Features of Childhood Colorectal Carcinomas and Frequency of K-ras Mutations

Ayşe Büyükcam; Canan Akyüz; Diclehan Orhan; Bilgehan Yalçın; Ali Varan; Münevver Büyükpamukçu; Tezer Kutluk

doi:10.5152/eurjther.2021.20034

Authors

Ayşe Büyükcam Department of Pediatrics, Hacettepe University School of Medicine, Ankara https://orcid.org/0000-0002-4015-4210
Canan Akyüz Department of Pediatric Oncology, Hacettepe University School of Medicine, Ankara https://orcid.org/0000-0002-7105-4191
Diclehan Orhan Department of Pediatric Pathology, Hacettepe University School of Medicine, Ankara https://orcid.org/0000-0003-3637-5392
Bilgehan Yalçın Department of Pediatric Oncology, Hacettepe University School of Medicine, Ankara https://orcid.org/0000-0003-2840-0308
Ali Varan Department of Pediatric Oncology, Hacettepe University School of Medicine, Ankara https://orcid.org/0000-0003-4911-1476
Münevver Büyükpamukçu Department of Pediatric Oncology, Hacettepe University School of Medicine, Ankara https://orcid.org/0000-0001-8716-4750
Tezer Kutluk Department of Pediatric Oncology, Hacettepe University School of Medicine, Ankara https://orcid.org/0000-0002-1918-4407

DOI:

https://doi.org/10.5152/eurjther.2021.20034

Keywords:

Childhood colorectal carcinoma, K-ras mutation

Abstract

Objective: Colorectal carcinoma (CRC) is extremely rare in childhood and has a poor prognosis in young patients. The tumorigenesis of CRC in children and adolescents is still unclear and probably evolves through different stages. There are not enough studies about the rarity of K-ras mutations with childhood CRC. This study aimed to investigate the features and outcomes of childhood CRC as well as examine the frequency of K-ras mutations in CRC among children and adolescents.

Methods: The clinical and pathologic features, prognostic factors, and outcomes of CRC in 28 children and adolescents (ages 10 to 17 years) referred to the Pediatric Oncology Department of Hacettepe University Children’s Hospital between 1974 and 2010 were reviewed for this study. Paraffin-embedded tissues of 18 patients were available and these tissues were analyzed by using the “pyrosequencing” method to detect K-ras mutations.

Results: The median age of patients was 14 years and the male/female ratio was 2.5/1. At presentation, the most common symptoms were abdominal pain (57%) and weight loss (43%). The time between symptoms and diagnosis was 4 months. The most common sites of involvement were the rectum (43%) and sigmoid colon (25%). Mucinous adenocarcinoma was the most common histiotype (71%). At presentation, 89% of patients had metastatic disease, especially to the peritoneal surface (39%). Overall survival rates at 3 and 5 years were 10%. Distant stage (p=0.045), incomplete resection, and macroscopic tumor (p=0.000) were poor prognostic outcomes. A K-ras mutation was identified in three of the 18 patients (17%). The most common mutation of the patients was GGT→GAT at codon 12.

Conclusion: Childhood colorectal carcinomas occur in a shorter time than in adults, with different histiotypes and more likely different steps. It seems that K-ras mutation plays a role in this different biology of pediatric CRC. However, further studies are essential to investigate and understand the biology of childhood CRC.

Metrics

Metrics Loading ...

References

Pappo AS, Radriguez-Galindo C, Furman WL. Management of Infrequent cancers of childhood In: Pizzo PA, Poplack DG, editors. Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia: Lipincott Williams & Wilkins; 2010. p. 1109-12.

Ferrari A, Rognone A, Casanova M, Zaffignani E, Piva L, Collini P, et al. Colorectal carcinoma in children and adolescents: the experience of the Istituto Nazionale Tumori of Milan, Italy. Pediatr Blood Cancer 2008; 50: 588-93.

Ferrari A, Brecht IB, Gatta G, Schneider DT, Orbach D, Cecchetto G, et al. Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 2019; 110: 120-6.

Kravarusic D, Feigin E, Dlugy E, Steinberg R, Baazov A, Erez I, et al. Colorectal carcinoma in childhood: a retrospective multicenter study. J Pediatr Gastroenterol Nutr 2007; 44: 209-11.

Hill DA, Furman WL, Billups CA, Riedley SE, Cain AM, Rao BN, et al. Colorectal carcinoma in childhood and adolescence: a clinicopathologic review. J Clin Oncol 2007; 25: 5808-14.

Durno C, Aronson M, Bapat B, Cohen Z, Gallinger S. Family history and molecular features of children, adolescents, and young adults with colorectal carcinoma. Gut 2005; 54: 1146-50.

Palmirotta R, Savonarola A, Ludovici G, Marchis MLD, Covello R, Ettorre GM, et al. Concurrent mutation in exons 1 and 2 of the K-ras oncogene in colorectal cancer. Folia Histochem Cytobiol 2011; 49: 729-33.

Einspahr JG, Martinez ME, Jiang R, Hsu CH, Rashid A, Bhattacharrya AK, et al. Associations of Ki-ras proto-oncogene mutation and p53 gene overexpression in sporadic colorectal adenomas with demographic and clinicopathologic characteristics. Cancer Epidemiol Biomarkers Prev 2006; 15: 1443-50.

Kressner U, Bjorheim J, Westring S, Wahlberg SS, Påhlman L, Glimelius B, et al. Ki-ras mutations and prognosis in colorectal cancer. Eur J Cancer 1998; 34: 518-21.

Sherlock P, Lipkin M, Winawer SJ. Predisposing factors in carcinoma of the colon. Adv Intern Med 1975; 20: 121-50.

Poehlmann A, Kuester D, Meyer F, Lippert H, Roessner A, Schneider-Stock R. K-ras mutation detection in colorectal cancer using the Pyrosequencing technique. Pathol Res Pract 2007; 203: 489-97.

Gao J, Li YY, Sun PN, Shen L. Comparative analysis of dideoxy sequencing, the KRAS StripAssay and pyrosequencing for detection of KRAS mutation. World J Gastroenterol 2010; 16: 4858-64.

Saab R, Furman WL. Epidemiology and management options for colorectal cancer in children. Paediatr drugs. 2008; 10: 177-92.

Kim G, Baik SH, Lee KY, Hur H, Min BS, Lyu CJ, et al. Colon carcinoma in childhood: review of the literature with four case reports. Int J Colorectal Dis 2013; 28: 157-64.

Khan SA, Morris M, Idrees K, Gimbel MI, Rosenberg S, Zeng Z, et al. Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients. J Pediatr Surg 2016; 51: 1812-7.

Chen TA, Kang HY, Chang HC, Lin WC, Chao TM, Horng JT. Gender differences in colorectal cancer during the past 20 years in Taiwan. Int J Colorectal Dis 2012; 27: 345-53.

Teng A, Lee DY, Cai J, Patel SS, Bilchik AJ, Goldfarb MR. Patterns and outcomes of colorectal cancer in adolescents and young adults. J Surg Res 2016; 205: 19-27.

Henrikson NB, Webber EM, Goddard KA, Scrol A, Piper M, Williams MS, et al. Family history and the natural history of colorectal cancer: systematic review. Genet Med 2015; 17: 702-12.

Taylor DP, Burt RW, Williams MS, Haug PJ, Cannon-Albright LA. Population-based family history-specific risks for colorectal cancer: a constellation approach. Gastroenterology 2010; 138: 877-85.

Sandhu MS, Luben R, Khaw KT. Prevalence and family history of colorectal cancer: implications for screening. J Med Screen 2001; 8: 69-72.

Blumer SL, Anupindi SA, Adamson PC, Lin H, Price AP, Markowitz RI, et al. Sporadic adenocarcinoma of the colon in children: case series and review of the literature. J Pediatr Hematol Oncol 2012; 34: e137-41.

Poles GC, Clark DE, Mayo SW, Beierle EA, Goldfarb M, Gow KW, et al. Colorectal carcinoma in pediatric patients: A comparison with adult tumors, treatment and outcomes from the National Cancer Database. J Pediatr Surg 2016; 51: 1061-6.

Salas-Valverde S, Lizano A, Gamboa Y, Vega S, Barrantes M, Santamaría S, et al. Colon carcinoma in children and adolescents: prognostic factors and outcome-a review of 11 cases. Pediatr Surg Int 2009; 25: 1073-6.

Sultan I, Rodriguez-Galindo C, El-Taani H, Pastore G, Casanova M, Gallino G, et al. Distinct features of colorectal cancer in children and adolescents: a population-based study of 159 cases. Cancer 2010; 116: 758-65.

Lamego CM, Torloni H. Colorectal adenocarcinoma in childhood and adolescent. Report of 11 cases and review of the literature. Pediatr radiology 1989; 19: 504-8.

Goldberg J, Furman WL. Management of colorectal carcinoma in children and young adults. J Pediatr Hematol Oncol 2012; 34 Suppl 2: S76-9.

Singer G, Hoellwarth ME. Colorectal carcinomas in children: an institutional experience. Pediatr Surg Int 2012; 28: 591-5.

Kaplan MA, Isikdogan A, Gumus M, Arslan UY, Geredeli C, Ozdemir N, et al. Childhood, adolescents, and young adults (=25 y) colorectal cancer: study of Anatolian Society of Medical Oncology. J Pediatr Hematol Oncol 2013; 35: 83-9.

Weber ML, Schneider DT, Offenmuller S, Kaatsch P, Einsiedel HG, Benesch M, et al. Pediatric Colorectal Carcinoma is Associated With Excellent Outcome in the Context of Cancer Predisposition Syndromes. Pediatr Blood Cancer 2016; 63: 611-7.

LaQuaglia MP, Heller G, Filippa DA, Karasakalides A, Vlamis V, Wollner N, et al. Prognostic factors and outcome in patients 21 years and under with colorectal carcinoma. J Pediatr Surg 1992; 27: 1085-9.

Koh KJ, Lin LH, Huang SH, Wong JU. CARE--pediatric colon adenocarcinoma: a case report and literature review comparing differences in clinical features between children and adult patients. Medicine 2015; 94: e503.

Rao BN, Pratt CB, Fleming ID, Dilawari RA, Green AA, Austin BA, et al. Colon carcinoma in children and adolescents. A review of 30 cases. Cancer 1985; 55: 1322-6.

Anthony T, George R, Rodriguez-Bigas M, Petrelli NJ. Primary signet-ring cell carcinoma of the colon and rectum. Ann Surg Oncol 1996; 3: 344-8.

Kim HS, Kang SH, Park CH, Yang WI, Jeung HC, Chung HC, et al. Genome-wide molecular characterization of mucinous colorectal adenocarcinoma using cDNA microarray analysis. Oncol Rep 2011; 25: 717-27. doi:10.3892/or.2010.1126.

Raskov H, Pommergaard HC, Burcharth J, Rosenberg J. Colorectal carcinogenesis--update and perspectives. World J Gastroenterol 2014; 20: 18151-64.

Inoue Y, Saigusa S, Iwata T, Okugawa Y, Toiyama Y, Tanaka K, et al. The prognostic value of KRAS mutations in patients with colorectal cancer. Oncol Rep 2012; 28: 1579-84.

Dobre M, Comanescu M, Arsene D, Iosif C, Bussolati G. K-ras gene mutation status in colorectal cancer: comparative analysis of pyrosequencing and PCR-RFLP. Rom J Morphol Embryol 2013; 54: 567-74.

Moon BS, Jeong WJ, Park J, Kim TI, Min DS, Choi K. Role of oncogenic K-Ras in cancer stem cell activation by aberrant Wnt/beta-catenin signaling. J Natl Cancer Inst 2014; 106: djt373. doi:10.1093/jnci/djt373.

Guibert N, Ilie M, Long E, Hofman V, Bouhlel L, Brest P, et al. KRAS Mutations in Lung Adenocarcinoma: Molecular and Epidemiological Characteristics, Methods for Detection, and Therapeutic Strategy Perspectives. Curr Mol Med 2015; 15: 418-32.

Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci 2014; 39: 91-100.

de Macedo MP, de Lima LG, Begnami MD, de Melo FM, Andrade LDB, Lisboa BCG, et al. KRAS insertions in colorectal cancer: what do we know about unusual KRAS mutations? Exp Mol Pathol 2014; 96: 257-60.

Li W, Zhi W, Zou S, Qiu T, Ling Y, Shan L, et al. Distinct Clinicopathological Patterns of Mismatch Repair Status in Colorectal Cancer Stratified by KRAS Mutations. PloS one 2015; 10: e0128202.

Markman B, Javier Ramos F, Capdevila J, Tabernero J. EGFR and KRAS in colorectal cancer. Advances in clinical chemistry. 2010; 51: 71-119.

Yantiss RK, Goodarzi M, Zhou XK, Rennert H, Pirog EC, Banner BF, et al. Clinical, pathologic, and molecular features of early-onset colorectal carcinoma. Am J Surg Pathol 2009; 33: 572-82.

Goel A, Nagasaka T, Spiegel J, Meyer R, Lichliter WE, Boland CR. Low frequency of Lynch syndrome among young patients with non-familial colorectal cancer. Clin Gastroenterol Hepatol 2010; 8: 966-71.

Chang DT, Pai RK, Rybicki LA, Dimaio MA, Limaye M, Jayachandran P, et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features. Mod Pathol 2012; 25: 1128-39.

Alsop K, Mead L, Smith LD, Royce SG, Tesoriero AA, Young JP, et al. Low somatic K-ras mutation frequency in colorectal cancer diagnosed under the age of 45 years. Eur J Cancer 2006; 42: 1357-61.

Watson R, Liu TC, Ruzinova MB. High frequency of KRAS mutation in early onset colorectal adenocarcinoma: implications for pathogenesis. Hum Pathol 2016; 56: 163-70.

Karnak I, Ciftci AO, Senocak ME, Buyukpamukcu N. Colorectal carcinoma in children. Journal of pediatric surgery. 1999; 34: 1499-504.

Chattopadhyay S, Gupta P, Aich RK, Deb AR. Colorectal carcinoma in a ten-year-old girl: a case report. J Cancer Res Ther 2012; 8: 120-2.

Angel CA, Pratt CB, Rao BN, Schell MJ, Parham DM, Lobe TE, et al. Carcinoembryonic antigen and carbohydrate 19-9 antigen as markers for colorectal carcinoma in children and adolescents. Cancer 1992; 69: 1487-91.