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\begin{document}

\title{Pediatric colon cancer - when enemies band together.}



\author[1]{Thomas Attard}%
\affil[1]{Children's Mercy Hospitals and Clinics}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\textbf{--Title:}

Pediatric Colon Cancer - When Enemies Band Together.

\textbf{--Author affiliation:}

Thomas M Attard MD

\textbf{--Corresponding author:}

Thomas M Attard MD

2401 Gillham Rd, Kansas City, MO 64108

Office: (816) 302-8149

Fax: (816) 234-1553

E-mail: tmattard@cmh.edu

\textbf{--Word Count}

770

\textbf{--The number of Tables, Figures, and Supporting Information
files;}

0

\textbf{--A short running title}

Pediatric colon cancer

\textbf{--Three to six keywords to index the content.}

Pediatric, colorectal cancer, polyposis

\textbf{--Abbreviations key.}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
CRC & Colorectal Cancer\tabularnewline
\midrule
\endhead
EOCRC & Early-onset colorectal cancer\tabularnewline
AYA & Adolescents and young adults\tabularnewline
PV & Pathogenic variant\tabularnewline
FAP & Familial Adenomatous Polyposis\tabularnewline
MAP & \emph{MUTYH}-associated polyposis\tabularnewline
JPI & Juvenile Polyposis of Infancy\tabularnewline
BMMRD & Biallelic Mismatch Repair Deficiency\tabularnewline
\bottomrule
\end{longtable}

The last decades have seen strides made in early detection and effective
management of colorectal cancer(CRC). Less encouraging has been an
observed increase in CRC in young adults, or early onset colorectal
cancer (EOCRC) defined as under 30, 35 or 40 years of age at diagnosis.

In contrast with the observed steady decrease in age adjusted incidence
of CRC in individuals over 50 years of age, a 1.3\% increase incidence
in CRC in individuals 20 -- 49 years of age has been observed since
1996. The largest percent increase in incidence is reported among ages
20--29 years, with an increase of 5.2 \% in men and 5.6 \% in women per
year, and largely attributable to left sided and rectal lesions. In the
pediatric age range, CRC incidence has remained stable and favors a
right sided localization, more common in males between 15 -- 17 years of
age and from lower socioeconomic background.

The diagnosis of EOCRC in adolescents and young adults (AYA) tends to be
delayed for various reasons including under-utilized health care
services, and physicians harboring a low index of suspicion. This
population is also outside the scope of screening unless individuals are
known to have a predisposing syndrome. Younger patients tend to have
more advanced stage of disease, less favorable histopathology, and worse
prognosis at the time of diagnosis compared with older patients.

Younger patients are more likely to harbor a recognized hereditary,
therefore syndromic etiology for CRC. Even then however, only a small
minority of individuals harbor pathogenic variants (PV) in the well
characterized genetic loci including Familial Adenomatous Polyposis
(FAP), Lynch syndrome (LS), MUTYH-associated polyposis (MAP) and the
less common hamartomatous polyposis syndromes (Peutz--Jeghers syndrome
and juvenile polyposis syndrome).

Phen and colleagues describe 3 patients with CRC diagnosed at 15 years
of age, one harbored PV in \emph{MLH1} and \emph{MSH3} , a second
with\emph{MSH2} and \emph{APC} risk allele and a third with PV in
both\emph{MLH1} and \emph{APC} . This report entails two broad
implications. In the context of the increased impact of EOCRC, it offers
potentially new insight wherein concurrent pathogenic mutations in Lynch
and FAP loci or biallelic Lynch mutations may explain the occurrence of
CRC in a subset in adolescents. Conversely, this paper may be an
important wake up call on the need for a more aggressive approach to AYA
referred for a family history of Lynch Syndrome.

Our current understanding of the molecular pathophysiology of EOCRC,
especially during childhood and adolescence is very limited, genetic
mechanisms are presumed to dominate over environmental factors. An
underlying genetic predisposition is however rarely cited in case
reports and, conversely even within the population at risk, for example,
Familial Adenomatous Polyposis, CRC is a rare occurrence in the first
two decades of life. However, the classic paradigm for a non-syndromic
familial predisposition for CRC has included a low-penetrance polygenic
inherited predisposition, and the paper by Phen et al. may well be a
demonstration of this concept in the adolescent age group. As such, this
implies the need for greater awareness of these largely novel, genetic
factors. This concept itself is not entirely novel, an aggressive form
of juvenile polyposis (Juvenile Polyposis of Infancy; JPI) is associated
with contiguous deletion of two tumor suppressor genes, BMPR1A and PTEN.
An even closer analogy is biallelic mismatch repair deficiency syndrome
(BMMRD) wherein a mismatch repair defect is inherited from each parent
with the mean age at diagnosis of CRC being 16 years.

At present, a patient with a family history of Lynch Syndrome will, if a
PV is identified in the family, undergo directed genetic testing and, if
discovered to be a carrier, will be referred to screening at no earlier
than at 20 -- 25 years of age. However, in view of the description of
EOCRC associated with polygenic etiology, given the decreased cost and
availability of comprehensive predisposing gene panel testing, perhaps
we should be moving toward more aggressive testing at an early age. This
is certainly not a call for indiscriminate testing, genetic testing has
far reaching implications; more than just cost, however this and similar
observations warrant a discussion reappraising risk, outcomes and
testing - bearing in mind the clear impact of presymptomatic endoscopic
surveillance.

Pediatric colorectal cancer remains a challenge, often with devastating
consequences to patients and families. Delay in diagnosis is a major
contributor to adverse outcomes and is, multifactorial but includes our
inability, thus far, to identify the majority of patients at risk. The
paper by Phen and colleagues offers a tantalizing opportunity to impact
our recognition of some, perhaps a significant proportion, of the
individuals at risk and therefore warrants further discussion.

Bibligraphy

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