With this work (Hatvani et al. 2014), our major aim was to analyze Hungarian MPM patients for the first time from clinical and genetic point of view and to find associations between these results focusing on MC1R carrier status.
Based on our findings in this MPM study we can conclude, that
1. The following results were in accordance with previous data from the literature:
Rate of MPM occurrence among MM patients
Higher number of common nevi or presence of dysplastic naevus as susceptibility factors for MPM development
Younger age of onset in women MPM patients than in men
Subsequent MMs in MPM patients are thinner, more likely Mis than invasive MM, and develop commonly on the same body site with the first MM
Rate of CDKN2A mutations among MPM patients
Frequency of certain CDKN2A SNPs (c.*29 C>G, c.*69 C>T)
Frequency of MC1R non-synonymous variants
Frequency of ‘R’ variants (R151C, R160W, D294H) among MPM patients 2. The following of our observations differed from those reported in the literature, or brought novel results:
Less frequent positive family history of MM among the MPM patients
A higher rate of synchronous first and second MMs
More frequent non-melanoma malignancy occurrence among MPM patients
Two Hungarian MPM patients with CDKN2A mutations (p.E69G, p.R99P)
Lower frequency of CDKN2A SNP A148T
Higher allele and carrier frequency of CDKN2A SNP c.-191 G>A
The lack of presence of two otherwise common MC1R variants (D84E, R142H) among the Hungarian MPM patients
The MC1R R163Q variant to be exceptionally common among Hungarian MPM patients, a variant otherwise frequent in Asia, but not in Europe, supporting the previous findings on geographical differences regarding MC1R variant occurrence.
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Identification of a new MC1R variant firstly in humans (c.350 A>G;p.D117G)
some new potentially unfavorable predictive observations among MC1R ‘R’
carriers compared to MC1R ‘r’ carriers
younger age of onset
MPM co-occurrence with more non-melanoma primary tumors, or with multiple BCCs
more ulcerated first MMs, less ulcerated second MMs
TILs in second MMs (significantly).
Therefore we hypothesize that as already suspected in terms of other MM predisposing genes (CDKN2A), MC1R genotype details may also carry additional useful information concerning patient survival and prognosis if confirmed on bigger sample sizes.
This work is the first Hungarian description of MPM populations regarding cliniopathological and genetic characteristics.
VI.2. Unique MM-associated cases
VI.2.1. Two cancer prone families
We examined two unique cancer prone families and their two common offspring. In family A, an unfavorable coincidence of inherited and environmental risk factors induced the reported new constellation of 4 primary malignancies (MPM, BCC, PrC, LC) in two non-twin siblings. In family B with a dominantly inherited PaC aggregation we could identify only a number of SNPs with unknown significance regarding PaC development. The inheritance of predisposing genetic events from the two families resulted in early onset malignant tumor formation in both of the offspring, in one of them even with fatal outcome. These data also indicate the necessity of a very close follow up of the uninvolved family members too in such cancer prone families.
VI.2.2. Six primary MMs
Immunosuppressed state (also due to immunosuppressive therapy in OTRs) makes one vulnerable to cancer and also to MM development by many mechanisms. Development of six primary MMs in an OTR patient however raises the possibility of an additional genetic susceptibility to MM too. There was a complex interplay between the diverse
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environmental (UV, sun tan habit, combined long term use of harmful pharmacological agents, bad compliance) and genetic (MC1R ‘R’ variant) predisposing factors in the skin tumor formations. This case points out the importance of the careful dermatological follow-up of OTRs under immunosuppressive therapy, and also of their education about the subsequent harmful environmental predisposing factors.
VI.2.3. MM and phenotype suggesting PHTS/CS
As a rare co-aggregation, MM(Mis) was described in a patient with phenotype highly suspicious for PHTS/CS.
Identification of pathogenic genetic loci in rare, unique phenotypes with standard methods (Sanger sequencing) is time, and cost demanding, with many limitations (large deletion or insertions). Therefore such patients may remain without identified genetic background however with clear phenotype.
In this case, although the involvement of a particular signal transduction pathway (PTEN) and other genetic loci (SDHB, SDHD) were highly suspicious, we could not identify the exact underlying genetic disturbance. Germline involvement of further downstream genes in the PTEN/PI3K/AKT pathway (PI3K, AKT1) is possible, that would be of a great interest to study. Next-generation, high throughput techniques (exome-, genome sequencing) would serve to identify rare disease causing mutations in new genes in such cases. To prove PS as other suspicious diagnosis, somatic AKT1 mutation analysis would be diagnostic.
VI.2.4. Conclusions of Unique MM-associated cases:
In unique cancer cases with suspicious genetic predisposition, traditional techniques are helpful for identifying known, rare, highly penetrant disease causing gene mutations. With next-generation sequencing methods, many new data are already available about common, low penetrance alterations in a huge number of genes, and some of them are already linked to certain cancers as additional significant predisposing factors.
In some of our analyzed cases we could not identify mutations in high penetrance genes, but detected a number of more common SNPs, however their
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individual or aggravated significance is not determined. These findings also support the emerging need of further high throughput studies in cases like these, to find associations between common germline or somatic genetic factors and the development of particular tumors or tumor-constellations.
In cancer development, gene-environment interactions are highly diverse with wide variety of causal burden. In our highly civilized lifestyle, many of the additional extrinsic factors and their potential harmful effect on malignant transformation might not have been identified. Even if an environmental factor is proved to be linked to a specific cancer development in general, the complexity of all extrinsic factors and their interplay with the harbored genetic events are hard to define.
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