Abstract
Background
Lynch syndrome (LS) 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 LS carriers are at highest UTC risk. Our aim was to identify clinical factors associated with UTC among LS carriers.
Methods
The study population was a cohort of 52,758 consecutively-ascertained individuals undergoing LS 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 LS carriers.
Results
Compared to non-carriers, LS carriers were significantly more likely to have had UTC (4.1% vs. 1.2%; P<0.0001). LS-associated UTC was independently associated with male sex (OR 1.95; 95% 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 1st/2nd-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 LS-associated malignancy. 143/158 (90.5%) LS carriers with UTC had ≥1 of the following characteristics: male sex, EPCAM/MSH2 variants, or family history of UTC; 1236/1251 (98.8%) LS carriers lacking all of these characteristics had no history of UTC.
Conclusions
Specific clinical factors can reliably identify LS carriers most likely to be at risk for UTC.
Impact
A predictable subset of LS carriers may be most likely to benefit from UTC surveillance/prevention.
Keywords: hereditary nonpolyposis colorectal cancer, urine cytology, risk factor, urothelium, urinalysis
INTRODUCTION
With an estimated 1:279 prevalence in the general population, Lynch syndrome (LS) is one of the most common inherited cancer predisposition syndromes, conferring markedly increased lifetime risks of gastrointestinal, gynecologic, urinary tract, and other cancers.(1–4) LS is caused by inheritance of pathogenic germline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or EPCAM, and identifying LS carriers can greatly facilitate genetically-driven cancer prevention strategies. Specifically, there are proven risk-reducing interventions for the three most common LS-associated cancers: early and frequent colonoscopic surveillance(5) and aspirin chemoprevention(6) can substantially reduce colorectal cancer incidence for male and female LS carriers, and risk-reducing hysterectomy and salpingo-oophorectomy(7) virtually eliminates female LS carriers’ risk of LS-associated endometrial and ovarian cancer, respectively.
In aggregate, urinary tract cancers (UTCs) – including renal pelvis, ureter, bladder, and possibly kidney cancers – are arguably the 2nd and 4th most common LS-associated cancers in male and female LS carriers, respectively, and are the most common LS-associated neoplasms for which there is no proven effective screening or prevention strategies.(1–3) The very limited data examining UTC surveillance in unselected LS carriers have found unacceptably low sensitivity and high false positive rates,(8) and consequently most professional society guidelines(9–14) do not recommend UTC screening in LS, even though it is a significant contributor to the overall burden of LS-associated malignancy. Furthermore, recent prospective analyses have found inferior survival outcomes for LS-associated UTC compared to the more classic LS-associated malignancies, with prospective data demonstrating 71% (95% CI 34–89%) and 81% (95% CI 42–95%) 10-year survival rates for LS-associated kidney/ureter and bladder cancers, respectively, versus 88% (95% CI 77–94%) and 93% (95% CI 85–97%) for LS-associated colon and endometrial cancers, respectively.(1)
Since the performance characteristics of any cancer screening modality are inherently improved when used in individuals at particularly increased risk, identifying risk factors for LS-associated UTC is critical for the development of effective patient-specific UTC surveillance and prevention strategies. Multiple studies have consistently found that LS carriers with pathogenic germline MSH2 variants have particularly high likelihood for developing UTC,(1,3,15–21) but other risk factors for LS-associated UTCs remain unknown. The aim of this study was to examine patient-specific factors that may help identify which individuals with LS are at particular risk for UTC.
MATERIALS AND METHODS
As previously described,(22) we analyzed clinical data from a cohort of 52,758 consecutively ascertained individuals unknown to be related to one another who underwent germline testing of two or more LS genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) at a commercial laboratory (Myriad Genetic Laboratories, Inc., Salt Lake City, UT) from 6/2006–7/2013 for evaluation of suspected LS. Individuals undergoing site-specific germline analysis for a specific LS variant were not included, and all germline testing was ordered as syndrome-specific testing for LS genes only, rather than multisyndromic multigene panel testing. Germline testing methodologies and variant classification were performed by Myriad Genetic Laboratories, Inc., as previously described.(22,23)
Clinical data were obtained from the test order form completed by patients’ healthcare provider ordering germline LS testing, as previously described.(23) Data collected included sex, age at genetic testing, race, personal history of cancer (including specific cancer types and ages at diagnosis), and family history of cancer (including relationship to the proband, specific cancer types, and ages at diagnosis) in first- and second-degree relatives (FDRs and SDRs, respectively). The results of germline testing along with the aforementioned clinical data were provided to investigators as a de-identified dataset by Myriad Genetic Laboratories, Inc. Individuals with pathogenic or likely pathogenic alterations detected in MLH1, MSH2, MSH6, PMS2, or EPCAM were collectively defined as LS carriers and those lacking any such germline alterations (including those with germline variants of uncertain significance) were defined as non-carriers.(23) Family history of UTC was examined as both a categorical (yes/no) and continuous variable (aggregate number of FDRs and SDRs with UTC).
The chi-square test was used to analyze differences between categorical variables. Continuous variables were compared using the Kruskal-Wallis test. Clinical factors associated with UTC in LS carriers were analyzed using univariate and multivariate logistic regression models. Selected variables found to have a significant association with UTC on univariate analysis were included in the multivariate analysis. Clinical variables with possible association to UTC were assessed via their odds ratios with 95% confidence intervals (CIs). P-values were two-tailed and considered statistically significant at alpha <0.05. SAS statistical software version 9.4 (SAS Institute, Inc.) was used for data management and univariate analysis, and R version 3.3.3 (R Foundation for Statistical Computing) was used for multivariate logistic regression. A waiver of consent for study participants was obtained since analyses were performed on de-identified data and did not require patient contact. The study was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board.
RESULTS
After excluding 1672 individuals from analysis due to missing clinical data (n=1664) or presence of multiple pathogenic germline LS variants (n=8), the final study cohort consisted of 51,086 individuals (Table 1), 3828 (7.5%) of whom carried of a pathogenic germline LS variant: 1346 MLH1, 1639 MSH2, 670 MSH6, 145 PMS2 and 28 with EPCAM variants. Compared to non-carriers, LS carriers were significantly more likely to have a personal history of any UTC (4.1% vs. 1.2%; P<0.0001; OR 3.22; 95% CI 2.66–3.90; P<0.0001) and were significantly more likely to have ureter/renal pelvis cancer (1.6% vs. 0.1%; P<0.0001), bladder cancer (1.8% vs. 0.4%; P<0.0001), and kidney cancer (1.3% vs. 0.7%; P=0.0003). Additionally, LS carriers were significantly more likely to have a family history of any UTC in FDR/SDRs than non-carriers (9.6% vs. 6.5%; P<0.0001). Compared to non-carriers, LS carriers with pathogenic germline variants in MLH1 (OR 1.64; 95% CI 1.11–2.27; P=0.01), EPCAM/MSH2 (OR 6.07; 95% CI 4.93–7.48; P<0.0001), and MSH6 (OR 2.31; 95% CI 1.43–3.71; P=0.0006) were significantly more likely to have a personal history of UTC, but not those with PMS2 (OR 0.58; 95% CI 0.08–4.15; P=0.59) variants.
Table 1:
Clinical characteristics of 51,086 consecutively ascertained individuals undergoing germline testing for Lynch syndrome
| Total cohort (N=51,086) | Lynch syndrome carriers (N=3828) | Non-carriers (N=47,258) | P value | |
|---|---|---|---|---|
| N (%) | N (%) | N (%) | ||
| Male | 10599 (20.7) | 1397 (36.5) | 9202 (19.5) | <0.001 |
| Female | 40487 (79.3) | 2431 (63.5) | 38056 (80.5) | |
| Median age at LS testing, years (IQR) | 49.0 (41.0, 58.0) | 50.0 (41.0, 59.0) | 49.0 (41.0, 58.0) | 0.001 |
| Ethnicity | 0.001 | |||
| Caucasian | 29880 (58.5) | 2271 (59.3) | 27609 (58.4) | |
| African American/Black | 2349 (4.6) | 185 (4.8) | 2164 (4.6) | |
| Asian | 1251 (2.4) | 111 (2.9) | 1140 (2.4) | |
| Other/Multiple | 6591 (12.9) | 528 (13.8) | 6063 (12.8) | |
| Missing/No Answer | 11015 (21.6) | 733 (19.1) | 10282 (21.8) | |
| Personal history of Lynch-associated cancer | ||||
| Any Lynch syndrome-associated cancer | 26721 (52.3) | 3186 (83.2) | 23535 (49.8) | <0.001 |
| Urinary tract cancer (any)* | 717 (1.4) | 158 (4.1) | 559 (1.2) | <0.001 |
| Ureter/renal pelvis cancer | 120 (0.2) | 62 (1.6) | 58 (0.1) | <0.001 |
| Bladder cancer | 269 (0.5) | 67 (1.8) | 202 (0.4) | <0.001 |
| Kidney cancer | 385 (0.8) | 49 (1.3) | 336 (0.7) | <0.001 |
| Multiple urinary tract cancers | 63 (0.1) | 21 (0.5) | 42 (0.1) | <0.001 |
| Colorectal cancer | 19866 (38.9) | 2496 (65.2) | 17370 (36.8) | <0.001 |
| Endometrial cancer** | 6135/40487 (15.2)* | 908/2431 (37.4)* | 5227/38056 (13.7)* | <0.001 |
| Ovarian cancer** | 2161/40487 (5.3)* | 194/2431 (8.0)* | 1967/38056 (5.2)* | <0.001 |
| Gastric cancer | 266 (0.5) | 41 (1.1) | 225 (0.5) | <0.001 |
| Pancreatic cancer | 266 (0.5) | 23 (0.6) | 243 (0.5) | 0.47 |
| Small bowel cancer | 192 (0.4) | 56 (1.5) | 136 (0.3) | <0.001 |
| Other Lynch syndrome-cancer*** | 494 (1.0) | 166 (4.3) | 328 (0.7) | <0.001 |
| Multiple Lynch syndrome-associated cancers | 3885 (7.6) | 878 (22.9) | 3007 (6.4) | <0.001 |
| Family history of Lynch-associated cancer**** | ||||
| Urinary tract cancer | 3417 (6.7) | 369 (9.6) | 3048 (6.4) | <0.001 |
| Colorectal cancer | 33952 (66.5) | 2997 (78.3) | 30955 (65.5) | <0.001 |
| Endometrial cancer | 9771 (19.1) | 966 (25.2) | 8805 (18.6) | <0.001 |
| Ovarian cancer | 7603 (14.9) | 411 (10.7) | 7192 (15.2) | <0.001 |
| Gastric cancer | 4633 (9.1) | 350 (9.1) | 4283 (9.1) | 0.87 |
| Pancreatic cancer | 3619 (7.1) | 253 (6.6) | 3366 (7.1) | 0.23 |
| Small bowel cancer | 357 (0.7) | 70 (1.8) | 287 (0.6) | <0.001 |
| Other Lynch-associated cancer*** | 3949 (7.7) | 310 (8.1) | 3639 (7.7) | 0.38 |
Includes urinary tract cancer not otherwise specified
Denominator is for females only
Includes hepatobiliary cancers, brain cancers/gliomas, and sebaceous neoplasms of the skin
First and second-degree relatives
Of the 158 LS carriers with a history of UTC, 62 (39.2%) had ureter/renal pelvis cancer, 67 (42.4%) had bladder cancer, 49 (31.0%) had kidney cancer, and 21 (13.3%) had multiple urinary tract cancers. 73/158 (46%) LS carriers with UTC were male, 48 (30.4%) had a family history of UTC in at least one FDR and/or SDR, and 113 (71.5%) harbored pathogenic germline EPCAM/MSH2 variants (Table 2; Supplemental Table 1). Of the 369 LS carriers with a family history of UTC in ≥1 FDR/SDR, 202 (54.7%) carried pathogenic germline EPCAM/MSH2 variants, 35 of whom had both a personal and family history of UTC (Supplemental Table 2). Compared to LS carriers without UTC, LS carriers with UTC were more likely to be Caucasian (69.6% versus 58.9%; P=0.05), harbor pathogenic EPCAM/MSH2 variants (71.5% versus 42.3%; P<0.0001), and have a personal history of other LS cancers besides UTC (88.6% versus 82.5%; P=0.047), including colorectal, endometrial, gastric, and small bowel cancers.
Table 2:
Clinical characteristics of individuals with Lynch syndrome
| Lynch syndrome carriers with a personal history of UTC (N=158) | Lynch syndrome carriers without a personal history of UTC (N=3670) | P value | |
|---|---|---|---|
| N (%) | N (%) | ||
| Male | 73 (46.2) | 1324 (36.1) | 0.01 |
| Female | 85 (53.8) | 2346 (63.9) | |
| Median age at LS testing, years (IQR) | 64.0 (57.0, 70.0) | 49.0 (41.0, 58.0) | <0.0001 |
| Median age at UTC diagnosis, years (IQR)* | 56.0 (48.0, 64.0) | - | - |
| Race | 0.05 | ||
| Caucasian/White | 110 (69.6) | 2161 (58.9) | |
| African American/Black | 2 (1.3) | 183 (5.0) | |
| Asian | 3 (1.9) | 108 (2.9) | |
| Other/Multiple | 18 (11.4) | 510 (13.9) | |
| Missing/No Answer | 25 (15.8) | 708 (19.3) | |
| Pathogenic MMR gene variant | <0.0001 | ||
| MLH1 | 26 (16.5) | 1320 (36.0) | |
| EPCAM/MSH2 | 113 (71.5) | 1554 (42.3) | |
| MSH6 | 18 (11.4) | 652 (17.8) | |
| PMS2 | 1 (0.6) | 144 (3.9) | |
| Personal history of Lynch-associated cancer | |||
| Any Lynch syndrome-associated cancer (except UTC) | 140 (88.6) | 3028 (82.5) | 0.047 |
| Colorectal cancer | 119 (75.3) | 2377 (64.8) | 0.006 |
| Endometrial cancer** | 43/85 (50.6) | 865/2346 (36.9) | 0.01 |
| Ovarian cancer** | 5/85 (5.9) | 189/2346 (8.1) | 0.47 |
| Gastric cancer | 5 (3.2) | 36 (1.0) | 0.009 |
| Pancreatic cancer | 2 (1.3) | 21 (0.6) | 0.27 |
| Small bowel cancer | 7 (4.4) | 49 (1.3) | 0.002 |
| Other Lynch syndrome cancer*** | 22 (13.9) | 144 (3.9) | <0.001 |
| Family history of Lynch-associated cancer**** | |||
| Urinary tract cancer | 48 (30.4) | 321 (8.7) | <0.001 |
| Colorectal cancer | 126 (79.7) | 2871 (78.2) | 0.65 |
| Endometrial cancer | 44 (27.8) | 922 (25.1) | 0.44 |
| Ovarian cancer | 25 (15.8) | 386 (10.5) | 0.035 |
| Gastric cancer | 16 (10.1) | 334 (9.1) | 0.66 |
| Pancreatic cancer | 15 (9.5) | 238 (6.5) | 0.14 |
| Small bowel cancer | 6 (3.8) | 64 (1.7) | 0.059 |
| Other Lynch-associated cancer*** | 25 (15.8) | 285 (7.8) | <.001 |
Age at UTC diagnosis missing for 19 LS carriers
Denominator is for females only
Includes hepatobiliary cancers, brain cancers/gliomas, and sebaceous neoplasms of the skin
First and second-degree relatives
By multivariable logistic regression analysis, personal history of UTC among Lynch syndrome carriers was independently associated with male sex (OR 1.95; 95% 1.38–2.76), increasing age (OR 2.44 per 10 years; 95% CI 2.11–2.82), familial burden of UTC (OR 2.69 per FDR/SDR with UTC; 95% CI 1.99–3.63), and germline EPCAM/MSH2 variants (OR 4.01; 95% CI 2.39–6.72; ref: MSH6/PMS2) but not MLH1 variants, race, or personal history of LS-associated cancer other than UTC (Table 3).
Table 3:
Multivariate logistic regression analysis of association between clinical factors personal history of UTC in individuals with Lynch syndrome
| Odds ratio | 95% CI | P value | |
|---|---|---|---|
| Sex | |||
| Male | 1.95 | 1.38 – 2.76 | <0.0001 |
| Female | 1.0 | Reference | – |
| Age | 2.44 (per 10 years) | 2.11 – 2.82 | <0.0001 |
| Race | |||
| Caucasian/White | 1.14 | 0.79 – 1.65 | 0.489 |
| Non-Caucasian/White | 1.0 | Reference | – |
| Mutated MMR gene | |||
| MLH1 | 1.17 | 0.63 – 2.17 | 0.620 |
| MSH2/EPCAM | 4.01 | 2.39 – 6.72 | <0.0001 |
| MSH6/PMS2 | 1.0 | Reference | – |
| Personal history of other (non-UTC) Lynch-associated cancer | |||
| Yes | 0.82 | 0.48 – 1.40 | 0.463 |
| No | 1.0 | Reference | – |
| Number of 1st/2nd degree relatives with UTC | 2.69 (per relative with UTC) | 1.99 – 3.63 | <0.0001 |
Abbreviations: CI, confidence interval; MMR, mismatch repair; UTC, urinary tract cancer
Of the 158 LS carriers with UTC, 143 (90.5%) had at least one of the following characteristics: male sex, pathogenic germline EPCAM/MSH2 variants, or family history of UTC in one or more FDR/SDR. Conversely, only 15/1251 (1.2%) LS carriers lacking all three of these characteristics had a personal history of UTC. Of the 49 LS carriers with particularly strong family histories of UTC (≥2 FDR/SDRs with UTC), only 7 (14.3%) had a personal history of UTC.
DISCUSSION
This study of over 51,000 individuals with suspected LS and more than 3800 confirmed LS carriers found UTCs to be the second and fourth most common malignancy (behind colorectal, endometrial, and ovarian cancers) in male and female LS carriers, respectively. Furthermore, the vast majority of LS carriers with UTC in this cohort also had a personal history of other LS-associated malignancies, indicating potential missed opportunities for LS-associated cancer prevention and screening. These findings are consistent with other large cohorts,(1–3) and emphasize the critical need for effective UTC surveillance for LS carriers. Compared to gastrointestinal and gynecologic malignancies, however, UTCs remain strikingly understudied in LS, and there are minimal data about patient-specific factors that contribute to UTC risk in LS carriers. Our findings demonstrate that male sex, increasing age, pathogenic EPCAM/MSH2 variants, and familial burden of UTC are each independently associated with UTC in LS carriers, suggesting that a predictable fraction of LS patients is most likely to benefit from UTC risk-reduction strategies.
Numerous prior studies(1,3,15–21) have clearly established that LS carriers with pathogenic germline variants in MSH2 are at disproportionately increased risk of UTC, compared to LS carriers with pathogenic variants in other DNA mismatch repair genes. In particular, recent data from 3119 LS carriers in the multinational Prospective Lynch Syndrome Database described a cumulative incidence to age 75 years of 17.0% and 8.1% for ureter/kidney cancer and bladder cancer, respectively, among MSH2 carriers, versus 4.6% and 4.1% for MLH1 carriers, 3.0% and 8.2% for MSH6 carriers, and 0% for PMS2 carriers.(1) Another study(3) of 2118 LS carriers from the German and Dutch national LS registries found pathogenic MSH2 variants to be significantly associated with history of bladder cancer (HR 5.42; 95% CI 1.89–15.56) and other urothelial cancer (HR 8.27; 95% CI 2.95–23.19), compared to MLH1 and MSH6 variants, though no significant association was found with male or female sex for either bladder or other urothelial cancers. Our data confirm this important association with MSH2 variants and significantly add to the existing body of literature by identifying other potential independent risk factors, including familial burden of UTC.
To date, the role of family history as a risk factor for UTC in LS carriers has not been thoroughly studied. One study examining 136 UTCs from 288 LS families in the Danish national registry found that only 30 (22.1%) of UTCs developed in LS carriers with a family history of UTC, and the authors thus concluded that UTC screening should not be restricted only to those with such family histories.(19) Although our data likewise demonstrate that a minority (30.4%) of LS patients with UTC had a family history, our multivariate analysis found familial burden of UTC to have a significant association with personal history of UTC, such that the likelihood of UTC in LS carriers was almost tripled for each affected FDR/SDR.
Our data can inform UTC surveillance and prevention strategies by identifying a subset of LS carriers with particularly increased risk of UTC (beyond just those with MSH2 variants) while also providing reassurance to the large fraction of LS patients for whom such surveillance may be particularly low-yield. In fact, >90% of all LS-associated UTCs in our large cohort developed in LS patients who were male, EPCAM/MSH2 variant carriers, and/or had a FDR/SDR with UTC, whereas UTCs were very rarely reported in LS carriers lacking all three of these features.
Unfortunately, there are currently no evidence-based approaches to UTC screening and prevention for individuals with LS. The largest study to date of UTC screening in LS examined 1868 urine cytology screening specimens from 977 individuals with known or suspected LS enrolled in the Danish HNPCC register.(8) Investigators found that only 2/1868 (0.11%) of urine cytology specimens led to the diagnosis of an asymptomatic UTC and that there were at least 11 false positive urine cytology results for every 1 true positive result.(8) Of the 7 UTCs diagnosed in individuals undergoing regular urine cytology screening, 5 (71.4%) were in individuals who developed UTC symptoms in spite of normal urine cytology in the preceding 36 months, suggesting a poor (28.6%) sensitivity to such screening in unselected LS carriers.(8) Other forms of UTC screening (e.g. urinalysis for microscopic hematuria; ultrasound; ureterocystoscopy) have not been robustly studied in asymptomatic LS patients, and the question of how to best identify early-stage asymptomatic LS-associated UTCs remains a critical unanswered question. Our findings, however, demonstrate that a predictable subset of LS patients are at particularly elevated risk for UTC, meaning that UTC screening should be more sensitive and specific in these higher risk carriers than in all-comers with LS.
Novel forms of molecular-based UTC screening(24,25) attempting to detect neoplastic genomic alterations in urine specimens have shown early promise in case-control studies. Given that LS-associated UTCs may have different molecular phenotypes than non-LS UTCs, it is unclear if such approaches would be appropriate for LS-associated UTC screening. In light of our findings, we would propose that molecular-based UTC screening be prospectively studied in LS carriers to evaluate the efficacy of such approaches, particularly focusing on those who may be at highest risk (e.g. males, carriers of pathogenic EPCAM/MSH2 variants, and those with family histories of UTC). Prospective evaluation will also allow for critical examination of other clinical, behavioral, and lifestyle factors that could not be addressed in the current study, including tobacco use and exposure.
Currently, no professional society guidelines overtly recommend routine UTC surveillance in all asymptomatic individuals with LS, however these guidelines vary significantly in their conditional recommendations related to LS-associated UTC surveillance (Table 4). The question of how (and whom) to screen for LS-associated cancers beyond colorectal cancer is a critical real-world problem for all extracolonic cancers in LS, not just UTC. Risk-reducing hysterectomy and salpingo-oophorectomy effectively minimize the risk of LS-associated gynecologic cancer, but there are currently no evidence-based methods by which to prevent or even screen for cancers of the stomach, small intestine, pancreaticobiliary tract, brain, or urinary tract in LS carriers. As such, a common practice (endorsed by several of the aforementioned guidelines(11–13,26)) has been to selectively screen LS carriers for non-colorectal non-gynecologic cancers based on family history of these specific malignancies. Our finding that familial burden of UTC is independently associated with LS patients’ likelihood of UTC lends support to this approach of family history-based risk assessment while also identifying other clinical factors that may identify high-risk LS carriers. It will be of particular interest to examine whether family history of other LS-associated malignancies (gastric, pancreatic, biliary, small bowel cancers) is a similarly effective risk stratification technique in future studies.
Table 4:
Lynch syndrome (LS) urinary tract cancer (UTC) screening recommendations from various professional society guidelines
| Professional Society | Guidelines |
|---|---|
| American College of Gastroenterology (ACG)(12) | Suggests that UTC screening be considered for LS carriers with family history of UTC. No guidance on specific screening methods. |
| American Society of Clinical Oncology (ASCO)(11) | Endorses the ESMO clinical practice guidelines (below). Adds the caveat that LS carriers with family histories of specific extracolonic cancers (including UTC) could be considered for specialized surveillance. |
| European Hereditary Tumour Group (EHTG; formerly the Mallorca group)(9) | Recommends against screening for UTC in LS patients |
| European Society of Digestive Oncology(13) | UTC screening with urine cytology or ultrasonography “could be discussed” with LS carriers that have a family history of UTC |
| European Society for Medical Oncology (ESMO)(10) | No specific comments on UTCs. Broadly recommends against surveillance for LS associated cancers beyond colorectal, gynecologic, and gastric. |
| National Comprehensive Cancer Network (NCCN) version 2.2019 (https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf) | “There is no clear evidence to support surveillance for urothelial cancers in LS. Surveillance may be considered in selected [LS carriers] such as those with a family history of urothelial cancer or individuals with MSH2 pathogenic variants (especially males) as these groups appear to be at higher risk.” No guidance on specific screening methods |
| United States Multi-Society Task Force on Colorectal Cancer(14) | UTC screening with annual urinalysis “should be considered” in all LS patients beginning at age 30–35. |
Several important strengths of our study are worth highlighting. Our cohort was consecutively ascertained through a large commercial testing laboratory and allowed us to evaluate a geographically diverse population that is representative of the greater United States population of patients with known or suspected LS. The size of our cohort allowed us to simultaneously assess the association of multiple clinical factors with LS-associated UTC in parallel (e.g. controlling for the impact of MSH2 variants in order to quantify the relative effect of family history of UTC). Additionally, evaluating family history of UTC as both a continuous and categorical variable allowed us to uncover the incrementally strengthened relationship with each additional FDR/SDR. Finally, our study included PMS2 and EPCAM carriers whereas most previous studies assess UTC in LS have focused on only those with germline variants in MLH1, MSH2, and MSH6.
We acknowledge that there are several important limitations to our study. First, because this was a cross-sectional study we were unable to prospectively study the impact of these clinical factors on UTC risk, screening, or survival. We did not have any data on behavioral, lifestyle, or otherwise modifiable UTC risk factors such as smoking or chemical exposures, precluding our ability to assess whether such factors (often shared within families) may account for the observed link between personal and family history of UTC among LS carriers. The predominance of Caucasian and female patients is likely due to the ascertainment from a commercial genetic testing laboratory, and the cohort may likewise have been biased towards individuals with higher socioeconomic status, those receiving care at tertiary care centers, possible lower likelihood of smoking, and other potential confounding factors. All germline testing was performed specifically to assess for LS, rather than multigene panel testing, which may have biased the cohort to more penetrant clinical histories, particularly those with pathogenic germline MLH1 and MSH2 variants. As such, there were comparatively few PMS2 carriers in this study (even though such pathogenic variants appear to be the most prevalent in the general U.S. population(4)), though recent data(27) have suggested that PMS2 carriers may have no increased risk of UTC compared to the general population. Although this study’s primary comparison was between LS carriers with a personal history of UTC and LS carriers without such personal history, it is important to acknowledge that the non-carriers in this study were all ascertained to the cohort because of a personal/family history of LS-associated cancer and are thus not representative of the general population. We recognize the possibility of survival bias in that some LS patients with a cancer diagnosis may not have lived long enough to undergo LS testing and thus would not have been included in this cohort. We also acknowledge that these data cannot effectively quantify the risk of UTC in LS carriers versus the general population, since the non-carriers in this study were all referred for germline LS testing and likely had a higher likelihood of UTC in their personal and family histories than the general population.
Finally, we were unable to verify the accuracy or completeness of each individual’s reported personal and family history of cancer, which were collected from test request forms. In particular, this raises the possibility of recall bias, considering that a patient with UTC may be more likely to report a family history of UTC. To this end, however, a recent publication(26) studied the accuracy and completeness of data collected on commercial laboratory test requisition forms for 824 probands undergoing genetic testing and 3954 relatives. By medical record review, this study(26) found >99% accuracy for probands’, first-, and second-degree relatives’ cancer diagnoses provided on test requisition forms, though varying completeness of family history of cancer, with a higher likelihood of incomplete family history reporting in more distant family members, particularly third- and fourth-degree relatives.
However, one important consideration for our study is the postulated link between LS and “kidney cancer.” While our data echo those from numerous prior registry studies(1,2,28) which have described an increased risk of kidney cancer among individuals with LS, these studies and ours cannot rule out the very real possibility that diagnoses labeled as “kidney cancer” in many of these individuals actually represent upper tract urothelial (i.e. renal pelvis) carcinomas rather than renal cell carcinomas (often colloquially referred to as “kidney cancers”), which are genetically and histologically distinct neoplasms from one another.(29–31) Adding further skepticism about the questionable link between LS and renal cell carcinomas, a recent large study(32) of paired germline and microsatellite instability testing in over 15,000 cancer patients demonstrated that only 11/458 (2.4%) of biopsy proven renal cell carcinomas demonstrated microsatellite instability, none of whom had an identified germline LS variants; two renal cell carcinoma patients were found to carry germline MSH6 variants, but their tumors lacked microsatellite instability, suggesting that they were not etiologically linked to the germline variant. By contrast, the same study(32) found microsatellite instability in 32/551 (5.8%) of bladder/urothelial carcinomas, 12/32 (37.5%) of whom were confirmed LS carriers.
In conclusion, we have identified several important clinical factors that are independently associated with UTC in individuals with LS. In addition to the previously well-described link to MSH2 variants, we found that male sex, increasing age, and familial burden of UTC were all independently associated with UTC in LS carriers. We are hopeful that, by identifying a subset of LS carriers with particular risk for UTC, this will allow for more rational design of personalized UTC surveillance and prevention strategies. Furthermore, the significant link with family history of UTC raises intriguing questions about risk stratification for other uncommon but potentially deadly LS cancers, though prospective studies will certainly be required to account for potential confounders, including recall bias and shared environmental effects. Future endeavors should focus on prospectively examining these potential UTC risk factors in prospective cohorts of LS patients, improving UTC surveillance and prevention, and investigating the role of family history and other personalized clinical factors in the risk for other extracolonic LS-associated malignancies.
Supplementary Material
Acknowledgments
Financial Support:
Supported by the National Institutes of Health (National Cancer Institute) K24CA113433 (S. Syngal), R01CA132829 (S. Syngal), K07CA151769 (F. Kastrinos), and The Pussycat Foundation Helen Gurley Brown Presidential Initiative (C. Ukaegbu).
Abbreviations
- CI
confidence interval
- FDR
first-degree relative
- LS
Lynch syndrome
- MMR
mismatch repair
- OR
odds ratio
- SDR
second-degree relative
- UTC
urinary tract cancer
Footnotes
Conflict of Interest Statement:
S. Syngal is a consultant for Myriad Genetic Laboratories, Inc. and Digital China Health, and has rights to an inventor portion of licensing revenues from PREMM5. The authors report no other conflicts of interest.
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