Contralateral Breast Cancer after Radiotherapy among BRCA1 and BRCA2 Mutation Carriers: A WECARE Study Report

Abstract

BACKGROUND

Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers.

METHODS

A population-based, nested case-control study was conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC). Cases were 603 women with CBC and controls were 1199 women with UBC individually matched on age at diagnosis, race, year of first diagnosis and cancer registry. All women were tested for BRCA1 and BRCA2 mutations. Radiation absorbed dose from the initial radiotherapy (RT) to the CBC location within the contralateral breast was reconstructed from measurements in a tissue-equivalent phantom and details available in the therapy records.

FINDINGS

Among women treated with radiation, the mean radiation dose was 1.1 Gy (range=0.02-6.2 Gy). Risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR=4.5, confidence interval, CI=3.0-6.8), and also among those treated with RT (RR=1.2, CI=1.0-1.6). However, among mutation carriers, an incremental increase in risk associated with radiation dose was not statistically significant.

INTERPRETATION

Multiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers, but this was not apparent. Accordingly, there was no clear indication that carriers of deleterious BRCA/BRCA2 mutations were more susceptible to the carcinogenic effects of radiation than non-carriers. These findings are reassuring and have important clinical implications for treatment decisions and the clinical management of patients harboring deleterious BRCA1/BRCA2 mutations.

FUNDING

All work associated with this study was supported by the U.S. National Cancer Institute [R01CA097397, U01CA083178].

BACKGROUND

Adjuvant radiation therapy (RT) for breast cancer reduces ipsilateral recurrence and improves survival (1-3). RT is effective, in part, because it generates a wide spectrum of damage to DNA in tumor cells, including DNA double-strand breaks (4, 5). The BRCA1 and BRCA2 gene products are integrally involved in the normal cellular response to DNA damage, particularly double strand breaks, and deficiencies in this response can predispose to cancer (6, 7). Among BRCA/BRCA2 gene mutation carriers, estimates of lifetime risk of developing a first primary breast cancer range from 26%-84% (8-10) and about 22%-60% for developing asynchronous CBC (9, 11-15). During adjuvant RT, the contralateral breast is exposed to radiation at doses that may induce breast cancer in women treated at a young age (16, 17). It is plausible that women who carry BRCA1/BRCA2 mutations may be especially susceptible to radiation-induced CBC due to deficient or error-prone repair of radiation-induced DNA lesions. If true, alternatives to treatment and diagnostic strategies involving radiation in BRCA1/BRCA2 carriers might be considered.

Previously we reported that CBC was positively associated with dose of radiation received by the contralateral breast and inversely related to age at radiation treatment (18) and that carriers of deleterious BRCA1/BRCA2 mutations had a high absolute risk of CBC (9). In this study of CBC, we examine whether the relative risk of developing CBC associated with RT is significantly greater for deleterious BRCA1/BRCA2 mutation carriers than for non-carriers.

METHODS

Study Population

The WECARE Study is a multi-center, population-based, nested case-control study selected from a cohort of 52,536 women with histologically confirmed invasive breast cancer (19). The study includes 705 women with CBC (cases) and 1,398 women with unilateral breast cancer (UBC, controls), all of whom were ascertained through five population-based cancer registries covering the country of Denmark, the state of Iowa, Los Angeles County and the Orange County-San Diego regions of California, and three western Washington counties in the United States (all of the US registries participate in the Surveillance, Epidemiology, and End Results [SEER] registry system).

All cases and controls were diagnosed before age 55 years from 1985 to 2000 with a first primary invasive breast cancer that had not spread beyond regional lymph nodes. Cases were diagnosed with a second primary invasive or in situ CBC at least 1 year after first primary diagnosis from 1986 to 2001. Two controls were individually matched to each case on birth year (within 5-year strata), year of first primary diagnosis (within 4-year strata), registry, and race/ethnicity and were required to have an intact contralateral breast. Cases and controls were counter-matched on registry-reported radiotherapy so that each triplet included one radiation-unexposed woman and two radiation treated women (for 12 cases with one control identified, matched pairs included one radiation exposed and one unexposed woman), as described previously (19) Each control’s at-risk period was the same length as the interval between her matched case’s first and second cancer diagnoses. This at-risk period began on the control’s date of diagnosis and ended on the reference date reflecting the end of her at-risk period. Cases and controls were required to have had no other prior/intervening cancers, to have resided in a registry catchment area at the initial diagnosis and at the CBC diagnosis/reference date, and to provide a blood sample. The study protocol was approved by the institutional review boards at each US site and by the ethical committee system in Denmark. Written informed consent was obtained from all participants.

Data Sources

A detailed questionnaire was administered during a telephone interview to each eligible participant and a blood sample was collected during an in-home visit. Treatment history and tumor characteristics were ascertained through a review of medical records, pathology reports, and radiation records. For each patient who received RT as treatment for the first primary breast cancer, estimated absorbed radiation doses to each of the four quadrants and the nipple area of the contralateral breast were reconstructed for each treatment regimen using tissue-equivalent phantoms and modeling procedures. Measurements were made on an average size female phantom with medium breasts, using orthovoltage, cobalt-60 and megavoltage (6 MV) energies. Phantoms contained lithium fluoride powder, that was calibrated and standardized using output of a cobalt-60 unit in the Accredited Dosimetry Calibration Laboratory located at MD Anderson Cancer Center, which is certified by the National Institute of Standards and Technology (19, 20). Individual dose estimates were based on each patient’s tumor dose, field configurations, and energy of photon and/or electron radiation beams ; these details were available for 96% of cases and 95% of controls.

Dose estimates were performed by staff who were blinded as to case-control status (19, 20). For the cases included in this study, the location of the contralateral breast tumor was known, permitting dose to be estimated for that breast location for exposed cases and matched controls (18). The average specific dose to each quadrant of the breast was used for analyses because quadrant was the most specific location available for the majority of the cases. Using average quadrant dose to represent the dose to the tumor could result in uncertainty as great as a factor of 3 for the medial quadrants where the dose gradient is large.Laboratory Methodology. Coding and flanking intronic regions of BRCA1 and BRCA2 were screened for DNA variants by denaturing high-performance liquid chromatography as previously described (9). Data analyses focused exclusively on sequence variants known to have a deleterious effect including changes known or predicted to truncate the protein, splice site mutations located within 2 base pairs of an intron/exon boundary or shown to result in aberrant splicing, and missense changes definitively demonstrated to have a deleterious effect on function. Our mutation classification strategy followed current clinical care standards and Breast Cancer Information Core (BIC) classifications (http://research.nhgri.nih.gov/projects/bic/).

Statistical Methodology

Of the 708 cases and 1399 controls(2107), 3 cases and 1control were not tested for BRCA1 or BRCA2 mutations, 4 cases and 4 controls were missing dose, and 102 cases were missing location of the contralateral breast tumor. Therefore there were 603 cases and 1199 matched controls for whom information on RT and location of case’s contralateral breast tumor were known and who had BRCA1/BRCA2 mutation carrier status determined. Multivariable-adjusted rate ratios (RRs) with corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression modeling techniques with an “offset” term to account for the counter-matched design (19). Models were adjusted for factors that were significantly associated with CBC in univariate models, including age at first diagnosis, age at menarche, number of full-term pregnancies, age at menopause, breast cancer family history in a first-degree relative, treatment (chemotherapy and hormonal therapy), histology, and stage of the first primary. RRs assessing the effect of radiation dose were calculated by comparing, within each triplet, the dose received to the case’s specific CBC location and the dose received at the same breast location for her matched controls (21). An indicator was included if covariate data were missing (22). The RRs shown in Table 2 are genotype-specific radiation effects (i.e., the RT effect within BRCA1/BRCA2 mutation carrier/non-carrier). The inclusion of interaction terms between RT dose (or ever/never received radiation) and BRCA1/BRCA2 indicator variables permits investigation of potential effect modification by mutation carrier status. Presence of a multiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers. Heterogeneity in the RT effect across carriers and non-carriers was evaluated using a likelihood ratio test comparing models that included main effects for BRCA 1 and/or BRCA2 carrier status and RT dose (or ever/never) only and models that contained those effects plus their interaction terms.

Table 2.

Effect of radiation exposure on risk of developing contralateral breast cancer by BRCA1 or BRCA2 carrier status.

Radiation	No BRCA1/BRCA2 mutation				BRCA1					BRCA2					BRCA1 or BRCA2
Exposure	Case n (%)	Control n (%)	RRa	95%CI	Case n (%)	Control n (%)	RRa	95%CI	Pb	Case n (%)	Control n (%)	RRa	95%CI	Pc	Case n (%)	Control n (%)	RRa	95%CI	Pd
No	261 (51)	229 (50)	1.0		23 (40)	3 (38)	1.0			17 (44)	6 (42)	1.0			40 (42)	9 (41)	1.0
Yes	246 (49)	908 (50)	1.1	0.9-1.4	34 (60)	34 (62)	0.8	0.2-3.2	0.8	22 (56)	19 (58)	2.2	0.7-7.3	0.2	56 (58)	53 (59)	1.4	0.6-3.3	0.7
Estimated dose to contralateral breast
No	261 (52)	229 (50)	1.0		23 (40)	3 (38)	1.0			17 (44)	6 (42)	1.0			40 (42)	9 (41.0)	1.0
0<1.0Gy	128 (25)	502 (27)	1.0	0.8-1.3	18 (32)	15 (22)	1.1	0.2-4.8		17 (44)	12 (38)	2.9	0.8-10.3		35 (36)	27 (30.0)	1.9	0.7-4.8
≥1.0Gy	118 (23)	406 (23)	1.2	1.0-1.6	16 (28)	19 (40)	0.6	0.1-2.6	0.5	5 (12)	7 (20)	1.5	0.3-7.0	0.3	21 (22)	26 (29.0)	1.0	0.4-2.8	0.2

^aRate ratios are adjusted for age at first diagnosis, age at menarche, number of full term pregnancies, age at menopause, family history, treatment (chemotherapy and hormonal therapy), histology, and stage of the first primary. Please note that RRs can only be calculated after appropriately adjusting for counter-matching and cannot be calculated based on the raw frequencies alone, the proportions presented are weighted by the counter-matching (Bernstein et al, Br Ca Res 2004; 6(3):R199-214).

^bP value for heterogeneity of effect of radiation exposure in BRCA1 carriers versus non-carriers.

^cP value for heterogeneity of effect of radiation exposure in BRCA2 carriers versus non-carriers.

^dP value for heterogeneity of effect of radiation exposure in BRCA1 and BRCA2 carriers combined versus non-carriers.

All analyses were conducted using SAS TPHREG (SAS Institute, Cary, NC).

Role of the Funding Source

The data collection, analysis and interpretation of the data presented, and writing of the manuscript was supported through grants awarded from the National Cancer Institute, which had no role in any of these activities. The decision to submit the work for publication was made jointly with all of the named authors; the final decision to submit was the responsibility of Dr. Jonine Bernstein who had full access to all of the data.

RESULTS

We identified 96 carriers (57 BRCA1, 39 BRCA2) of deleterious germline mutations among the 603 cases (15.9%), and 62 carriers (37 BRCA1, 25 BRCA2) among the 1399 controls (4.4%) (Table 1). Among women who received RT, the mean radiation dose was 1.1 Gy (range 0.02-6.2 Gy); the risk among those exposed to more than 1Gy was slightly elevated (RR=1.2, 95% CI=1.0-1.6).. The risk of developing CBC was four and one half-fold greater among carriers of either a BRCA1 or BRCA2 deleterious mutation than among non-carriers (RR=4.5, 95% CI=3.0-6.8). The prevalence of carriers was similar in controls who did versus did not receive radiation: 5.5% (53/961) versus 3.8% (9/238). In cases, the corresponding carrier frequency was modestly higher among those receiving radiation: 18.5% (56/302) versus 13.3% (40/301). The multiplicative effect of radiation in carriers was not statistically significantly elevated (RR=1.4, CI=0.6-3.3) (Table 2). Although larger in BRCA2 than BRCA1 carriers, this difference was also not statistically significant. The departure from an additive model was even larger, but still not statistically significant (both interaction chisq <1). When this analysis was examined by the dosage of radiation received, no trend was observed. Although limited by statistical power, when dose of radiation received and BRCA1/BRCA2 carrier status were examined by age at diagnosis of first breast cancer and time since first breast cancer, no meaningful trends were observed in the carriers (data not shown).

Table 1.

The effect of carrying BRCA1 or BRCA2 mutations on risk of developing contralateral breast cancer.

	Mutation Carrier Status	Cases (%)	Controls (%)	Rate Ratioa	95% CI
BRCA1 or BRCA2	No	507 (84)	1137 (95)	1.0
	Yes	96 (16)	62 (5)	4.5	3.0-6.8
BRCA1	No	546 (90)	1162 (98)	1.0
	Yes	57 (10)	37 (2)	5.1	3.0-8.5
BRCA2	No	564 (93)	1174 (98)	1.0
	Yes	39 (6)	25 (2)	3.9	2.2-7.0

^aRate ratios are adjusted for age at first diagnosis, age at menarche, number of full term pregnancies, age at menopause, family history, treatment (chemotherapy and hormonal therapy), histology, and stage of the first primary. Please note that RRs can only be calculated after appropriately adjusting for counter-matching and cannot be calculated based on the raw frequencies alone. The proportions are weighted by the counter-matching (Bernstein et al, Br Ca Res 2004; 6(3):R199-214)

INTERPRETATION

This is the first population-based study designed specifically to evaluate the joint effects of BRCA1/BRCA2 mutations, radiation exposure, and CBC risk. Breast location-specific estimates of absorbed radiation dose were utilized for evaluation of dose-response. We found that carriers of deleterious BRCA1/BRCA2 mutations had a 4-fold greater risk of CBC than non-carriers. However, mutation carriers who were exposed to radiation from RT for primary invasive breast cancer were not at significantly higher relative risk of CBC than unexposed carriers and there was little evidence of a dose-response relationship.

Given the known roles of the breast cancer susceptibility genes BRCA1 and BRCA2 in biochemical pathways involved in DNA damage responses, it is frequently suggested that carriers of such mutations might be radiosensitive. If true, then among radiation-exposed women, such sensitivity could result in an even greater increased risk of breast cancer. However, the data addressing this issue at either the cellular or population levels are limited and conflicting. Nieuwenhuis et al. (23) reported no difference in the repair of DNA double strand breaks in a blind comparison of irradiated lymphocytes or fibroblasts derived from carriers or healthy controls. Micronucleus tests do reveal increased mutagen sensitivity in lymphocytes from BRCA1 carriers relative to cells from healthy controls (24). However, when the micronucleus test was applied to irradiated cells derived from BRCA1/BRCA2 carriers with breast cancer, non-carriers with breast cancer, healthy BRCA1/BRCA2 carriers, and healthy non-carriers, no significant differences were observed in the radiosensitivity of cells from breast cancer patients when comparing carriers to non-carriers or among healthy controls for the same comparison (25).

Our study provides additional insights into the findings of the few published studies that have examined risk of CBC associated with RT among BRCA1/BRCA2 carriers (12, 26-30). The multi-center follow-up study of breast cancer patients attending high risk clinics conducted by Pierce and colleagues (28, 31) compared patients treated with breast-conserving surgery and RT. All 655 BRCA1/BRCA2 mutation carriers were followed for 15 years, and over 40% developed CBC; however, there was no statistically significant difference by use of RT indicating no additional risk from scatter RT at 10 and 15 years. Their finding of an increased risk of CBC among carriers is also consistent with ours. In a case-only study, Broeks et al. examined 247 CBC cases to identify carriers of a germline mutation in ATM, BRCA1/BRCA2, or CHEK2 (26) and found an interaction of RT with carriers of these mutations. However, this study only examined risk by aggregating genes and the extent of interaction attributable to BRCA1/BRCA2 carrier status was not reported.

Previous studies have also examined whether mammography-associated radiation was related to an increased risk of breast cancer (32-37). In contrast to the doses of radiation delivered to the contralateral breast during RT, the average radiation dose received during a mammogram (average ≤ 0.01 Gy) is lower by more than two orders of magnitude (2). As women with hereditary risk of breast cancer often begin annual mammographic screening at young ages, their risk of developing radiation-induced breast cancer could be increased as a result of this early exposure to radiation (2, 33). This risk might be further increased if mutation carriers are more sensitive to radiation carcinogenesis than the general population, providing the radiation dose received from mammography is sufficient to modify risk, such as that suggested by previous experimental studies (37). Two studies, Narod et al. (36) and Goldfrank et al., (34) examined whether breast cancer risk was associated with mammography among BRCA1/BRCA2 carriers; neither found a significant association. On the other hand, Andrieu et al. (32) observed an increase in breast cancer risk associated with self-reported numbers of chest x-rays in a retrospective cohort of BRCA1/BRCA2 carriers recruited to the International BRCA1/BRCA2 Carrier Cohort Study. Although their study provided no dose estimates and latency could not be established, the total radiation dose was estimated to be less than 20 mGy. Most recently, Pijpe et al. reported findings from the retrospective Gene-Rad-Risk Study, a large clinical cohort study of BRCA1/BRCA2 conducted in France, the Netherlands and the UK (38) which demonstrated that carriers of BRCA1/BRCA2 mutations exposed to diagnostic radiation before age 30 had an increased risk of breast cancer. However, the estimates for screening mammography alone (either defined as ever/never or as total number) were not statistically significant. Our findings of no significantly increased risk from considerably higher radiation doses (in our study, mean 1.1Gy) among BRCA1/BRCA2 mutation carriers, suggests that exposure to such low doses as from mammography is unlikely to increase risk of radiation-induced breast cancer among carriers to a greater degree than among non-carriers.

Along with the many strengths of this unique, large-scale epidemiologic study, there are some important limitations to consider. A major strength of our study is the large, well-characterized, population-based sample of long-term breast cancer survivors with individual location-specific radiation dose estimates. Nonetheless, the number of carriers identified was somewhat limited, resulting in relatively wide confidence intervals that reflect the uncertainty in the risk estimates. The quadrant-specific dose estimates calculated for each woman individually in this study are a significant improvement over prior studies without such specificity; however, some uncertainty remains in these estimates, especially within the inner quadrants, due to occasional incomplete or imprecise information on tumor-location (20). Further, while our genotyping strategy allowed us to identify a wide range of deleterious BRCA1/BRCA2 mutations, we recognize that large genomic deletions or duplications would be missed. Lastly, we used the published BIC classifications to classify deleterious mutations. However, if unclassified variants of unknown clinical significance in these genes (39-41) are associated with radiation-induced CBC, we may have under-estimated the association.

In conclusion, the baseline risk of developing CBC among BRCA1/BRCA2 mutation carriers is large and we did not find that carriers are proportionally more susceptible than non-carriers to the carcinogenic effects of radiation received to the contralateral breast during treatment for the first invasive breast cancer. Further, there was little evidence for a dose-response relationship between CBC risk and radiation dose among mutation carriers. At face value these results suggest that, in view of the known benefits of RT for primary breast cancer, RT remains an appropriate option for carriers of BRCA1/BRCA2 mutations. We did not directly investigate the cumulative effect of very low dose radiation from mammography, which for some women—particularly BRCA1/BRCA2 carriers— might begin at ages much earlier than the age at treatment for most of our radiotherapy patients. Nevertheless, our results showing little or no increased risk of CBC for an exposure of substantially greater magnitude, suggest that low-dose x-ray mammograms are unlikely to disproportionately increase CBC risk in carriers compared with non-carriers.

WECARE Study Collaborative Group Memorial Sloan Kettering Cancer Center (New York, NY): Jonine L. Bernstein Ph.D. (WECARE Study P.I.), Colin B. Begg. Ph.D., Marinela Capanu Ph.D., Xiaolin Liang M.D., Anne S. Reiner M.P.H., Tracy M. Layne M.P.H.

City of Hope (Duarte, CA) (some work performed at University of Southern California, Los Angeles CA): Leslie Bernstein Ph.D., Laura Donnelly-Allen

Danish Cancer Society (Copenhagen, Denmark): Jørgen H. Olsen M.D., D.M.Sc., Michael Andersson M.D., D.M.Sc., Lisbeth Bertelsen M.D., Ph.D., Per Guldberg Ph.D., Lene Mellemkjær Ph.D

Fred Hutchinson Cancer Research Center (Seattle, WA): Kathleen E. Malone Ph.D.

International Epidemiology Institute (Rockville, MD) and Vanderbilt University (Nashville, TN): John D. Boice Jr. Sc.D.

Lund University (Lund, Sweden): Åke Borg Ph.D., Therese Törngren M.Sc., Lina Tellhed, B.Sc.

National Cancer Institute (Bethesda, MD): Daniela Seminara Ph.D. M.P.H

New York University (New York, NY): Roy E. Shore Ph.D., Dr.PH.

Norwegian Radium Hospital (Oslo, Norway): Laila Jansen, Anne-Lise Børresen-Dale Ph.D. (also University of Oslo, Norway)

University of California at Irvine (Irvine, CA): Hoda Anton-Culver, Ph.D., Joan Largent Ph.D. M.P.H.

University of Iowa (Iowa City, IA): Charles F. Lynch M.D., Ph.D., Jeanne DeWall M.A.

University of Southern California (Los Angeles, CA): Robert W. Haile DrPH., Graham Casey, Ph.D., Bryan Langholz Ph.D., Duncan C. Thomas Ph.D., Nianmin Zhou, M.D, Anh T. Diep, Evgenia Ter-Karapetova

University of Southern Maine (Portland, ME):W. Douglas Thompson Ph.D.

University of Texas, M.D. Anderson Cancer Center (Houston, TX): Marilyn Stovall Ph.D., Susan Smith M.P.H.

University of Virginia (Charlottesville, VA) (some work performed at Benaroya Research Institute, Seattle WA): Patrick Concannon, Ph.D., Sharon N.Teraoka, Ph.D., Eric R. Olson, Nirasha Ramchurren, Ph.D.

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Conflicts of Interest: None.

Disclaimers: None

CONFLICTS OF INTEREST None of the authors declare a financial or personal conflict of interest.

AUTHORS CONTRIBUTIONS Conception and Design. Jonine L. Bernstein, Duncan C. Thomas, Roy E. Shore, Mark Robson, John D. Boice, Marilyn Stovall, Michael Andersson, Leslie Bernstein, Kathleen E. Malone, Charles F. Lynch, Colin B. Begg, Jorgen H. Olsen, Lene Mellemkjaer, Ake Borg, Patrick Concannon, Robert W. Haile

Collection and Assembly of Data and Patients. Jonine L. Bernstein, Marilyn Stovall, Michael Andersson, Leslie Bernstein, Kathleen E. Malone, Charles F. Lynch, Susan A. Smith, Lina Tellhed, Sharon N. Teraoka, Jorgen H. Olsen, Lene Mellemkjaer, Xiaolin Liang, Anh T. Diep, Ake Borg, Patrick Concannon, Robert W. Haile

Data analysis and Interpretation. Jonine L. Bernstein, Duncan C. Thomas, Roy E. Shore, Mark Robson, John D. Boice, Marilyn Stovall, Michael Andersson, Leslie Bernstein, Kathleen E. Malone, Anne S. Reiner, Charles F. Lynch, Marinela Capanu, Sharon N. Teraoka, Colin B. Begg, Jorgen H. Olsen, Lene Mellemkjaer, Xiaolin Liang, Ake Borg, Patrick Concannon, Robert W. Haile

Manuscript Writing. Jonine L. Bernstein, Duncan C. Thomas, Roy E. Shore, Mark Robson, John D. Boice, Marilyn Stovall, Michael Andersson, Leslie Bernstein, Kathleen E. Malone, Charles F. Lynch, Colin B. Begg, Jorgen H. Olsen, Lene Mellemkjaer, Ake Borg, Patrick Concannon, Robert W. Haile

Final Approval of Manuscript. Jonine L. Bernstein, Duncan C. Thomas, Roy E. Shore, Mark Robson, John D. Boice, Marilyn Stovall, Michael Andersson, Leslie Bernstein, Kathleen E. Malone, Anne S. Reiner, Charles F. Lynch, Marinela Capanu, Susan A. Smith, Lina Tellhed, Sharon N. Teraoka, Colin B. Begg, Jorgen H. Olsen, Lene Mellemkjaer, Xiaolin Liang, Anh T. Diep, Ake Borg, Patrick Concannon, Robert W. Haile