Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer

Walid K. Chatila; Jin K. Kim; Henry Walch; Michael R. Marco; Chin Tung Chen; Fan Wu; Dana M. Omer; Danny N. Khalil; Karuna Ganesh; Xuan Qu; Anisha Luthra; Seo Hyun Choi; Yu Jui Ho; Ritika Kundra; Katharine I. Groves; Oliver S. Chow; Andrea Cercek; Martin R. Weiser; Maria Widmar; Iris H. Wei; Emmanouil P. Pappou; Garrett M. Nash; Philip B. Paty; Qian Shi; Efsevia Vakiani; S. Duygu Selcuklu; Mark T.A. Donoghue; David B. Solit; Michael F. Berger; Jinru Shia; Raphael Pelossof; Paul B. Romesser; Rona Yaeger; J. Joshua Smith; Nikolaus Schultz; Francisco Sanchez-Vega; Julio Garcia-Aguilar

doi:10.1038/s41591-022-01930-z

Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer

Walid K. Chatila, Jin K. Kim, Henry Walch, Michael R. Marco, Chin Tung Chen, Fan Wu, Dana M. Omer, Danny N. Khalil, Karuna Ganesh, Xuan Qu, Anisha Luthra, Seo Hyun Choi, Yu Jui Ho, Ritika Kundra, Katharine I. Groves, Oliver S. Chow, Andrea Cercek, Martin R. Weiser, Maria Widmar, Iris H. WeiEmmanouil P. Pappou, Garrett M. Nash, Philip B. Paty, Qian Shi, Efsevia Vakiani, S. Duygu Selcuklu, Mark T.A. Donoghue, David B. Solit, Michael F. Berger, Jinru Shia, Raphael Pelossof, Paul B. Romesser, Rona Yaeger, J. Joshua Smith, Nikolaus Schultz, Francisco Sanchez-Vega, Julio Garcia-Aguilar

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival.

Original language	English (US)
Pages (from-to)	1646-1655
Number of pages	10
Journal	Nature Medicine
Volume	28
Issue number	8
DOIs	https://doi.org/10.1038/s41591-022-01930-z
State	Published - Aug 2022

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/s41591-022-01930-z

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Chatila, W. K., Kim, J. K., Walch, H., Marco, M. R., Chen, C. T., Wu, F., Omer, D. M., Khalil, D. N., Ganesh, K., Qu, X., Luthra, A., Choi, S. H., Ho, Y. J., Kundra, R., Groves, K. I., Chow, O. S., Cercek, A., Weiser, M. R., Widmar, M., ... Garcia-Aguilar, J. (2022). Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer. Nature Medicine, 28(8), 1646-1655. https://doi.org/10.1038/s41591-022-01930-z

Chatila, WK, Kim, JK, Walch, H, Marco, MR, Chen, CT, Wu, F, Omer, DM, Khalil, DN, Ganesh, K, Qu, X, Luthra, A, Choi, SH, Ho, YJ, Kundra, R, Groves, KI, Chow, OS, Cercek, A, Weiser, MR, Widmar, M, Wei, IH, Pappou, EP, Nash, GM, Paty, PB, Shi, Q, Vakiani, E, Duygu Selcuklu, S, Donoghue, MTA, Solit, DB, Berger, MF, Shia, J, Pelossof, R, Romesser, PB, Yaeger, R, Smith, JJ, Schultz, N, Sanchez-Vega, F & Garcia-Aguilar, J 2022, 'Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer', Nature Medicine, vol. 28, no. 8, pp. 1646-1655. https://doi.org/10.1038/s41591-022-01930-z

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title = "Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer",

abstract = "The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival.",

author = "Chatila, {Walid K.} and Kim, {Jin K.} and Henry Walch and Marco, {Michael R.} and Chen, {Chin Tung} and Fan Wu and Omer, {Dana M.} and Khalil, {Danny N.} and Karuna Ganesh and Xuan Qu and Anisha Luthra and Choi, {Seo Hyun} and Ho, {Yu Jui} and Ritika Kundra and Groves, {Katharine I.} and Chow, {Oliver S.} and Andrea Cercek and Weiser, {Martin R.} and Maria Widmar and Wei, {Iris H.} and Pappou, {Emmanouil P.} and Nash, {Garrett M.} and Paty, {Philip B.} and Qian Shi and Efsevia Vakiani and {Duygu Selcuklu}, S. and Donoghue, {Mark T.A.} and Solit, {David B.} and Berger, {Michael F.} and Jinru Shia and Raphael Pelossof and Romesser, {Paul B.} and Rona Yaeger and Smith, {J. Joshua} and Nikolaus Schultz and Francisco Sanchez-Vega and Julio Garcia-Aguilar",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = aug,

doi = "10.1038/s41591-022-01930-z",

language = "English (US)",

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AU - Chatila, Walid K.

AU - Kim, Jin K.

AU - Walch, Henry

AU - Marco, Michael R.

AU - Chen, Chin Tung

AU - Wu, Fan

AU - Omer, Dana M.

AU - Khalil, Danny N.

AU - Ganesh, Karuna

AU - Qu, Xuan

AU - Luthra, Anisha

AU - Choi, Seo Hyun

AU - Ho, Yu Jui

AU - Kundra, Ritika

AU - Groves, Katharine I.

AU - Chow, Oliver S.

AU - Cercek, Andrea

AU - Weiser, Martin R.

AU - Widmar, Maria

AU - Wei, Iris H.

AU - Pappou, Emmanouil P.

AU - Nash, Garrett M.

AU - Paty, Philip B.

AU - Shi, Qian

AU - Vakiani, Efsevia

AU - Duygu Selcuklu, S.

AU - Donoghue, Mark T.A.

AU - Solit, David B.

AU - Berger, Michael F.

AU - Shia, Jinru

AU - Pelossof, Raphael

AU - Romesser, Paul B.

AU - Yaeger, Rona

AU - Smith, J. Joshua

AU - Schultz, Nikolaus

AU - Sanchez-Vega, Francisco

AU - Garcia-Aguilar, Julio

PY - 2022/8

Y1 - 2022/8

N2 - The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival.

AB - The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival.

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JO - Nature Medicine

JF - Nature Medicine

IS - 8

ER -

Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer

Abstract

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