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Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome.

ABSTRACT: BACKGROUND:Lynch syndrome confers markedly increased risks of various malignancies, including urinary tract cancers (UTC; renal pelvis, ureter, bladder, and possibly kidney cancers). It is unknown how to determine which Lynch syndrome carriers are at highest UTC risk. Our aim was to identify clinical factors associated with UTC among Lynch syndrome carriers. METHODS:The study population was a cohort of 52,758 consecutively ascertained individuals undergoing Lynch syndrome testing at a commercial laboratory. Clinical data were obtained from test request forms completed by the ordering provider. Univariate analysis and multivariate logistic regression were performed to identify factors associated with UTC among Lynch syndrome carriers. RESULTS:Compared with noncarriers, Lynch syndrome carriers were significantly more likely to have had UTC (4.1% vs. 1.2%; P < 0.0001). Lynch syndrome-associated UTC was independently associated with male sex [OR 1.95; 95% confidence interval (CI), 1.38-2.76], increased age (OR 2.44 per 10 years; 95% CI, 2.11-2.82), familial burden of UTC (OR 2.69 per first-/second-degree relative with UTC; 95% CI, 1.99-3.63), and pathogenic EPCAM/MSH2 variants (OR 4.01; 95% CI, 2.39-6.72) but not MLH1 variants (OR 1.17; 95% CI, 0.63-2.17), race, or history of other Lynch syndrome-associated malignancy. A total of 143 of 158 (90.5%) Lynch syndrome carriers with UTC had ?1 of the following characteristics: male sex, EPCAM/MSH2 variants, or family history of UTC; 1,236 of 1,251 (98.8%) Lynch syndrome carriers lacking all of these characteristics had no history of UTC. CONCLUSIONS:Specific clinical factors can reliably identify Lynch syndrome carriers most likely to be at risk for UTC. IMPACT:A predictable subset of Lynch syndrome carriers may be most likely to benefit from UTC surveillance/prevention.

SUBMITTER: Wischhusen JW

PROVIDER: S-EPMC6954282 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome.

Wischhusen Jonathan W JW Ukaegbu Chinedu C Dhingra Tara G TG Uno Hajime H Kastrinos Fay F Syngal Sapna S Yurgelun Matthew B MB

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20191015 1

<h4>Background</h4>Lynch syndrome confers markedly increased risks of various malignancies, including urinary tract cancers (UTC; renal pelvis, ureter, bladder, and possibly kidney cancers). It is unknown how to determine which Lynch syndrome carriers are at highest UTC risk. Our aim was to identify clinical factors associated with UTC among Lynch syndrome carriers.<h4>Methods</h4>The study population was a cohort of 52,758 consecutively ascertained individuals undergoing Lynch syndrome testing ...[more]

PMID: 31615790

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Project description:Background & aimsLynch syndrome is the most common inherited cause of gastrointestinal cancer and increases risk for a variety of malignancies, including gastric cancer. We aimed to identify clinical factors associated with gastric cancer in carriers of germline variants causing Lynch syndrome.MethodsWe collected data from 52,758 consecutive individuals tested for genetic variants associated with Lynch syndrome from June 2006 through July 2013 at a commercial laboratory. We obtained clinical and demographic data, as well as information on personal and family histories of cancer (first- and second-degree relatives) from forms completed by ordering providers. We performed multivariate logistic regression to identify clinical factors associated with gastric cancer in carriers of mutations that cause Lynch syndrome (pathogenic mutations).ResultsAfter we excluded individuals with missing clinical data (n = 1664) or with multiple pathogenic mutations (n = 8), we analyzed data from 51,086 individuals. Of these, 3828 persons carried pathogenic mutations (1346 with mutations in MLH1, 1639 with mutations in MSH2, 670 with mutations in MSH6, 145 with mutations in PMS2, and 28 with mutations in EPCAM). Of the 3828 carriers of pathogenic mutations, 41 (1.1%) had a previous gastric cancer and 350 (9.1%) had 1 or more first- or second-degree relatives with gastric cancer. In multivariate analysis, male sex (odds ratio [OR], 2.82; 95% CI, 1.48-5.38), older age (OR, 2.07 per 10 years; 95% CI, 1.64-2.61), mutations in MLH1 (OR, 6.53; 95% CI, 1.50-28.42) or MSH2 (OR, 5.23 compared to mutations in MSH6, PMS2, or EPCAM; 95% CI, 1.21-22.71), and number of first-degree relatives with gastric cancer (OR, 2.52; 95% CI, 1.42-4.45), but not second-degree relatives (OR, 1.12; 95% CI, 0.40-3.18) were independently associated with gastric cancer among carriers of pathogenic mutations.ConclusionsIn an analysis of data from almost 4000 carriers of Lynch syndrome-associated mutations, we found history of gastric cancer to be independently associated with male sex, older age, mutations in MLH1 or MSH2, and number of first-degree relatives with gastric cancer. These findings suggest that personalized, risk-stratified approaches to gastric cancer surveillance may be appropriate for individuals with Lynch syndrome-associated mutations.

Project description:Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with a mismatch repair gene mutation (Lynch syndrome).To investigate the association between hormonal factors and endometrial cancer risk in Lynch syndrome.A retrospective cohort study included 1128 women with a mismatch repair gene mutation identified from the Colon Cancer Family Registry. Data were analyzed with a weighted cohort approach. Participants were recruited between 1997 and 2012 from centers across the United States, Australia, Canada, and New Zealand.Age at menarche, first and last live birth, and menopause; number of live births; hormonal contraceptive use; and postmenopausal hormone use.Self-reported diagnosis of endometrial cancer.Endometrial cancer was diagnosed in 133 women (incidence rate per 100 person-years, 0.29; 95% CI, 0.24 to 0.34). Endometrial cancer was diagnosed in 11% (n?=?70) of women with age at menarche greater than or equal to 13 years compared with 12.6% (n?=?57) of women with age at menarche less than 13 years (incidence rate per 100 person-years, 0.27 vs 0.31; rate difference, -0.04 [95% CI, -0.15 to 0.05]; hazard ratio per year, 0.85 [95% CI, 0.73 to 0.99]; P?=?.04). Endometrial cancer was diagnosed in 10.8% (n?=?88) of parous women compared with 14.4% (n?=?40) of nulliparous women (incidence rate per 100 person-years, 0.25 vs 0.43; rate difference, -0.18 [95% CI, -0.32 to -0.04]; hazard ratio, 0.21 [95% CI, 0.10 to 0.42]; P?<?.001). Endometrial cancer was diagnosed in 8.7% (n?=?70) of women who used hormonal contraceptives greater than or equal to 1 year compared with 19.2% (n?=?57) of women who used contraceptives less than 1 year (incidence rate per 100 person-years, 0.22 vs 0.45; rate difference, -0.23 [95% CI, -0.36 to -0.11]; hazard ratio, 0.39 [95% CI, 0.23 to 0.64]; P?<?.001). There was no statistically significant association between endometrial cancer and age at first and last live birth, age at menopause, and postmenopausal hormone use.For women with a mismatch repair gene mutation, some endogenous and exogenous hormonal factors were associated with a lower risk of endometrial cancer. These directions and strengths of associations were similar to those for the general population. If replicated, these findings suggest that women with a mismatch repair gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk.

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Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome.

Publications

Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome.

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