Pathways from Genotype & Environment to Melanoma
Study Code:CN
Start Date:Jan.2002
Status:In progress
Contact:Anjali Henders
More Info:QIMR only




The incidence of cutaneous malignant melanoma has increased dramatically in white skinned populations throughout the world over past decades. The state of Queensland has the highest incidence of melanoma in the world with life time incidences of 1 in 13 males and a in 16 females. Over the past 20 years, the principal investigators have conducted several large scale studies into the molecular genetics and genetic epidemiology of melanoma and its risk factors, particularly nevus density and pigmentation. Recently, the focus has been on the roles of sun exposure and known melanoma susceptibility genes (CDKN2A and CDK4) and pigmentation genes (MC1R). We now have the largest and best-described population-based sample of melanoma cases and their families in the world. We wish to extend these resources and perform new analyses to elucidate the pathways from genotype and environmental risk factors, via intervening phenotypic variables to melanoma.

1a. Background

The investigators for this National Institutes of Health (NIH) funded study of the genetics of melanoma have been studying the molecular genetics and genetic epidemiology of melanoma and its risk factors for around 20 years. This study will follow up the participants of previous studies. There are 6 groups of respondents, based on their previous participation in the following studies:

The Queensland Familial Melanoma Project (QFMP)

Beginning in 1994, the QFMP was undertaken by Nick Martin, Joanne Aitken and others. This is the largest family and twin study study of CMM yet conducted in an unselected, geographically-defined population, and includes the largest population-based sample of melanoma cases in the world. Family history information was obtained from all 12,014 Queensland residents with a first primary CMM diagnosed between 1982-1990 (sourced from the Queensland Cancer registry). Further detailed information on melanoma history and standard risk factors was sought from all twins, familial CMM cases, and their relatives; and from a sample of non-familial CMM cases and their relatives, to give a final sample of 1,912 families. Of these families, 1,403 families contain a single member with CMM, 415 contain two, 67 contain three, and 27 families contain 4 or more cases. These families are the basis for the three groups refered to as high, medium and low risk. Each family has a proband, who is the principal contact for the family. Members of these families have been bled and asked questionnaires in three separate waves between about 1994 and now.

High Familial Risk Melanoma Study - Nick Hayward

Some families included in a study by Nick Hayward of high risk melanoma families (3+cases) that began around 1985 overlap with families in the QFMP.

Childhood Melanoma Study

Undertaken by David Whiteman in 1995, this matched (1:3) case control study sought to determine whether plausible determinants of adult CMM were associated with CMM in childhood. 61 cases of CMM in children under 15 years were notified to the QCR from January 1987 to June 30, 1994. Controls were randomly selected from schools and matched for sex and age. 31 cases were bled.

Adolescent Melanoma study

A population based case-control study was carried out to examine the risk factors for melanoma in adolescents. All 250 cases of melanoma diagnosed in adolescents aged 15-19 years, between 1987 to 1994 and notified to the QCR were included in the study. Melanoma cases were matched to a control by sex, age and region of residence. 201 cases were bled.

Men over 50 study

This study by David Whiteman was of 150 men over 50 diagnosed with melanoma. Participants were not asked to give a blood sample.

1b. Specific aims

  • To follow up 1,912 families of the Queensland Familial Melanoma Project (QFMP) in order to update survival status and risk factor information.
  • To obtain blood samples from all melanoma cases, one unaffected sibling of proband, and available parents of all high familial risk families, intermediate risk families, and a 50% sample of low risk families.
  • To follow-up probands and families from three overlapping substudies of melanoma in children, adolescents and older men using the same interview and blood collection protocols as above.
  • To augment these samples with previously collected DNA samples from 600 age matched, sex, ethnically matched community controls for whom camparible risk factor data are available.
  • To identify all common intronic single nucleotide polymorphisms (SNPs) of the CDKN2A gene, and exonic SNPs of the P gene by sequencing these genes in 100 subjects of diverse melanoma risk and pigmentation type.
  • To type by allele specific oligonucleotide hybridisation (ASO) newly identified and previously discovered SNPs in genes of the cell cycle axis (CDKN2A, CDKN2B, CDK4), and pigmentation axis (MC1R, P).
  • To fine map a major quantitative trait locus (QTL) affecting nevus density linked to CDKN2A in the Brisbane Twin Nevus Study (BTNS)
  • To extend a 10cM genome scan of the BTNS to 800 twin families.


We will interview all probands, all affected sibs and one unaffected sib closest in age to the proband.

For every family for whom we obtain a proband sample, we shall attempt to obtain a sample from one unaffected sibling, all available parents and all other affected relatives. In the absence of parents, we will aim to obtain samples from 2 unaffected sibs per unavailable parent.


Click on the links below to access the following publications in PDF format:

(If you do not have Adobe Acrobat Reader you can download it here)

Zhu G, Duffy DL, Eldridge A, Grace M, Mayne C, O'Gorman L, Aitken JF, Neale MC, Hayward NK, Green AC, Martin NG: A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs. Am J Hum Genet 1999 Aug;65(2):483-92. (PMID: 10417291)

Palmer JS, Duffy DL, Box NF, Aitken JF, O'Gorman LE, Green AC, Hayward NK, Martin NG, Sturm RA: Melanocortin-1 receptor polymorphisms and risk of melanoma: Is the association explained solely by pigmentation phenotype? American Journal of Human Genetics 66:176-186, 2000.

Neil F Box, David L Duffy, Rachel E. Irving, Anne Russell, Wei Chen, Lyn R GrifĂths,▓ Peter G Parsons, Adele C Green, and Richard A Sturm. Melanocortin-1 Receptor Genotype is a Risk Factor for Basal and Squamous Cell Carcinoma. Journal of Investigative Dermatology 116(2):1-7, Feb, 2001

Welch J, Millar D, Goldman A, Heenan P, Stark M, Eldon M, Clark S, Martin NG, Hayward NK: Lack of genetic and epigenetic changes in Cdkn2a in melanocytic nevi. Journal of Investigative Dermatology 117(2):383-384, Aug 2001.

Box NF, Duffy DL, Chen W, Stark M, Martin NG, Sturm RA, Hayward NK: MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations. American Journal of Human Genetics 69(4):765-773, Oct 2001.

Siskind V, Aitken J, Green A, Martin, NG: Sun exposure and interaction with family history in risk of melanoma in Queensland, Australia. International Journal of Cancer 97(1): 90-95, Jan 2002.

Pollock, Pamela M. et al. High frequency of BRAF mutations in nevi. Published online 25 November 2002. Doi:10.1038/ng1054


Families from the Queensland Familial Melanoma Project

Participants from the Adolescent Melanoma Study and their families

Participants from the Childhood Melanoma Study and their families

Participants from the 50+ Men Melanoma Study and their families



Queensland Cancer Fund