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Page 2 of 13 Ambe et al. Mini-invasive Surg 2018;2:37 I http://dx.doi.org/10.20517/2574-1225.2018.45

the underlying pathogenesis, three distinct groups of CRC can be identified. Sporadic CRC is usually diag-
nosed in individuals aged 50 years and above and represents approximately 60%-70% of CRC and is as such
the most common entity. These patients by definition do not harbor a deleterious predisposing hereditary
[2]
mutation .
The second group has been termed, familial colorectal cancer and describes families with an increased in-
cidence of CRC. Typically, CRC has been diagnosed in more than one close relative. By definition this ap-
[3]
plies when a first - degree relative (parent, sibling or child) has been diagnosed with CRC . Screening colo-
noscopy is recommended for the relatives at risk beginning at the age of 40 or 10 years before the youngest
[3]
age of onset in the family. This group has been reported to account for about 20%-30% of all CRC .
The third group includes cases with hereditary CRC, due to a single deleterious mutation in one of the
known predisposing genes. Based on multiple mutational abnormalities in different organ systems and
additionally a heterogenous phenotype, these mutational pathologies are best summarized as syndromes,
which are defined based on clinical, histopathological and genetic findings. With advances in genetic
research, it is expected that many more genes involved in predisposition to cancer will be identified in af-
fected individuals.

Well studied hereditary syndromes with predisposition to CRC currently include: hereditary non-polyposis
colon cancer (HNPCC) or Lynch syndrome (LS), familial adenomatous polyposis (FAP), attenuated familial
[4,5]
adenomatous polyposis (aFAP), Peutz-Jeghers syndrome (PJS) and MUTYH associated polyposis (MAP) .
Recently described inheritable genetic alterations with increased risk for CRC further include polymerase
[5]
proofreading associated polyposis (PPAP), NAD, MSH3 and NTH like DNA glycosylase 1 (NTHL1) . All these
hereditary syndromes do not only vary widely in terms of clinical presentation but individually present with
variable risks of CRC and also involvement of additional benign and malignant neoplastic growth. Interest-
ingly, intrafamilial heterogeneity is common, despite the fact that the affected harbor the identical deleterious
mutation. This is an indication of the influence of modifying genetic and epigenetic factors.

The surgical management of patients with hereditary CRC warrants identification and an understanding of
the underlying syndrome. The heterogeneity of the phenotype, risk of organ-specific malignant transfor-
mation and the quality of life following surgery amongst others must be taken into consideration and dis-
cussed at the time of CRC ideally prior to surgery. A personalized approach should always be considered to
offer each individual patient the best management option based on gene and gender and the estimated risk,
depending on available evidence. However, patient preference is important and the explanation of risk can
be challenging.

This review focuses on hereditary syndromes with predisposition to CRC. The most relevant syndromes
will be addressed with focus on surgical considerations regarding oncological and functional outcome.

HNPCC (LS)
LS describes a wide spectrum of clinical findings with a high risk of gastrointestinal, urinary and gyneco-
[6,7]
logical cancers . The underlying pathology is related to defective mismatch repair (MMR) genes, which
are associated with a high level of microstatellite instability (MSI-H). These germline mutations are autoso-
[8]
mal dominantly transmitted and thus carry a 50% risk of inheritance . The identification of a pathogenic
[8]
germline MMR mutation (and implicitly a MSI-H tumor phenotype) defines LS . HNPCC is the clinical
colorectal manifestation following the familial pattern of inheritance as described in the clinical pattern of
the Bethesda or Amsterdam criteria, whereas LS is attributed to an individual with a pathogenic mutation
in one of the MMR genes (MLH1, MSH2, MSH6, PMS2, EPCAM).

LS is often associated with a young age of onset and is accountable for 3%-5% of CRC with a predominance