Prevalence of germline alterations on targeted tumor-normal sequencing of esophagogastric cancer Journal Article


Authors: Ku, G. Y.; Kemel, Y.; Maron, S. B.; Chou, J. F.; Ravichandran, V.; Shameer, Z.; Maio, A.; Won, E. S.; Kelsen, D. P.; Ilson, D. H.; Capanu, M.; Strong, V. E.; Molena, D.; Sihag, S.; Jones, D. R.; Coit, D. G.; Tuvy, Y.; Cowie, K.; Solit, D. B.; Schultz, N.; Hechtman, J. F.; Offit, K.; Joseph, V.; Mandelker, D.; Janjigian, Y. Y.; Stadler, Z. K.
Article Title: Prevalence of germline alterations on targeted tumor-normal sequencing of esophagogastric cancer
Abstract: IMPORTANCE Among patients with esophagogastric cancers, only individuals who present with known features of heritable cancer syndromes are referred for genetic testing. Broader testing might identify additional patients with germline alterations. OBJECTIVES To examine the prevalence of likely pathogenic or pathogenic (LP/P) germline alterations among patients with esophagogastric cancer and to assess associations between germline variant prevalence and demographic and clinicopathologic features. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study was performed at a tertiary referral cancer center from January 1, 2014, to December 31, 2019, in 515 patients with esophagogastric cancer who consented to tumor and blood sequencing. MAIN OUTCOMES AND MEASURES Presence or absence of LP/P variants in up to 88 genes associated with cancer predisposition syndromes as identified by targeted sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets). RESULTS Among 515 patients (median age, 59 years; range, 18-87 years; 368 [71.5%] male; 398 [77.3%] White), 243 (47.2%) had gastric cancer, 111 (21.6%) had gastroesophageal junction (GEJ) cancer, and 161 (31.3%) had esophageal cancer. A total of 48 patients with gastric cancer (19.8%), 16 (14.4%) with GEJ cancer, and 17 (10.6%) with esophageal cancer had LP/P germline variants. The number of LP/P variants in high- and moderate-penetrance genes was significantly higher in patients with gastric cancer (29 [11.9%]; 95% CI, 8.1%-16.7%) vs patients with esophageal cancer (8 [5.0%]; 95% CI, 2.2%-9.6%; P =.03), and the difference was greater for high-penetrance germline alterations in patients with gastric cancer (25 [10.3%]; 95% CI, 6.8%-14.8%) vs in patients with esophageal cancer (3 [1.9%]; 95% CI, 0.38%-5.3%; P =.001). The most frequent high- and moderate-penetrance LP/P alterations were in BRCA1/2 (14 [2.7%]), ATM (11 [2.1%]), CDH1 (6 [1.2%]), and MSH2 (4 [0.8%]). Those with early-onset disease (<= 50 years of age at diagnosis) were more likely to harbor an LP/P germline variant (29 [21.0%]; 95% CI, 14.5%-28.8%) vs those with late-onset disease (patients >50 years of age at diagnosis) (52 [13.8%]; 95% CI, 10.5%-17.7%; P =.046). ATM LP/P variants occurred in 6 patients (4.3%; 95% CI, 1.6%-9.1%) with early-onset esophagogastric cancer vs 5 (1.3%; 95% CI, 0.4%-3.1%; P =.08) of those with late-onset esophagogastric cancer. CONCLUSIONS AND RELEVANCE These results suggest that pathogenic germline variants are enriched in gastric and early-onset esophagogastric cancer and that germline testing should be considered in these populations. The role of ATM alterations in esophagogastric cancer risk warrants further investigation.
Keywords: genomics; mutations; breast-cancer; association; american-college; medical genetics
Journal Title: JAMA Network Open
Volume: 4
Issue: 7
ISSN: 2574-3805
Publisher: American Medical Association  
Date Published: 2021-07-01
Start Page: e2114753
Language: English
ACCESSION: WOS:000673009500003
DOI: 10.1001/jamanetworkopen.2021.14753
PROVIDER: wos
PMCID: PMC8276088
PUBMED: 34251444
Notes: Article -- Source: Wos
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MSK Authors
  1. Joanne Fu-Lou Chou
    333 Chou
  2. Kenneth Offit
    790 Offit
  3. David Solit
    781 Solit
  4. Geoffrey Yuyat Ku
    233 Ku
  5. Zsofia Kinga Stadler
    393 Stadler
  6. Marinela Capanu
    388 Capanu
  7. Yelena Yuriy Janjigian
    400 Janjigian
  8. Vivian Strong
    268 Strong
  9. Daniel Coit
    542 Coit
  10. David H Ilson
    436 Ilson
  11. Vijai Joseph
    212 Joseph
  12. David P Kelsen
    538 Kelsen
  13. Nikolaus D Schultz
    491 Schultz
  14. Yelena Kemel
    104 Kemel
  15. Elizabeth Siryeon Won
    41 Won
  16. Jaclyn Frances Hechtman
    212 Hechtman
  17. David Randolph Jones
    419 Jones
  18. Daniela   Molena
    277 Molena
  19. Diana Lauren Mandelker
    181 Mandelker
  20. Yaelle Tuvy
    12 Tuvy
  21. Smita Sihag
    98 Sihag
  22. Steven Maron
    106 Maron
  23. Zarina Shameer
    5 Zarina
  24. Kendall Emily Cowie
    3 Cowie
  25. Anna Maio
    35 Maio