |
Head and neck | 60 | Yes, late fibrosis (10Leu) | Alsbeih et al. (2010) |
Lung | 164 | Negative, pneumonitis (10Pro is protective) | Yuan et al. (2009) |
Lung | 213 | Positive, esophagitis (−509 T) | Zhang et al. (2010) |
This association has also been investigated in many studies of breast cancer patients (Table 3). In a study of breast cancer patients published by Andreassen, late fibrosis risk was associated with TGFB1 alleles 509T and 10Pro (Andreassen et al. 2003) and the same group also reported a higher risk of altered breast appearance with these alleles in 26 matched case–control pairs (Andreassen et al. 2005). A subsequent, larger study by the same group failed to validate the link to radiation fibrosis (Andreassen et al. 2006a, b). Over recent years, a handful of smaller studies in breast cancer gave mixed results, and a few positive associations of TGFB1 SNPs with late effects and breast fibrosis were published (Table 3). The largest study in breast cancer, prior to work by Barnett and the RAPPER trial, was reported by Suga and colleagues in Japan, who showed no relationship with acute toxicity in 399 patients. In the RAPPER trial, this gene was a focus of careful study and was represented by tag SNPs for all variants, as with ATM and XRCC1, and no significant relationship to radiotherapy toxicity was found in breast and prostate cancer treatment (Barnett et al. 2012).
7 Other Polymorphisms Implicated in DNA Repair and Radiation Toxicity
ATM, BRCA1 and BRCA2, XRCC1, and TGFB1 are only a few representatives of a long list of genes known to be important in the radiation response and DNA damage recognition and repair. Pathways that could be involved in normal tissue radiosensitivity also include activation of cell cycle checkpoints, oxidative stress responses, inflammation, and apoptosis, among others. Many studies have been carried out looking at candidate genes from these pathways and their normal variations between individuals, particularly single nucleotide polymorphisms (SNPs), to determine if there is a link to radiation sensitivity. These studies were often limited by small sample sizes and essentially failed to yield conclusive findings. No positive associations reported have been consistently validated in subsequent studies with other patient cohorts (Alsner and Andreassen 2008) and most of these yielded no statistically significant associations with late toxicity in the RAPPER study (Barnett et al. 2012). Breast cancer patients have been the most widely studied patient group in the genetic basis of radioresponse (Parliament and Murray 2010). Table 4 summarizes a number of the genes with SNPs that have been studied in this regard.
Table 4
Various genes with SNPs studied in relationship to radiotherapy toxicity in breast cancer (excludes genes summarized separately: ATM, BRCA1, BRCA2, XRCC1, and TGFB1)
Gene/SNP | Effects studied | Significant associations? | Reference(s) |
|---|---|---|---|
ABCA1b | Acute | Yes, acute (3 SNPs in 2 haplotype blocks)
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