||5R01CA080179-04 Interpret this number
||Phenotypic and Psychosocial Study of the L1307k Mutation
DESCRIPTION: (adapted from Investigator's abstract) The long-term objective of
this project is to determine if prevention of colorectal cancer (CRC) can be
improved by developing a novel clinically relevant screen. Such a screen would
identify individuals with a I1307K mutation in a cancer-susceptibility gene,
and would include carefully designed surveillance and management protocols. The
I1307K mutation has been identified in approximately 6 percent of Ashkenazi
Jews, approximately 10 percent of Ashkenazim with CRC, and approximately 28
percent of Ashkenazim who have both CRC and a family history of CRC.
Justification for allocating scarce health care resources to such a clinically
relevant screen requires additional knowledge. First, although most studies to
date show an increased risk for CRC in carriers of this mutation, a few do not,
and the magnitude of the risk is not fully established. Second, implementation
of a clinically relevant screen requires knowledge of the natural history and
clinical characteristics of I1307K-associated CRC, but this too is lacking.
Third, the screen will require genetic counseling, however, little known about
the feasibility or psychosocial impact of genetic counseling in situations
where the cancer-susceptibility mutation is of low penetrance. The current
application was developed to fill these gaps in current knowledge. To learn
more about risk, the study will identify 480 Ashkenazim with CRC (index cases),
then the subset with mutant I1307K (expected N=48), and then the first-degree
relatives of this subset with mutant I1307K (expected N=200). These data will
be used to estimate cancer risk among mutation carriers using retrospective
data and determine mutation-associated risk by comparing colonoscopic data
between mutation carriers and their non-carrier relatives. It is hypothesized
that mutation carriers will have more colonic neoplasia than noncarriers. With
regard to natural history, the study will see if, in index cases, phenotypic
expression of I1307K-associated CRC (age at diagnosis, frequency in each
gender, histologic type, colonic location of CRC, history and pathology of
other colorectal neoplasia and of extracolonic cancer, and family history of
cancer) differs from CRC in non-carriers. It is hypothesized that, similar to
other hereditary CRCs, CRC in mutation carriers will differ from that in
noncarriers. With regard to psychosocial impact, the study will quantitatively
assess the psychological impact of I1307K testing, identify predictors and
moderators of distress, and inform the development of stress-reducing
countermeasures. It is hypothesized that genetic testing will increase distress
more in mutation carriers and test decliners than in non-carriers. Ascertaining
risk, natural history and psychosocial impact will inform and may justify
development of a clinically relevant screen to improve cancer prevention and
decrease cancer-related mortality. Independent of screen development, this
study will be the first to characterize genetic testing distress where the
cancer-causing mutation is of low penetrance. Because recent advances in
genomics will likely lead to the discovery of other low penetrance genes that
predispose to cancer, this study could emerge as a model to aid future
understanding of the interactions among modifier genes, low-penetrance
mutations, the environment, and cancer.
The I1307K APC polymorphism in Ashkenazi Jews with colorectal cancer: clinical and pathologic features.
, Kaul K.
, Weinberg D.S.
, Gatalica Z.
, Gong G.
, Peterman A.
, Lynch J.
, Klatzco L.
, Olopade O.I.
, Bomzer C.A.
, et al.
Cancer genetics and cytogenetics, 2006 Aug; 169(1), p. 33-8.