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Role of Germline Genetics in Identifying Survivors at Risk for Adverse Effects of Cancer Treatment.

ABSTRACT: The growing population of cancer survivors often faces adverse effects of treatment, which have a substantial impact on morbidity and mortality. Although certain adverse effects are thought to have a significant heritable component, much work remains to be done to understand the role of germline genetic factors in the development of treatment-related toxicities. In this article, we review current understanding of genetic susceptibility to a range of adverse outcomes among cancer survivors (e.g., fibrosis, urinary and rectal toxicities, ototoxicity, chemotherapy-induced peripheral neuropathy, subsequent malignancies). Most previous research has been narrowly focused, investigating variation in candidate genes and pathways such as drug metabolism, DNA damage and repair, and inflammation. Few of the findings from these earlier candidate gene studies have been replicated in independent populations. Advances in understanding of the genome, improvements in technology, and reduction in laboratory costs have led to recent genome-wide studies, which agnostically interrogate common and/or rare variants across the entire genome. Larger cohorts of patients with homogeneous treatment exposures and systematic ascertainment of well-defined outcomes as well as replication in independent study populations are essential aspects of the study design and are increasingly leading to the discovery of variants associated with each of the adverse outcomes considered in this review. In the long-term, validated germline genetic associations hold tremendous promise for more precisely identifying patients at highest risk for developing adverse treatment effects, with implications for frontline therapy decision-making, personalization of long-term follow-up guidelines, and potential identification of targets for prevention or treatment of the toxicity.

SUBMITTER: Morton LM

PROVIDER: S-EPMC6415750 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Role of Germline Genetics in Identifying Survivors at Risk for Adverse Effects of Cancer Treatment.

Morton Lindsay M LM Kerns Sarah L SL Dolan M Eileen ME

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 20180501

The growing population of cancer survivors often faces adverse effects of treatment, which have a substantial impact on morbidity and mortality. Although certain adverse effects are thought to have a significant heritable component, much work remains to be done to understand the role of germline genetic factors in the development of treatment-related toxicities. In this article, we review current understanding of genetic susceptibility to a range of adverse outcomes among cancer survivors (e.g., ...[more]

PMID: 30231410

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Project description:Background: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-?-reductase gene, SRD5A2), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ?3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. Results: We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; P<.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; P<.001) or abdominal obesity (28.2% vs 40.1%; P<.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; P=.59), did not differ by treatment (P=.20), and was not related to rs523349 (P=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; P<.001), total cholesterol levels (26.3% vs 11.1%; P<.001), and body mass index ?25 kg/m2 (75.1% vs 69.1%; P=.04). On multivariate analysis, age at evaluation (P<.001), testosterone level ?3.0 ng/mL (odds ratio [OR], 2.06; P=.005), and elevated sICAM-1 level (ORhighest vs lowest quartile, 3.58; P=.001) were significantly associated with MetS. Conclusions and Recommendations: Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment-associated MetS requires further characterization.

Project description:BackgroundFor survivors of childhood cancer, awareness of personal health risks is a critical component of long-term health management.ObjectiveTo evaluate the awareness of the diagnosis, treatment and risk of late effects among survivors of childhood cancer in Hong Kong.MethodsBetween June 2019 and March 2020, this cross-sectional study recruited 155 adult survivors (mean age = 26.9, standard deviation [SD] = 6.4 years) and 45 parents of paediatric survivors (mean age = 11.1, SD = 3.6 years) from a long-term follow-up clinic. At >10 years post-treatment (mean = 13.4, SD = 7.6 years), they completed a structured questionnaire to report their cancer-specific knowledge. Multiple linear regression analysis was conducted to identify clinical, socioeconomic and behavioural factors associated with poor awareness.ResultsThe majority of participants accurately recalled their diagnoses (73.5%) and major treatment modalities (chemotherapy 92.4%, radiation 82.9% and surgery 88.2%). However, less than half (45%) of the participants recognized more than 25% of the total late effects for which they were at risk. The highest levels of awareness were reported for endocrine problems (49%), neurocognitive impairment (44%) and secondary cancers (43%), and the lowest for peripheral neuropathy (21%) and vision problems (23%). Compared with survivors of haematological malignancies, those of central nervous system (CNS) tumours (standardized estimate [B] = -9.33, 95% confidence interval [95% CI]: -13.41 to -5.26) and non-CNS solid tumours (B = -8.47, 95% CI: -12.39 to -4.94) had less knowledge about their diagnosis. Retaining medical records (P < .0001) and better medical information-seeking habits (P = .048) were associated with better awareness.ConclusionsSurvivors of childhood cancer in Hong Kong have deficient awareness of their personal health risks. They may benefit from the provision of a survivorship care plan and personalized education regarding treatment-related late effects.Patient contributionPatients contributed in designing the study tools. Results were presented at a non-governmental organization.

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Role of Germline Genetics in Identifying Survivors at Risk for Adverse Effects of Cancer Treatment.

Publications

Role of Germline Genetics in Identifying Survivors at Risk for Adverse Effects of Cancer Treatment.

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