Medicine (RMH) - Research Publications
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ItemPrevalence of PALB2 mutations in Australasian multiple-case breast cancer families(BMC, 2013)INTRODUCTION: Population-based studies of breast cancer have estimated that some PALB2 mutations confer a breast cancer risk (penetrance) comparable to the average pathogenic mutation in BRCA2. As this risk is of clinical relevance, we sought to identify mono-allelic PALB2 mutations and determine their frequencies in multiple-case breast cancer families attending Familial Cancer Clinics in Australia and New Zealand. METHODS: The youngest affected woman, not known to carry a mutation in BRCA1 or BRCA2, from 747 multiple-case breast cancer families participating in kConFab were selected for PALB2 mutation screening. The coding and flanking intronic regions of PALB2 in DNA extracted from blood were screened using high-resolution melt curve analysis with Sanger sequencing confirmation. Where possible, relatives of women found to carry PALB2 mutations were genotyped for the family-specific mutation, mutant transcripts were characterised and breast tumours arising in mutation carriers were recalled and reviewed. Missense mutations were assessed for potential to disrupt protein function via SIFT, Align GVGD and Polyphen-2. RESULTS: The mutation screen identified two nonsense mutations (PALB2 c.3113G>A in eight women and PALB2 c.196C>T in one woman), two frameshift mutations (PALB2 c.1947_1948insA and PALB2 c.2982_2983insT each in one woman), 10 missense variants, eight synonymous variants and four variants in intronic regions. Of the four PALB2 mutations identified that were predicted to produce truncated protein products, only PALB2 c.1947_1948insA had not previously been reported. PALB2 c.3113G>A and PALB2 c.196C>T were previously identified in the Australian population whereas PALB2 c.2982_2983insT was previously reported in the UK population. Transcripts derived from three of these mutant PALB2 alleles were vulnerable to nonsense-mediated decay. One missense mutation (PALB2 c.2993G>A) was predicted to disrupt protein function via the three in silico assessment methods applied. The majority of breast cancers arising in carriers that were available for review were high-grade invasive ductal carcinomas. CONCLUSIONS: About 1.5% (95% CI 0.6to 2.4) of Australasian multiple-case breast cancer families attending clinics are segregating protein-truncating mutations in PALB2, most being PALB2 c.3113G>A, p.Trp1038*. Given the prevalence, breast cancer risk, and tumour grade associated with this mutation, consideration of clinical PALB2 testing is warranted.
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ItemPALB2 and breast cancer: ready for clinical translation!(DOVE MEDICAL PRESS LTD, 2013)For almost two decades, breast cancer clinical genetics has operated in an environment where a heritable cause of breast cancer susceptibility is identified in the vast minority of women seeking advice about their personal and/or family history of breast and/or ovarian cancer. A new wave of genetic information is upon us that promises to provide an explanation for the greater proportion of current missing heritability of breast cancer. Whilst researchers refine bioinformatic and analytic methodology necessary to interpret the new genetic data, attention needs to be paid to defining appropriate and coordinated pathways for the translation of this information so that it can be applied in clinical genetic services for the benefit of the majority of women who currently have no explanation for their breast cancer susceptibility. The search for additional breast cancer susceptibility genes remains a very active area of research. Exhausting the power of linkage studies that identified BRCA1 and BRCA2, the research community moved to candidate gene studies that led to the identification of ATM, BRIP1, CHEK2, and PALB2 as so-called "moderate-risk" breast cancer susceptibility genes. Mutations in these genes are rare and although early reports suggested that, on average, they are associated with moderate risks of breast cancer; population-based studies have demonstrated that at least some mutations in these genes are associated with breast cancer risks that are comparable to the average risk associated with BRCA2 mutations. The search for additional breast cancer susceptibility genes has now moved onto research platforms applying massively parallel sequencing capable of sequencing whole human exomes and genomes in single instrument runs. These programs are identifying a large number of additional putative breast cancer susceptibility genes, many of which are currently undergoing validation. It is highly anticipated that the remaining missing heritability of breast cancer will be due to mutations in many different genes, each explaining a small proportion of the currently unexplained heritable breast cancer susceptibility. The characterization of PALB2 as a breast cancer susceptibility gene and subsequent research that has refined our understanding of the prevalence and penetrance of heritable mutations in PALB2 offers a precious opportunity to use the data as a model and develop modes of translation that would be appropriate for the anticipated volume of imminent new information.
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ItemUnmet support needs and distress among women with a BRCA1/2 mutation(SPRINGER, 2013-09)Distress levels among female BRCA1/2 mutation carriers can be similar to levels found among breast cancer patients. While psychological distress has been associated with unmet needs among cancer patients no study has examined this among BRCA1/2 mutation carriers. The objectives of this study were to: (1) describe the unmet support needs of women with a known BRCA1/2 mutation, (2) determine how unmet needs are related to psychological distress, and (3) identify variables that predict level of unmet need and distress. Female BRCA1/2 mutation carriers were identified through Familial Cancer Centers in 3 Australian states. Two-hundred and seventy-nine participants completed surveys assessing need for help on 16 information and support items. The Impact of Events Scale assessed genetic test related distress. Participants reported an average of 5.4 (SD = 4.9) moderate to very high unmet needs. Twenty-one percent had scores indicating moderate distress, and 13 % indicating severe distress. Younger age (t = -3.34; p < 0.01), not having someone to confide in about the gene mutation (t = 2.57; p = 0.01) and shorter time since notification of mutation status (t = -2.49; p = 0.01) were associated with higher unmet need scores in linear regression analyses. Greater number of unmet needs was associated with a greater likelihood of moderate to severe levels of distress (OR = 1.19; p < 0.01) in logistic regression analyses. Identifying appropriate interventions that target unmet needs among younger women and those with no confidante may help to reduce distress. Interventions that provide an opportunity for women to confide in someone, such as Peer support programs, may be one way of meeting the emotional needs of this population.
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ItemAre the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?(ELSEVIER SCI LTD, 2013-05)BACKGROUND: Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes. METHODS: A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the single nucleotide polymorphisms (SNPs): rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale). RESULTS: Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3 years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele=0.97, 95% confidence interval [CI]=0.88-1.07, p=0.52). CONCLUSIONS: We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome.
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ItemNo Preview AvailableRisks of Colorectal and Other Cancers After Endometrial Cancer for Women With Lynch Syndrome(OXFORD UNIV PRESS INC, 2013-02)BACKGROUND: Lynch syndrome is an autosomal dominantly inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Previous studies have shown that MMR gene mutation carriers are at increased risk of colorectal, endometrial, and several other cancers following an initial diagnosis of colorectal cancer. We estimated cancer risks following an endometrial cancer diagnosis for women carrying MMR gene mutations. METHODS: We obtained data from the Colon Cancer Family Registry for a cohort of 127 women who had a diagnosis of endometrial cancer and who carried a mutation in one of four MMR genes (30 carried a mutation in MLH1, 72 in MSH2, 22 in MSH6, and 3 in PMS2). We used the Kaplan-Meier method to estimate 10- and 20-year cumulative risks for each cancer. We estimated the age-, country-, and calendar period-specific standardized incidence ratios (SIRs) for each cancer, compared with the general population. RESULTS: Following endometrial cancer, women carrying MMR gene mutations had the following 20-year risks of other cancer cancers: colorectal cancer (48%, 95% confidence interval [CI] = 35% to 62%); cancer of the kidney, renal pelvis, or ureter (11%, 95% CI = 3% to 20%); urinary bladder cancer (9%, 95% CI = 2% to 17%); and breast cancer (11%, 95% CI = 4% to 19%). Compared with the general population, these women were at statistically significantly elevated risks of colorectal cancer (SIR = 39.9, 95% CI = 27.2 to 58.3), cancer of the kidney, renal pelvis, or ureter (SIR = 28.3, 95% CI = 11.9 to 48.6), urinary bladder cancer (SIR = 24.3, 95% CI = 8.56 to 42.9), and breast cancer (SIR = 2.51, 95% CI = 1.17 to 4.14). CONCLUSIONS: Women with Lynch syndrome who are diagnosed with endometrial cancer have increased risks of several cancers, including breast cancer.
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ItemNo Preview AvailableRisk of Metachronous Colon Cancer Following Surgery for Rectal Cancer in Mismatch Repair Gene Mutation Carriers(SPRINGER, 2013-06)BACKGROUND: Despite regular surveillance colonoscopy, the metachronous colorectal cancer risk for mismatch repair (MMR) gene mutation carriers after segmental resection for colon cancer is high and total or subtotal colectomy is the preferred option. However, if the index cancer is in the rectum, management decisions are complicated by considerations of impaired bowel function. We aimed to estimate the risk of metachronous colon cancer for MMR gene mutation carriers who underwent a proctectomy for index rectal cancer. METHODS: This retrospective cohort study comprised 79 carriers of germline mutation in a MMR gene (18 MLH1, 55 MSH2, 4 MSH6, and 2 PMS2) from the Colon Cancer Family Registry who had had a proctectomy for index rectal cancer. Cumulative risks of metachronous colon cancer were calculated using the Kaplan-Meier method. RESULTS: During median 9 years (range 1-32 years) of observation since the first diagnosis of rectal cancer, 21 carriers (27 %) were diagnosed with metachronous colon cancer (incidence 24.25, 95 % confidence interval [CI] 15.81-37.19 per 1,000 person-years). Cumulative risk of metachronous colon cancer was 19 % (95 % CI 9-31 %) at 10 years, 47 (95 % CI 31-68 %) at 20 years, and 69 % (95 % CI 45-89 %) at 30 years after surgical resection. The frequency of surveillance colonoscopy was 1 colonoscopy per 1.16 years (95 % CI 1.01-1.31 years). The AJCC stages of the metachronous cancers, where available, were 72 % stage I, 22 % stage II, and 6 % stage III. CONCLUSIONS: Given the high metachronous colon cancer risk for MMR gene mutation carriers diagnosed with an index rectal cancer, proctocolectomy may need to be considered.