The genetics of skin cancer and associated risk factors

Mr Sriniranjan Shekar (2008). The genetics of skin cancer and associated risk factors PhD Thesis, School of Medicine (Central); Queensland Institute of Medical Research, The University of Queensland.

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads
n40806084_phd_totalthesis.pdf n40806084_phd_totalthesis.pdf application/pdf 2.56MB 34
Author Mr Sriniranjan Shekar
Thesis Title The genetics of skin cancer and associated risk factors
School, Centre or Institute School of Medicine (Central); Queensland Institute of Medical Research
Institution The University of Queensland
Publication date 2008-03
Thesis type PhD Thesis
Supervisor Nicholas G. Martin
David L. Duffy
Total pages 106
Total colour pages 1
Total black and white pages 105
Subjects 320000 Medical and Health Sciences
Formatted abstract
Melanoma incidence rates have been increasing over the last two decades. To reduce the
burden of disease, studies have sought to identify genetic variations that increase susceptibility
to skin cancer. The scope of this PhD was to identify markers in the genome that are
linked to traits associated with skin cancer. Here, the traits include changes to the reticular
patterning on the epidermis and light-dark hair pigmentation. Finally, there was a study to
determine the proportion of variation in liability to melanoma due to genetic influences.
Genetic analysis of epidermal reticular patterning
A twin study comprising 332 monozygotic twin pairs and 488 dizygotic twin pairs at ages
12, 14 and 16 was used to investigate the aetiology of variation in skin pattern, particularly
in relation to measured sun exposure and skin colour. The results indicate that although self
reported sun exposure is a significant contributor to variation in skin pattern, its effect is small,
explaining only 3.4% of variation in skin pattern at age 14. Additive genetic effects explain
86% of variation in skin pattern at age 12 but these effects reduce with age so that 75% of variation
is due to additive genetic effects at age 14 and 72% at age 16. This trend of diminishing
genetic influences continues into adulthood with 62% of variation due to non-additive genetic
factors in a smaller adult sample (aged 32 to 86). Skin colour explains 10.4% of variation in
skin pattern at age 12, which is due to additive genetic influences common to both. Melanin
content appears to provide a protective effect against skin pattern deterioration.
The results of a genome-wide linkage scan of skin pattern in adolescent twins and siblings
from 428 nuclear twin families are presented. Sib-pair linkage analysis was performed on
skin pattern data collected from twins at age 12 (417 families) and 14 (399 families). Suggestive
linkage was found at marker D12S397 (12p13.31, lod score 1.94), when the effect of
the trait locus was modelled to influence skin pattern equally at both ages 12 and 14. In the
same bivariate analysis, a peak was seen at 4q23 with a lod of 1.55. A possible candidate for
the peak at 12p13.31 is α-2-macroglobulin like 1 (A2ML1).
Capturing eu-/pheomelanic variation using spectrophotometric methodsEumelanin (brown/black melanin) and pheomelanin (red/yellow melanin) in human hair
can be quantified using chemical methods or approximated using spectrophotometric methods.
This portion of the investigation sought to identify the spectrophotometric measures
that best explain the light-dark continuum of hair colour and the measure that is best able
to distinguish red hair from non-red hair. Genetic analysis was performed on these two
measures to determine the proportion of genetic and environmental influences on variation
in these traits. Reflectance curves along the visible spectrum and subjective ratings of hair
colour were collected from 1730 adolescent twin individuals. Discriminant class analyses
were performed to determine the spectrophotometric measure that could best proxy for
eumelanin and pheomelanin quantities. The ratio of light reflected in the green portion of
the spectrum to that reflected in the red portion of the spectrum was best able to distinguish
red hair from non-red hair. MC1R genotype explained some, but not all, variation in this
measure. Light absorbed in the red portion of the spectrum was best able to explain the
light-dark continuum of hair colour. Variance components analysis showed that there were
qualitatively different genetic influences between males and females for the light-dark continuum
of hair.
Genetic analysis of light-dark hair pigmentation
As a proxy to eumelanin quantity, absorbance at 650nm was used to look for chromosomal
regions that harbour genes affecting light-dark hair pigmentation. At 7p15.1, marker
D7S1808 was suggestive of linkage to light-dark hair colour (LOD ≈ 2.99). Marker D1S235
at 1q42.3 was suggestive of linkage to hair colour (light-dark or blonde-black continuum)
(LOD ~ 2.14). However, the most consistent linkage peak was over the gene OCA2 on chromosome
15. Linkage analysis of both spectrophotometrically quantified and ordered ratings
of hair colour both had LOD scores about 1.2, significant because of the almost perfect concordance.
A quantitative transmission disequilibrium test (QTDT) between light-dark hair
colour and 58 SNPs in OCA2 showed that the SNPs rs4778138 (also called rs11855019) and
rs1375164 were associated with significantly darker hair colour (p-values ≈ 3 x 10-4 and ≈
0.03 after correction for multiple testing, respectively). These two SNPs explain 1.54% and0.85% of variation in the A650t index, respectively.
A twin study of melanoma
Melanoma runs within families, but this may be due to shared genetic or shared environmental
influences within those families. Mandatory reporting of melanoma cases within the
state of Queensland yielded approximately 12,000 cases between 1982 and 1990. Twins in
this study and from the adjacent state of New South Wales (125 pairs in total) were used to
partition variation in liability to melanoma into genetic and environmental factors. Identical
twins were more concordant for melanoma (4 of 27 pairs) than non-identical twins (3 of 98
pairs; p-value ≈ 0.04). Non-identical co-twins of affected individuals were 1.76 times more
likely to be affected than by chance. However, identical co-twins of affected individuals were
9.8 times more likely to be affected than by chance. An MZ:DZ recurrence risk ratio greater
than 4 suggests that melanoma cases with a familial genetic basis are due to epistatic (genegene)
interactions. Individuals with melanoma had a greater number of moles on their arms
and legs than their unaffected co-twins for both identical and non-identical twins. This may
suggest that the relationship between the number of moles and cancer may be due to common
environmental influences rather than shared genetic influences. The relative risk of an
individual developing melanoma increased by 1% with each additional nevus.
Overall, these studies show a genetic basis for melanoma and for traits associated with
melanoma studied here. Further investigations are required to determine whether any genetic
variants influencing changes in epidermal reticular patterning or light-dark hair colour also
increase the risk of melanoma.
Additional Notes Page 45 is to be printed in colour. The remaining pages may be printed in black and white.

Citation counts: Google Scholar Search Google Scholar
Created: Thu, 18 Sep 2008, 14:46:43 EST by Mr Sriniranjan Shekar on behalf of School of Communication and Arts