Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients

Abstract

Introduction Colorectal cancer (CRC) diagnosed before age 30 is a fatal disease whose biology remains poorly understood. To understand its pathogenesis, we compared molecular and clinical data in surgically treated early-age onset and adult onset patients. Materials and methods Clinical data and tumor tissue were collected retrospectively for 94 patients with early-age onset CRC (≤age 30) and compared to 275 adult CRC patients (≥age 50). Tumor morphology, microsatellite instability (MSI) and stability (MSS), KRAS and BRAF mutations, and mismatch repair (MMR) expression (MSH2, MLH1, MSH6, PMS2) were assessed. Results Early-age CRC was distinguished from adult CRC by advanced stage presentation (P<0.001), frequent high grade cancers (P<0.001), and poor prognosis (P<0.001). MSI was associated with favorable survival and MMR loss in both groups. Compared to adults, MSI in early-onset CRC was more prevalent (P<0.01), not tightly linked to MLH1/PMS2 loss, and never associated with BRAFV600E mutations (P<0.01). MSS/BRAFV600E genotype had poor prognosis and was more prevalent in early-age CRC (9% vs. 3%). Discussion Specific genetic subtypes are found at different frequencies in early-age onset and adult onset CRC. Complete absence of the indolent MSI/BRAFV600E genotype and enrichment in the unfavorable MSS/BRAFV600E genotype help explain the poor prognosis of early onset CRC.

Impact of Patient Age on Molecular Alterations of Left-Sided Colorectal Tumors

“…Although it is well established that dMMR can be accurately measured by directly enumerating known MSI loci using targeted deep sequencing (MSI-NGS) [31] or by TMB [32], our results warrant some caution, and further validation is needed to elucidate this aspect. However, our findings are in accordance with previous studies that showed that MSI-H occurs more frequently in younger patients, although frequencies vary widely [33,34], and that the pattern of mutations leading to MSI-H in younger patients is different from older patients [35,36]. In fact, currently, we are examining whether mutations in specific MMR genes have a different impact on immune-related biomarker expression (e.g., PD-L1 overexpression and TMB level).…”

“…Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related death worldwide [1]. In the last 2 decades, adults aged 50 years have experienced increase by 90% and 124%, respectively, in patients aged 20-34 years and by 27.7% and 46.0%, respectively, in patients aged [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] years [3]. The cause remains unknown, although lack of screening, obesity, physical inactivity, and Western diets may play a crucial role in early-onset CRC.…”

Young-onset colorectal cancer in the North East of Scotland: survival, clinico-pathological features and genetics

“…These younger patients often present with more advanced disease and adverse pathological features compared to their older counterparts [7]. This may have a negative impact on their survival outcome [8].…”

“…Evidence regarding young-onset CRC (yCRC) patient prognosis is conflicting. Some retrospective studies suggest that younger patients have a poorer prognosis than those with later-onset disease [8]. However, other studies suggest their prognosis is better or equivalent to those aged over 55 years [9].…”

“…Inherited predispositions to CRC are sometimes responsible for causing the disease, especially within the younger demographic [8]. These predispositions can be divided into low-penetrance familial clusterings and high-penetrance autosomal dominant cancer syndromes [3].…”