Subsequent Thyroid Cancer Research Articles

6893 The Interaction Effect Between BMI, Diabetes, and Age at Diabetes Onset on the Risk of Thyroid Cancer: A Population-Based Cohort Study

Abstract Disclosure: T. Hou: None. Y. Li: None. J. Tian: None. Z. Bloomgarden: None. Y. Shi: None. ObjectiveThe relationship between type 2 diabetes mellitus (T2DM) and thyroid cancer was confounded by some characteristics of diabetes. We aimed to determine the association of the presence of diabetes and, among persons with diabetes, the age at T2DM onset, BMI, and the interactive effect with the subsequent thyroid cancer risk. MethodsWe conducted a population-based longitudinal cohort study including 428,568 persons with new-onset T2DM matched with the general population (100,649,346 person-years). Risk of thyroid cancer by subgroups were calculated based on standardized incidence ratio (SIR), hazard ratio (HR), and Cox proportional hazards models. ResultsIn T2DM patients, 1142 thyroid cancer cases were identified during eight years of follow-up, with an incidence rate of 59.01/100,000 person-years and a higher SIR: 1.21 (95% CI: 1.14-1.28) compared to the general population. New-onset T2DM had an overall 21% higher risk of thyroid cancer. Both the earlier age at T2DM onset and higher BMI were associated with a significant increasing risk of thyroid cancer independently (T2DM onset age <50: SIR 1.46 (1.27-1.69); BMI ≥30.0 Kg/m2 SIR: 1.93 (1.57-2.38)). The highest risk of cancer appeared in the patients with both BMI ≥30.0 Kg/m2 and T2DM onset age <50 years (SIR=3.91, HR=3.04). Among patients with T2DM onset age <60 years, SIR shows an increasing trend of cancer risk with higher BMI levels, while no significant increasing trends with higher BMI in T2DM onset age ≥60 years. For patients with BMI ≥25.0 Kg/m2, SIR of cancer risk decreases with an later T2DM onset age, whereas no significant decreasing trends of cancer risk in BMI <24.9 Kg/m2 group. Obese (BMI ≥30.0 Kg/m2) patients had a significant higher HR of thyroid cancer only when T2DM onset age <60 years. ConclusionsBoth earlier age of T2DM onset (<50 years) and higher BMI (≥30 Kg/m2) contributed to higher risk of thyroid cancer. These results suggest that earlier screening of thyroid cancer might be appropriate in patients diagnosed with T2DM, especially in individuals with young-onset T2DM and obesity. Presentation: 6/3/2024

The interaction effect between BMI, diabetes and age at diabetes onset on the risk of thyroid cancer: A population-based cohort study in Shanghai, China.

To determine the association of the presence of diabetes and, among persons with diabetes, the age at type 2 diabetes mellitus (T2DM) onset, BMI and the interactive effect with the subsequent thyroid cancer risk. We conducted a population register-based longitudinal cohort study in Shanghai, including 428 568 persons with new-onset T2DM matched with the general population. The risk of thyroid cancer among subgroups was calculated based on standardized incidence ratio (SIR), hazard ratio (HR) and Cox proportional hazards models. In total, 1142 thyroid cancer cases were identified during 8 years of follow-up, with an incidence rate of 59.01/100 000 person-years and a higher risk (SIR = 1.21) compared with the general population. The earlier age at T2DM onset and higher BMI were associated with an increasing risk of thyroid cancer independently (onset age <50, SIR: 1.46; BMI ≥30.0 kg/m2, SIR: 1.93), with the highest risk in patients with both BMI ≥30.0 kg/m2 and onset age <50 years (SIR = 3.91, HR = 3.04). Among patients with T2DM onset age <60 years, SIR increased with higher BMI, while there were no trends when onset age ≥60 years. Among patients with BMI ≥25.0 kg/m2, SIR increased with an earlier onset age, whereas no trends were shown in the BMI <24.9 kg/m2 groups. Obese (BMI ≥30.0 kg/m2) patients had a significantly higher HR of thyroid cancer only when T2DM onset age <60 years. Both earlier age of T2DM onset (<50 years) and higher BMI (≥30 kg/m2) contributed to the higher risk of thyroid cancer. Patients with young-onset T2DM and obesity are considered more vulnerable to thyroid cancer development.

Early-pregnancy sex steroid and thyroid function hormones, thyroid autoimmunity, and maternal papillary thyroid cancer incidence in the Finnish Maternity Cohort.

Thyroid cancer more commonly affects women than men and is the third most frequently diagnosed cancer among women of reproductive age. We conducted a nested case-control study within the Finnish Maternity Cohort to evaluate pre-diagnostic sex steroid and thyroid function markers in relation to subsequent maternal papillary thyroid cancer. Cases (n = 605) were women ages 18-44 years, who provided an early-pregnancy (<20 weeks gestation) blood sample and were diagnosed with papillary thyroid cancer up to 11 years afterward. Controls (n = 1185) were matched to cases 2:1 by gestational age, mother's age, and date at blood draw. Odds ratios (ORs) for the associations of serum thyroid peroxidase antibodies (TPO-Ab), thyroglobulin antibodies (Tg-Ab), thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), progesterone, and estradiol with papillary thyroid cancer were estimated using conditional logistic regression. TPO-Ab and Tg-Ab positivity (>95th percentile among controls) were associated with more than 3-fold (OR = 3.32, 95% confidence interval [CI] 2.33-4.72) and 2-fold (OR = 2.03, 95% CI 1.41-2.93) increased odds of papillary thyroid cancer, respectively. These associations were similar by time since blood draw, parity, gestational age, smoking status, and age and stage at diagnosis. In models excluding TPO-Ab or Tg-Ab positivity, TPO-Ab (quartile 4 vs. 1: OR = 1.66, 95% CI 1.17-2.37, p-trend = .002) and Tg-Ab (quartile 4 vs. 1: OR = 1.74, 95% CI 1.22-2.49, p-trend = .01) levels were positively associated with papillary thyroid cancer. No associations were observed for estradiol, progesterone, TSH, fT3, or fT4 overall. Our results suggest that thyroid autoimmunity in early pregnancy may increase the risk of maternal papillary thyroid cancer.

Unveiling Thyroid Disease Associations: An Exceptionality-Based Data Mining Technique

Background: The prevalence of thyroid disease has seen a rapid increase in recent times, primarily attributed to the fast pace of lifestyles that often result in poor dietary choices, work-life imbalances, social stress, genetic mutations, and improved diagnostic capabilities. However, the precise contribution of these factors to thyroid disease remains a subject of controversy. Consequently, there is a pressing need to gain a comprehensive understanding of the related associations in order to potentially mitigate the associated morbidity and mortality rates. Methods: This study employed association rule mining techniques to reveal hidden correlations among complex and diverse epidemiological connections pertaining to thyroid disease associations. We proposed a framework which incorporates text mining and association rule mining algorithms with exceptionality measurement to simultaneously identify common and exception risk factors correlated with the disease through real-life digital health records. Two distinctive datasets were analyzed through two algorithms, and mutual factors were retained for interpretation. Results: The results confirmed that age, gender, and history of thyroid disease are risk factors positively related to subsequent thyroid cancer. Furthermore, it was observed that the absence of underlying chronic disease conditions, such as diabetes, hypertension, or obesity, are associated with reduced likelihood of being diagnosed with thyroid cancer. Conclusions: Collectively, the proposed framework demonstrates its sound feasibility and should be further recommended for different disease in-depth knowledge discovery.

Joint effects of general population polygenic risk scores (PRS) and radiation treatment on subsequent neoplasm risk among childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS).

10008 Background: We examined whether PRS from general population studies are associated with risk of subsequent neoplasms (SNs) in childhood cancer survivors and evaluated joint associations between PRS and radiation treatment (RT), an established SN risk factor. Methods: Common genetic variants associated with risk of basal cell carcinoma (BCC), breast cancer, thyroid cancer, squamous cell carcinoma (SCC) or melanoma in general population studies were used to calculate cancer specific PRS among 5,911 5 year cancer survivors diagnosed &lt; 21 years of age and between 1970-1986 in the CCSS. We examined associations between each PRS and SN risk using conditional logistic regression in nested case control studies, with incidence density sampling and matching on childhood cancer type, age at diagnosis, sex, RT dose to the SN site, and chemotherapy exposure. Further analyses matching only on non-treatment factors assessed joint associations considering potential combinations of PRS and RT exposure. We calculated the relative excess risk due to interaction (RERI) to determine whether joint associations were consistent with additivity of the individual risk factors (RERI &gt; 0 indicates a more-than-additive joint association). Results: Among survivors (median age at follow-up 40 years, range 3-67; 62% exposed to RT), cancer specific PRS were associated with risk of subsequent BCC (N = 626; quartile 4 versus 1, OR [95% CI] = 1.9 [1.5-2.4]), breast cancer (N = 277; 4.5 [2.8-7.1]), thyroid cancer (N = 149; 1.9 [1.2-3.1]), and melanoma (N = 76; 2.7 [1.3-5.6]). Both PRS and RT were independently associated with SN risk, but joint analyses using a common reference group (PRS &lt; median, RT &lt; 1 Gy) found that both risk factors together resulted in more-than-additive increases in risk of BCC (RERI [95% CI] = 6.9 [2.0-11.8], breast cancer (6.6 [2.2-10.1], and thyroid cancer (4.8 [0.5-9.2]). Specifically, BCC risk was increased 28.8-fold for both PRS ≥ median and RT ≥ 1 Gy together, but only 3.3-fold for PRS ≥ median alone and 19.7-fold for RT ≥ 1 Gy alone. Similarly, breast cancer risk was increased 14.1-fold for both risk factors together, 2.5-fold for PRS ≥ median alone, and 6.5-fold for RT ≥ 1 Gy alone, and thyroid cancer risk was increased 12.3-fold for both risk factors together, 2.4-fold for PRS ≥ median alone, and 6.0-fold for RT ≥ 1 Gy alone. In joint analyses using more detailed RT categories, we found more-than-additive joint associations at both low and high RT doses. Conclusions: General population PRS were associated with SN risks after childhood cancer. More-than-additive increased risks with the combination of PRS and RT suggest that established markers of genetic susceptibility remain important in the context of treatment-related risks and may be useful in further refining risk assessment and follow-up guidelines for survivors.

High Prevalence of Gene Fusions and Copy Number Alterations in Pediatric Radiation Therapy-Induced Papillary and Follicular Thyroid Carcinomas.

Background: Childhood cancer survivors and bone marrow transplant recipients treated with radiation therapy (RT) are at increased risk for subsequent thyroid cancer. However, the genetic landscape of pediatric thyroid cancer, both primary and RT-induced, remains poorly defined, as pediatric papillary thyroid carcinoma (PTC) has been understudied compared with adults and data on pediatric follicular thyroid carcinoma (FTC) are virtually nonexistent. The objective of this study was to characterize and compare the molecular profiles of pediatric RT-induced PTC and FTC cases with primary pediatric thyroid cancers. Methods: A total of 41 differentiated thyroid carcinomas (11 RT cases and 30 primary cases) from 37 patients seen at Phoenix Children's Hospital between January 1, 2010 and December 31, 2019 were evaluated by targeted next-generation sequencing and/or BRAF immunohistochemistry. Results: Eighty-six percent (6/7) of RT-PTC harbored a gene fusion (GF) compared with 56% (14/25) of primary PTC; 14% (1/7) of RT-PTC had a single-nucleotide variant (SNV; specifically, a point mutation in the DICER1 gene) compared with 44% (11/25) of primary PTC (all of the latter had the BRAFV600E mutation). An exceedingly rare ROS1 fusion was identified in a child with RT-PTC. With respect to FTC, copy number alterations (CNAs) were seen in 75% (3/4) of RT cases compared with 40% (2/5) of primary cases. None of the RT-FTC had SNVs compared with 100% (5/5) of primary FTC. Conclusions: In children, the molecular profile of subsequent RT-induced thyroid cancers appears to differ from primary (sporadic and syndromic) cases, with a high prevalence of GFs in RT-PTC (similar to PTC occurring after the Chernobyl nuclear reactor accident) and CNAs in RT-FTC. A better understanding of the molecular mechanisms underlying these cancers may lead to more accurate diagnosis, prognosis, and treatment, as some of the genomic alterations are potentially targetable.

Screening Leads to Overestimated Associations of Thyroid Dysfunction and Thyroiditis with Thyroid Cancer Risk.

Simple SummaryThe association of thyroid dysfunction and thyroiditis with the risk of thyroid cancer is an important issue in clinical practice, and is controversial due to various confounders, including screening effects. In this large-sample, population-based, nationwide study, we demonstrated that the screening effect likely significantly contributed to the positive associations of thyroid dysfunction and thyroiditis with thyroid cancer. After adjustment for this confounder, thyroid cancer risk was positively associated with hypothyroidism and thyroiditis but negatively associated with hyperthyroidism and Graves’ disease. Multiple subgroup analyses showed consistent results. Given these overestimated associations, we suggest that unnecessary and excessive concerns or screening tests for thyroid cancer could be reduced in patients with thyroid dysfunction or thyroiditis.We aimed to assess the relationships of functional thyroid disease and thyroiditis with subsequent thyroid cancer, which is controversial due to various confounders, and the effect of thyroid disease workup on this association. We used the cohort data from 2002 to 2015 (Study I, n = 28,330) and the entire data from 2002 to 2019 (Study II, n = 883,074) of the Korean National Health Insurance Service database, and performed logistic regression and subgroup analyses with various covariates. In Study I, hypothyroidism, thyroiditis, autoimmune thyroiditis, hyperthyroidism, and Graves’ disease showed positive associations with thyroid cancer. In Study II, after adjustment for covariates including the number of thyroid function tests, the ORs for thyroid cancer were significantly reduced in all thyroid diseases. Hypothyroidism, thyroiditis, and autoimmune thyroiditis were positively associated (adjusted odds ratio, OR (95% confidence interval, CI) 1.28 (1.25–1.32), 1.36 (1.31–1.42), and 1.17 (1.11–1.24), respectively), whereas hyperthyroidism and Graves’ disease were negatively associated with thyroid cancer (adjusted OR (95% CI) 0.80 (0.77–0.83) and 0.69 (0.65–0.74), respectively). Multiple subgroup analyses in both studies showed consistent results. In this large population-based, nationwide study, we confirmed that thyroid disease workup leads to overestimation of associations of thyroid dysfunction and thyroiditis with thyroid cancer risk.

Increased risk of second primary malignancies among endometrial cancer survivors receiving surgery alone: A population-based analysis.

BackgroundWomen with endometrial cancer (EC) have favorable prognoses, leaving them vulnerable to the development of second primary cancers (SPCs). We investigated the SPC risk and survival outcomes among EC patients treated with surgery alone in order to exclude the impact of adjuvant treatment on the results.MethodsData from the Taiwan Cancer Registry from 1995 to 2013 were analyzed. Standardized incidence ratios (SIRs) of SPCs among EC survivors were calculated.ResultsAmong 7725 women enrolled, 478 developed an SPC. The overall SIR for SPCs in EC survivors was 2.84 (95% confidence interval [CI] 2.59–3.10) compared with the general female population. Women diagnosed with EC at age <50 years had a higher SIR for an SPC than those diagnosed at age ≥50 years (SIR = 4.38 vs. 1.28). The most frequent site of an SPC was the small intestine (SIR = 8.39, 95% CI 2.72–19.58), followed by the kidney (SIR = 4.84, 95% CI 1.78–10.54), and oral cavity (SIR = 4.52, 95% CI 2.17–8.31). Women, regardless of age at EC diagnosis, had significantly higher SIRs for subsequent breast, colorectal, lung, and thyroid cancer, and lymphoma. Women with an SPC had shorter overall survival than those without (5‐year: 88.9 vs. 94.2%, 10‐year: 71.3 vs. 89.8%, 15‐year: 62.3 vs. 86.1%, and 20‐year: 47.6 vs. 81.1%, all ps<0.001).ConclusionsEven women treated for EC with surgery alone, especially young EC survivors, had an increased risk of SPCs. Genetic counseling/testing is recommended for young EC patients, and all are recommended to receive regular surveillance and screening for breast, colorectal, and lung cancers.

Presentation and outcome of subsequent thyroid cancer among childhood cancer survivors compared to sporadic thyroid cancer: a matched national study

Presentation and outcome of subsequent thyroid cancer among childhood cancer survivors compared to sporadic thyroid cancer: a matched national study

Polygenic Risk Score Improves Risk Stratification and Prediction of Subsequent Thyroid Cancer after Childhood Cancer.

Subsequent thyroid cancer (STC) is one of the most common malignancies in childhood cancer survivors. We aimed to evaluate the polygenic contributions to STC risk and potential utility in improving risk prediction. A polygenic risk score (PRS) was calculated from 12 independent SNPs associated with thyroid cancer risk in the general population. Associations between PRS and STC risk were evaluated among survivors from St. Jude Lifetime Cohort (SJLIFE) and were replicated in survivors from Childhood Cancer Survivor Study (CCSS). A risk prediction model integrating the PRS and clinical factors, initially developed in SJLIFE, and its performance were validated in CCSS. Among 2,370 SJLIFE survivors with a median follow-up of 28.8 [interquartile range (IQR) = 21.9-36.1] years, 65 (2.7%) developed STC. Among them, the standardized PRS was associated with an increased rate of STC [relative rate (RR) = 1.57; 95% confidence interval (CI) = 1.24-1.98; P < 0.001]. Similar associations were replicated in 6,416 CCSS survivors, among whom 121 (1.9%) developed STC during median follow-up of 28.9 (IQR = 22.6-34.6) years (RR = 1.52; 95% CI = 1.25-1.83; P < 0.001). A risk prediction model integrating the PRS with clinical factors showed better performance than the model considering only clinical factors in SJLIFE (P = 0.004, AUC = 83.2% vs. 82.1%, at age 40), which was further validated in CCSS (P = 0.010, AUC = 72.9% vs. 70.6%). Integration of the PRS with clinical factors provided a statistically significant improvement in risk prediction of STC, although the magnitude of improvement was modest. PRS improves risk stratification and prediction of STC, suggesting its potential utility for optimizing screening strategies in survivorship care.

Exposure to radiotherapy for first primary cancer as a risk factor for second primary thyroid cancer: A case-control study

BackgroundSecond primary neoplasms are associated with high mortality and morbidity rates in cancer survivors successfully treated for the first malignancy. Studies suggested an association between the type of first neoplasm and risk of subsequent thyroid cancer, with part of this risk attributable to exposure to radiotherapy during treatment of the first primary tumor. This study aimed to determine whether radiotherapy is a risk factor for thyroid cancer in patients previously treated for another neoplasm. MethodsThis retrospective case-control study included patients diagnosed with their first cancer between 2007 and 2017. Patients who subsequently developed thyroid cancer as a second primary neoplasm were defined as “cases”, and patients who did not develop a second cancer were defined as “controls”. Exposure to radiotherapy was the primary risk factor of interest; other risk factors were the site to which radiotherapy was delivered and the first neoplasm type. ResultsExposure to radiotherapy was associated with an increased risk of thyroid cancer (odds ratio [OR]=2.410, 95% confidence interval [CI]: 1.219–4.764), in particular, in women (OR=3.121, 95% CI: 1.232–7.907) and in patients receiving radiotherapy to the thorax (OR=6.298, 95% CI: 2.581–15.370). The median survival time from first cancer recovery to thyroid cancer occurrence was 63.80 months; there was no difference in survival between patients who did and did not receive radiotherapy (P=0.899). ConclusionRadiation to the thorax can increase the risk of thyroid cancer as a second neoplasm among patients with cancer successfully treated for their first cancer.

Exposure to Polychlorinated Biphenyls and Organochlorine Pesticides and Risk of Thyroid Cancer in Women

Background: Both polychlorinated biphenyls (PCB) and organochlorine pesticides (OCP) have been associated with thyroid hormone disruption, but their relationship to thyroid cancer is not known. Methods: We investigated the relationship between serum PCB and OCP concentrations and papillary thyroid cancer (PTC) in 250 incident female PTC cases and 250 female controls frequency-matched on age, all residing in Connecticut. Interviews and serum samples were collected from 2010-2013. Samples were analyzed for 32 different chemicals using gas chromatography with isotope dilution high resolution mass spectrometry. We calculated odds ratios (OR) and 95% confidence intervals (CI) using single pollutant logistic regression models for concentrations (per interquartile range) of individual PCB/OCP and summed groups of structurally or biologically similar PCB/OCP, adjusted for education, family history of cancer, alcohol consumption, and body mass index. Sub-analyses included stratification by tumor size (&lt;=1 cm and &gt;1 cm) and birth cohort (born before or in 1960 and born after 1960). We also applied three multi-pollutant approaches (standard multi-pollutant regression, hierarchical Bayesian modeling, principal components regression analysis) to investigate associations with exposures to multiple PCB/OCPs. Results: No PCB/OCPs were positively associated with PTC risk in primary analyses. Statistically significant associations were observed for 9 of the 32 chemicals and 3 summed groups of similar chemicals in the younger birth cohort based on single-pollutant models. Multi-pollutant analyses suggested null associations overall. Conclusions: Our results using single and multi-pollutant modeling do not generally support an association between PCB or OCP exposure and PTC risk, but some associations in the younger birth cohort suggest that additional investigation into early-life exposures and subsequent thyroid cancer risk may be warranted.

Exposure to polychlorinated biphenyls and organochlorine pesticides and thyroid cancer in connecticut women

BackgroundThyroid cancer incidence has increased substantially over the past decades, and environmental risk factors have been suggested to play a role. Polychlorinated biphenyls (PCB) and organochlorine pesticides (OCP) are established thyroid hormone disruptors, but their relationship to thyroid cancer is not known. MethodsWe investigated the relationship between serum PCB and OCP concentrations and papillary thyroid cancer (PTC) in 250 incident female PTC cases and 250 female controls frequency-matched on age, all residing in Connecticut. Interviews and serum samples were collected from 2010 to 2013. Samples were analyzed for 32 different chemicals using gas chromatography with isotope dilution high resolution mass spectrometry. We calculated odds ratios (OR) and 95% confidence intervals (CI) using single pollutant logistic regression models for concentrations (per interquartile range) of individual PCB/OCP and summed groups of structurally or biologically similar PCB/OCP, adjusted for education, family history of cancer, alcohol consumption, age, and body mass index. Sub-analyses included stratification by tumor size (≤ and >1 cm) and birth before or during peak PCB production (born in 1960 or earlier and born after 1960), as exposures during early life may be important. We also applied three multi-pollutant approaches (standard multi-pollutant regression, hierarchical Bayesian modeling, principal components regression analysis) to investigate associations with co-exposures to multiple PCB/OCPs. ResultsNo PCB/OCPs were positively associated with PTC in primary analyses. Statistically significant associations were observed for 9 of the 32 chemicals and 3 summed groups of similar chemicals in the those born during peak production based on single-pollutant models. Multi-pollutant analyses suggested null associations overall. ConclusionsOur results using single and multi-pollutant modeling do not generally support an association between PCB or OCP exposure and PTC, but some associations in those born during peak production suggest that additional investigation into early-life exposures and subsequent thyroid cancer risk may be warranted.

Thyroid cancer after hysterectomy and oophorectomy: a nationwide cohort study.

Little is known about the role of estrogen in thyroid cancer development. We aimed to evaluate the association between hysterectomy or bilateral salpingo-oophorectomy (BSO) and the risk of subsequent thyroid cancer. A nationwide cohort study. Data from the Korea National Health Insurance Service between 2002 and 2017 were used. A total of 78 961 and 592 330 women were included in the surgery group and no surgery group, respectively. The surgery group was categorized into two groups according to the extent of surgery: hysterectomy with ovarian conservation (hysterectomy-only) and BSO with or without hysterectomy (BSO). During 8 086 396.4 person-years of follow-up, 12 959 women developed thyroid cancer. Women in the hysterectomy-only (adjusted hazard ratio = 1.7, P < 0.001) and BSO (adjusted hazard ratio = 1.4, P < 0.001) groups had increased risk of thyroid cancer compared to those in the no surgery group. In premenopausal women, hysterectomy-only (adjusted hazard ratio = 1.7, P < 0.001) or BSO (adjusted hazard ratio = 1.4, P < 0.001) increased the risk of subsequent thyroid cancer, irrespective of hormone therapy, whereas, there was no significant association between hysterectomy-only (P = 0.204) or BSO (P = 0.857) and thyroid cancer development in postmenopausal women who had undergone hormone therapy. Our findings do not support the hypotheses that sudden or early gradual decline in estrogen levels is a protective factor in the development of thyroid cancer, or that exogenous estrogen is a risk factor for thyroid cancer.

Pathogenic Germline Mutations in DNA Repair Genes in Combination With Cancer Treatment Exposures and Risk of Subsequent Neoplasms Among Long-Term Survivors of Childhood Cancer.

To investigate cancer treatment plus pathogenic germline mutations (PGMs) in DNA repair genes (DRGs) for identification of childhood cancer survivors at increased risk of subsequent neoplasms (SNs). Whole-genome sequencing was performed on blood-derived DNA from survivors in the St Jude Lifetime Cohort. PGMs were evaluated in 127 genes from 6 major DNA repair pathways. Cumulative doses of chemotherapy and body region-specific radiotherapy (RT) were abstracted from medical records. Relative rates (RRs) and 95% CIs of SNs by mutation status were estimated using multivariable piecewise exponential models. Of 4,402 survivors, 495 (11.2%) developed 1,269 SNs. We identified 538 PGMs in 98 DRGs (POLG, MUTYH, ERCC2, and BRCA2, among others) in 508 (11.5%) survivors. Mutations in homologous recombination (HR) genes were significantly associated with an increased rate of subsequent female breast cancer (RR, 3.7; 95% CI, 1.8 to 7.7), especially among survivors with chest RT ≥ 20 Gy (RR, 4.4; 95% CI, 1.6 to 12.4), or with a cumulative dose of anthracyclines in the second or third tertile (RR, 4.4; 95% CI, 1.7 to 11.4). Mutations in HR genes were also associated with an increased rate of subsequent sarcoma among those who received alkylating agent doses in the third tertile (RR, 14.9; 95% CI, 4.0 to 38.0). Mutations in nucleotide excision repair genes were associated with subsequent thyroid cancer for those treated with neck RT ≥ 30 Gy (RR, 12.9; 95% CI, 1.6 to 46.6) with marginal statistical significance. Our study provides novel insights regarding the contribution of genetics, in combination with known treatment-related risks, for the development of SNs. These findings have the potential to facilitate identification of high-risk survivors who may benefit from genetic counseling and/or testing of DRGs, which may further inform personalized cancer surveillance and prevention strategies.

Uterine Fibroids Increase the Risk of Thyroid Cancer.

Objectives: The formation of uterine fibroids (UF) is potentially linked to the development of thyroid cancer through a common factor: female sex hormones. Methods: We conducted a nationwide population-based cohort study to determine whether Taiwanese women with UF have an increased risk of thyroid cancer. The data of both the UF and control groups were derived from the National Health Insurance Research Database (NHIRD) of Taiwan. Groups were matched by the year of UF diagnosis, age, income, urbanization level, occupation, and comorbidities. A Cox proportional hazard regression model was used to compare the incidence of thyroid cancer between the UF and control groups. In addition, the model was used to determine the hazard ratio of thyroid cancer in the UF group in comparison with the control group. Results: Women with UF had a statistically significantly increased risk of thyroid cancer compared with controls (adjusted hazard ratio (aHR): 1.64, 95% confidence interval (CI): 1.26–2.13). Stratified analyses showed that women with UF who had a significantly increased risk of thyroid cancer were more likely to be middle aged, have middle and higher income levels, and a medium follow-up period (1–5 years) of UF. No other UF patient characteristics and comorbidities showed association with the risk of thyroid cancer. In addition, UF patients had a significantly increased risk of thyroid cancer regardless of whether or not they underwent myomectomy. Conclusions: The results suggest that women with UF have an increased risk of subsequent thyroid cancer. Further research is needed to explore whether surveillance strategies for the early detection of thyroid cancer using ultrasonography should be implemented among patients with UF.

Mutational analysis of radiation-induced subsequent thyroid cancers in pediatric patients.

e22531 Background: The genetic landscape of radiation induced pediatric thyroid cancers is unclear. Radiation (RT) induced thyroid cancers frequently demonstrate tumorigenesis driven by fusion oncogenes. However, data is limited to children exposed to radioactive contamination after the Chernobyl nuclear accident. Little is known about the genetic landscape of subsequent pediatric thyroid cancers after RT exposure for the treatment of a primary malignancy or conditioning regimens prior to bone marrow transplantation (BMT). The objective of this study was to assess the prevalence of different mutations in a small cohort of pediatric patients who developed a subsequent thyroid cancer after RT exposure for the treatment of a primary disease. Methods: This is a single-center retrospective study. Thyroid tissue blocks from 10 pediatric patients who underwent thyroidectomy between 2010 and 2019 for subsequent thyroid cancers after RT for treatment of a primary malignancy or BMT were analyzed for genetic alterations using targeted next-generation sequencing for alterations in 112 genes linked to thyroid cancer. Thyroid cancers included 7 papillary (PTC) and 3 follicular thyroid carcinomas (FTC). Results: Ten samples (6 females) were genotyped. The mean age at thyroid cancer diagnosis was 15.7 years (range 11–22 years) at a mean of 10.3 years (range 6 – 19 years) after RT exposure. The mean RT dose was 2618 cGy (range 400 – 10,080 cGy) delivered to the head, neck, and/or chest. Mutations were noted in 6/10 (60%) of patients. Mutations were detected in 6/7 (85.7%) of PTC cases: EMLA/NTRK in 2 cases, STRN/ALK in 2 cases, RET in 1 case, and CCDC30/ROS in 1 case. A DICER.1 c.5438A &gt; C p.E1813A was also identified in a patient with an EMLA/NTRK fusion. Of 3 FTC patients, (2/3) 67% had copy number alterations, but no mutations were observed. BRAFV600E mutations were not present in any tissues analyzed. Conclusions: An exceedinlgy rare ROS fusion was identified. Multiple RT induced thyroid lesions were positive for classic therapeutic targets including NTRK3, ALK, ROS1, and RET fusions, demonstrating a potential role for tyrosine kinase inhibitor therapy for refractory, recurrent or metastatic disease. All cases were negative for mutant BRAFV600E consistent with the pathogenesis of RT induced thyroid cancers primarily activated by fusions rather than point mutations. Larger, pediatric cohorts with RT induced thyroid cancers followed long term will enable the genotypic variability, clinical presentation, and response to therapy to be better assessed.

Shortened Leukocyte Telomere Length Associates with an Increased Prevalence of Chronic Health Conditions among Survivors of Childhood Cancer: A Report from the St. Jude Lifetime Cohort.

We aimed to analyze and compare leukocyte telomere length (LTL) and age-dependent LTL attrition between childhood cancer survivors and noncancer controls, and to evaluate the associations of LTL with treatment exposures, chronic health conditions (CHC), and health behaviors among survivors. We included 2,427 survivors and 293 noncancer controls of European ancestry, drawn from the participants in St. Jude Lifetime Cohort Study (SJLIFE), a retrospective hospital-based study with prospective follow-up (2007-2016). Common nonneoplastic CHCs (59 types) and subsequent malignant neoplasms (5 types) were clinically assessed. LTL was measured with whole-genome sequencing data. After adjusting for age at DNA sampling, gender, genetic risk score based on 9 SNPs known to be associated with telomere length, and eigenvectors, LTL among survivors was significantly shorter both overall [adjusted mean (AM) = 6.20 kb; SE = 0.03 kb] and across diagnoses than controls (AM = 6.69 kb; SE = 0.07 kb). Among survivors, specific treatment exposures associated with shorter LTL included chest or abdominal irradiation, glucocorticoid, and vincristine chemotherapies. Significant negative associations of LTL with 14 different CHCs, and a positive association with subsequent thyroid cancer occurring out of irradiation field were identified. Health behaviors were significantly associated with LTL among survivors aged 18 to 35 years (P trend = 0.03). LTL is significantly shorter among childhood cancer survivors than noncancer controls, and is associated with CHCs and health behaviors, suggesting LTL as an aging biomarker may be a potential mechanistic target for future intervention studies designed to prevent or delay onset of CHCs in childhood cancer survivors.See related commentary by Walsh, p. 2281.

Ultrasound is superior to palpation for thyroid cancer detection in high-risk childhood cancer and BMT survivors

Thyroid cancer is a common subsequent malignant neoplasm in childhood cancer survivors (CCS). Patients who received radiotherapy (RT) to the head, neck, upper thorax, or total body irradiation (TBI) are considered to be at risk for subsequent thyroid cancer. Current Children's Oncology Group screening guidelines recommend annual neck palpation. Our objective was to determine if ultrasound (US) is more sensitive and specific than palpation to detect thyroid cancer in high-risk CCS and bone marrow transplant (BMT) survivors. Electronic medical records of patients followed in a longitudinal survivorship clinic from January 1, 2010 to December 31, 2017 were reviewed. Inclusion criteria included history of RT to the head, neck, upper thorax, or TBI for primary therapy or preparation for BMT prior to the age of 20years. Two hundred and twenty-five patients had documented palpation and 144 (64%) also had US evaluation. Mean radiation dose was 28.6Gy. Sixteen of 225 patients (7.1%) developed a subsequent thyroid cancer at a mean of 9.7years from the completion of RT. Sensitivity of US was 100% compared with 12.5% for palpation. US demonstrated higher accuracy, with a receiver operating characteristic (ROC) area under the curve (AUC) of 0.87 versus 0.56 for palpation (P < 0.0001). Routine screening with US was more sensitive than palpation for detection of subsequent thyroid cancer after high-risk RT in CCS and BMT survivors. Screening US may lead to earlier detection of thyroid cancer in this population. Earlier diagnosis has the potential to decrease operative complexity, and earlier definitive therapy reduces the likelihood of metastatic disease.

Polygenic risk of subsequent thyroid cancer after childhood cancer: A report from St. Jude lifetime cohort (SJLIFE) and Childhood Cancer Survivor Study (CCSS).

10060 Background: Subsequent thyroid cancer (STC) is among the most common malignancies in childhood cancer survivors, especially those with thyroid exposure to radiotherapy (RT). Identification of genetic risk factors may inform screening practices. Methods: Twelve SNPs were previously identified as thyroid cancer risk loci in the general population of European ancestry. A polygenic risk score (PRS) was calculated as a sum of risk alleles carried by a survivor, weighted by the natural logarithm of the published per-allele odds ratios (range: 1.2-1.8). With piecewise exponential models, associations of STC rates with PRS were assessed, both overall and stratified by neck RT exposure. Models were adjusted for sex, age at primary diagnosis, attained age, neck RT dose, epipodophyllotoxin therapy, and eigenvectors within survivors of European ancestry from SJLIFE with whole-genome sequencing data and CCSS with SNP data imputed to Haplotype Reference Consortium. Results: Among 2,324 SJLIFE survivors, 61 (43 with, 18 without neck RT) developed STC. The rate of STC was increased by 5.3-fold (95% confidence interval (CI), 2.2-12.6) and 3.1-fold (CI, 1.3-7.7) for survivors in the third and second PRS tertiles, respectively, compared to those in the first tertile, with corresponding cumulative incidence at age of 40 years of 5.3% (CI, 3.3-7.3%), 2.5% (CI, 1.1-3.9%), and 1.0% (CI, 0.005-2.0%), respectively. Stratified by neck RT, the corresponding rate increases were 7.6 (CI, 2.3-25.3) and 3.8 (CI, 1.1-13.4), respectively, among survivors exposed to neck RT; however, no association was observed among survivors without neck RT (only 18 STC cases). Replication was performed among 4,302 CCSS survivors, 100 (61 with, 39 without neck RT) developed STC. The rates of STC were increased by 2.3-fold (CI, 1.4-3.9) and 1.7-fold (CI, 1.0-2.9) for survivors in the third and the second PRS tertiles, compared to those in the first tertile. The similar significant associations were observed in survivors with and without neck RT ( Ptrend = 0.04 and 0.02, respectively). Conclusions: High PRS conferring STC risk can inform screening practices and help personalize and improve survivorship care.