Inherited Cancer Susceptibility Gene Sequence Variations Among Patients With Appendix Cancer

Abstract

ImportanceGermline sequence variations in APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53 genes are associated with susceptibility to gastrointestinal cancers. As a rare cancer, the evaluation of appendiceal cancer (AC) predisposition has been limited.ObjectiveTo assess the prevalence and spectrum of inherited cancer susceptibility gene sequence variations in patients with AC and the utility of germline genetic testing for this population.Design, Setting, and ParticipantsThis cohort study included patients with AC who underwent germline genetic testing of 14 cancer susceptibility genes performed by a clinical testing laboratory between March 1, 2012, and December 31, 2016. Data were analyzed from March to August 2022. Clinical, individual, and family histories were obtained from clinician-completed test requisition forms. Multigene panel testing was performed by targeted custom capture and sequencing and chromosome rearrangement analysis.Main Outcomes and MeasuresThe main outcomes were germline sequence variation prevalence and spectrum in patients with AC.ResultsAmong the 131 patients with AC in the cohort (90 female [68.7%]), a total of 16 deleterious sequence variations were identified in 15 patients (11.5%). Similarly, when limited to the 74 patients with AC as the first and only primary tumor, a total of 8 patients (10.8%) had at least 1 deleterious sequence variation in a cancer susceptibility gene. Overall, 6 patients (4.6%) had a deleterious sequence variation observed in MUTYH (5 with monoallelic MUTYH and 1 with biallelic MUTYH). All 4 patients with Lynch syndrome (3.1%) had a sequence variation in the MLH1 gene, of whom 3 were aged 50 years or older at AC diagnosis. Five patients (3.8%) had deleterious sequence variations in other cancer predisposition genes (1 with APC [c.3920T>A, p.I1307K], 2 with CHEK2 [c.470T>C, p.I157T], 1 with SMAD4 [c.263 287dup, p.L98IFS*14], and 1 with TP53 [c.524G>A, p.R175H]).Conclusions and RelevanceIn this cohort study, 1 in every 10 patients with AC who underwent testing for hereditary cancer predisposition carried an inherited gene sequence variation associated with cancer susceptibility. Given the high frequency and broad spectrum of germline gene sequence variations, these data suggest that genetic evaluation might be warranted for all patients diagnosed with this rare malignant tumor. A systemic sequencing effort for all patients with AC may also identify cancer vulnerabilities to exploit for therapeutic development in a cancer type for which clinical trials are limited.

Is Appendiceal Cancer a Lynch Syndrome–Associated Cancer?

“…While this is impossible to determine without pathology review, it is worth noting that a similar phenomenon has been perpetuated in the literature with Lynch syndrome–associated ureter/renal pelvis urothelial carcinomas often being misclassified as kidney cancers, especially when cases have been ascertained from clinician/patient reporting rather than pathologic confirmation . Given that the clinical data in this cohort were obtained from test request forms, investigating any possible link between Lynch syndrome and appendiceal cancer risk will require cohorts with well-annotated pathologic characterization. We commend Holowatyj et al on drawing attention to appendiceal cancers, but we believe that conclusions regarding the potential link to Lynch syndrome and the utility of universal germline testing should be tempered by the referral bias and lack of pathologic annotation in their patient cohort.…”

“…Because Lynch syndrome–associated colorectal cancers occur disproportionately in the cecum, it is possible that the 4 MLH1 PGV carriers in this study actually had cecal cancers that were difficult to clinically distinguish from primary appendiceal cancers. While this is impossible to determine without pathology review, it is worth noting that a similar phenomenon has been perpetuated in the literature with Lynch syndrome–associated ureter/renal pelvis urothelial carcinomas often being misclassified as kidney cancers, especially when cases have been ascertained from clinician/patient reporting rather than pathologic confirmation .…”

“…To the Editor We read with interest the cohort study by Holowatyj et al examining the prevalence and spectrum of cancer susceptibility gene pathogenic germline variants (PGVs) among individuals with appendiceal cancer referred for germline testing. We want to congratulate the authors on their study, especially since appendiceal cancers have historically been understudied.…”

“…We want to congratulate the authors on their study, especially since appendiceal cancers have historically been understudied. As has now become common in the genetic testing literature, probands were ascertained from a genetic testing laboratory, suggesting elevated pretest suspicion for inherited cancer risk, so the findings are not generalizable to all patients with appendiceal cancer.…”

“…Given that the clinical data in this cohort were obtained from test request forms, investigating any possible link between Lynch syndrome and appendiceal cancer risk will require cohorts with well-annotated pathologic characterization. We commend Holowatyj et al on drawing attention to appendiceal cancers, but we believe that conclusions regarding the potential link to Lynch syndrome and the utility of universal germline testing should be tempered by the referral bias and lack of pathologic annotation in their patient cohort.…”