To unravel the genetic makeup of colorectal cancer (CRC) in adolescents and young adults (AYAs) in order to improve genetic counseling, surveillance and, ultimately, treatment and disease outcome.
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
- Malignant and unspecified neoplasms gastrointestinal NEC
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Understanding the molecular etiology and pathogenesis of CRC in AYAs is
expected to yield novel genetic risk factors. that will facilitate clinical
decision making, including early tumor detection, in AYAs with CRC and their
siblings at risk.
Secondary outcome
Identification of novel genetic risk factors voor CRC will facilitate clinical
decision making, including early tumor detection in AYAs with CRC and their
siblings at risk.
Background summary
AYAs with CRC represent a clinical entity distinct from elderly CRC patients,
with many mucinous and poorly differentiated adenocarcinomas and advanced-stage
tumors, resulting in a worse prognosis. Based on these clinical
characteristics, the genetic aberrations underlying tumor initiation and
progression are also expected to be different between these two patient groups.
A young age of onset is a hallmark of hereditary CRC. Indeed, occasionally CRCs
in AYAs can be explained by known CRC predisposing syndromes. In most cases,
however, a positive family history for cancer is absent. Considering the poor
prognosis within this subgroup, we hypothesize that strong genetic factors are
not inherited in a dominant fashion, but rather have occurred de novo or follow
a recessive or digenic pattern of inheritance.
Study objective
To unravel the genetic makeup of colorectal cancer (CRC) in adolescents and
young adults (AYAs) in order to improve genetic counseling, surveillance and,
ultimately, treatment and disease outcome.
Study design
We will perform whole-exome sequencing on germline DNA of 15 patients diagnosed
with CRC <=25 years of age and their healthy parents. This strategy will enable
the identification of high-penetrant variants that follow de novo, recessive or
digenic patterns of inheritance. In addition, we will perform genome-wide copy
number analysis and high-throughput targeted sequencing of tumor DNA of these
15 and 40 additional patients with CRC <=25 years of age, to uncover the
overlapping, and thus clinically most relevant, somatic mutation spectra of
these CRCs. This integrated germline-somatic approach on a stringently selected
CRC patient cohort is expected to entail enough power to draw firm conclusions.
Study burden and risks
The risk of this study is considered to be negligible. The only physical burden
is a venepuncture. There is a small risk of unsolicited findings when exome or
genome sequencing is performed. Patients and/or their caretakers will be
thoroughly counselled about these risks and possible psychosocial consequences.
Furthermore the protocol that is used for unsolicited findings has already been
established in the department of Clinical Genetics and is approved by the
Commissie Mensgebonden Onderzoek Regio Arnhem-Nijmegen (ref CD/CMO 0507).
Geert Grooteplein 10
Nijmegen 6500HB
NL
Geert Grooteplein 10
Nijmegen 6500HB
NL
Listed location countries
Age
Inclusion criteria
15 individuals diagnosed with CRC <=25 years of age and
• a mismatch repair-proficient tumor
• polyposis syndromes excluded if polyps are present;and their parents. ;In addition we will anonymously include tumor DNA of 40 patients with CRC diagnosed <=25 years of age.
Exclusion criteria
A known genetic defect in the family for a cancer unrelated condition, of which the child might be a carrier but about which the child/parents do not want to be informed.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL49317.091.14 |