Age-stratified reference intervals unlock the clinical potential of circulating cell-free DNA as a biomarker of poor outcome for healthy individuals and patients with colorectal cancer

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Age-stratified reference intervals unlock the clinical potential of circulating cell-free DNA as a biomarker of poor outcome for healthy individuals and patients with colorectal cancer. / Ørntoft, Mai-Britt Worm; Jensen, Sarah Østrup; Øgaard, Nadia; Henriksen, Tenna Vesterman; Ferm, Linnea; Christensen, Ib Jarle; Reinert, Thomas; Larsen, Ole Halfdan; Nielsen, Hans Jørgen; Andersen, Claus Lindbjerg.

I: International Journal of Cancer, Bind 148, Nr. 7, 04.2021, s. 1665-1675.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{e8da8c894f6d4edd9cdc3bb0ba56127b,
title = "Age-stratified reference intervals unlock the clinical potential of circulating cell-free DNA as a biomarker of poor outcome for healthy individuals and patients with colorectal cancer",
abstract = "Circulating cell-free DNA (cfDNA) has spurred much interest as a biomarker in oncology. However, inter- and intra-individual cfDNA levels vary greatly. Consequently, in order to base clinical decisions on cfDNA measurements, normal reference intervals are essential to avoid that ordinary variation is confused with clinically relevant change. The lack of reference intervals may potentially explain the ambiguous results reported in the field. Our study aimed to establish reference intervals and to evaluate the association between cfDNA and demographic and clinical variables, including colorectal cancer (CRC). Plasma samples and clinical data from 2817 subjects were collected including 1930 noncancer individuals and 887 CRC patients. cfDNA was measured using droplet digital polymerase chain reaction (PCR). The large cohort combined with robust cfDNA quantification enabled establishment of reference intervals (<67 years: 775-4860 copies/mL; ≥67 years: 807-6561 copies/mL). A cfDNA level above the age-stratified 90% percentile was prognostic of reduced survival in both noncancer individuals and CRC patients, with HR values of 2.56 and 2.01, respectively. Moreover, cfDNA levels increased significantly with age, elevated BMI and chronic diseases. In CRC, the cfDNA level was increased for Stage IV, but not Stage I to Stage III cancer. In summary, the use of reference intervals revealed that high cfDNA levels were predictive of shorter survival in both noncancer individuals and CRC patients, and that CRC development did not affect the cfDNA level until metastatic dissemination. Furthermore, cfDNA levels were impacted by age and chronic diseases. Conclusively, our study presents reference intervals that will help pave the way for clinical utilization of cfDNA.",
keywords = "biomarker, circulating cell-free DNA, colorectal cancer, overall survival, reference intervals, free DNA, INFLAMMATION, MARKERS, circulating cell&#8208, TUMOR DNA",
author = "{\O}rntoft, {Mai-Britt Worm} and Jensen, {Sarah {\O}strup} and Nadia {\O}gaard and Henriksen, {Tenna Vesterman} and Linnea Ferm and Christensen, {Ib Jarle} and Thomas Reinert and Larsen, {Ole Halfdan} and Nielsen, {Hans J{\o}rgen} and Andersen, {Claus Lindbjerg}",
note = "{\textcopyright} 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.",
year = "2021",
month = apr,
doi = "10.1002/ijc.33434",
language = "English",
volume = "148",
pages = "1665--1675",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "JohnWiley & Sons, Inc.",
number = "7",

}

RIS

TY - JOUR

T1 - Age-stratified reference intervals unlock the clinical potential of circulating cell-free DNA as a biomarker of poor outcome for healthy individuals and patients with colorectal cancer

AU - Ørntoft, Mai-Britt Worm

AU - Jensen, Sarah Østrup

AU - Øgaard, Nadia

AU - Henriksen, Tenna Vesterman

AU - Ferm, Linnea

AU - Christensen, Ib Jarle

AU - Reinert, Thomas

AU - Larsen, Ole Halfdan

AU - Nielsen, Hans Jørgen

AU - Andersen, Claus Lindbjerg

N1 - © 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

PY - 2021/4

Y1 - 2021/4

N2 - Circulating cell-free DNA (cfDNA) has spurred much interest as a biomarker in oncology. However, inter- and intra-individual cfDNA levels vary greatly. Consequently, in order to base clinical decisions on cfDNA measurements, normal reference intervals are essential to avoid that ordinary variation is confused with clinically relevant change. The lack of reference intervals may potentially explain the ambiguous results reported in the field. Our study aimed to establish reference intervals and to evaluate the association between cfDNA and demographic and clinical variables, including colorectal cancer (CRC). Plasma samples and clinical data from 2817 subjects were collected including 1930 noncancer individuals and 887 CRC patients. cfDNA was measured using droplet digital polymerase chain reaction (PCR). The large cohort combined with robust cfDNA quantification enabled establishment of reference intervals (<67 years: 775-4860 copies/mL; ≥67 years: 807-6561 copies/mL). A cfDNA level above the age-stratified 90% percentile was prognostic of reduced survival in both noncancer individuals and CRC patients, with HR values of 2.56 and 2.01, respectively. Moreover, cfDNA levels increased significantly with age, elevated BMI and chronic diseases. In CRC, the cfDNA level was increased for Stage IV, but not Stage I to Stage III cancer. In summary, the use of reference intervals revealed that high cfDNA levels were predictive of shorter survival in both noncancer individuals and CRC patients, and that CRC development did not affect the cfDNA level until metastatic dissemination. Furthermore, cfDNA levels were impacted by age and chronic diseases. Conclusively, our study presents reference intervals that will help pave the way for clinical utilization of cfDNA.

AB - Circulating cell-free DNA (cfDNA) has spurred much interest as a biomarker in oncology. However, inter- and intra-individual cfDNA levels vary greatly. Consequently, in order to base clinical decisions on cfDNA measurements, normal reference intervals are essential to avoid that ordinary variation is confused with clinically relevant change. The lack of reference intervals may potentially explain the ambiguous results reported in the field. Our study aimed to establish reference intervals and to evaluate the association between cfDNA and demographic and clinical variables, including colorectal cancer (CRC). Plasma samples and clinical data from 2817 subjects were collected including 1930 noncancer individuals and 887 CRC patients. cfDNA was measured using droplet digital polymerase chain reaction (PCR). The large cohort combined with robust cfDNA quantification enabled establishment of reference intervals (<67 years: 775-4860 copies/mL; ≥67 years: 807-6561 copies/mL). A cfDNA level above the age-stratified 90% percentile was prognostic of reduced survival in both noncancer individuals and CRC patients, with HR values of 2.56 and 2.01, respectively. Moreover, cfDNA levels increased significantly with age, elevated BMI and chronic diseases. In CRC, the cfDNA level was increased for Stage IV, but not Stage I to Stage III cancer. In summary, the use of reference intervals revealed that high cfDNA levels were predictive of shorter survival in both noncancer individuals and CRC patients, and that CRC development did not affect the cfDNA level until metastatic dissemination. Furthermore, cfDNA levels were impacted by age and chronic diseases. Conclusively, our study presents reference intervals that will help pave the way for clinical utilization of cfDNA.

KW - biomarker

KW - circulating cell-free DNA

KW - colorectal cancer

KW - overall survival

KW - reference intervals

KW - free DNA

KW - INFLAMMATION

KW - MARKERS

KW - circulating cell&#8208

KW - TUMOR DNA

U2 - 10.1002/ijc.33434

DO - 10.1002/ijc.33434

M3 - Journal article

C2 - 33320961

VL - 148

SP - 1665

EP - 1675

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 7

ER -