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. 2022 Nov 11;9(1):95-101.
doi: 10.1001/jamaoncol.2022.5425. Online ahead of print.

Inherited Cancer Susceptibility Gene Sequence Variations Among Patients With Appendix Cancer

Andreana N Holowatyj  1   2   3 , Mary K Washington  2   4 , Sean V Tavtigian  5 , Cathy Eng  1   2 , Carolyn Horton  6
Affiliations

Inherited Cancer Susceptibility Gene Sequence Variations Among Patients With Appendix Cancer

Andreana N Holowatyj et al. JAMA Oncol. .

Abstract

Importance: Germline 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.

Objective: To 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 participants: This 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 measures: The main outcomes were germline sequence variation prevalence and spectrum in patients with AC.

Results: Among 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 relevance: In 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Holowatyj reported receiving grants from The Dalton Family Foundation, the National Institutes of Health (NIH), and Pfizer during the conduct of the study; receiving grants from the American Cancer Society and the Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation outside the submitted work; and chairing the scientific advisory board for the ACPMP Research Foundation. Ms Horton reported receiving personal fees from Ambry Genetics during the conduct of the study. No other disclosures were reported.

Figures

Figure.
Figure.. Flowchart of Study Population
Germline genetic testing was done for the following 14 genes: APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53. MiNENs indicates mixed neuroendocrine-nonneuroendocrine neoplasms.
See this image and copyright information in PMC

Comment in

References

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