Cancer Risk in Patients With PTEN Hamartoma Tumor Syndrome
Cancer Risk in Patients With PTEN Hamartoma Tumor Syndrome
BackgroundPTEN hamartoma tumour syndrome (PHTS) encompasses several clinical syndromes with germline mutations in the PTEN tumour suppressor gene, including Cowden syndrome which is characterised by an increased risk of breast and thyroid cancers. Because PHTS is rare, data regarding cancer risks and genotype–phenotype correlations are limited. The objective of this study was to better define cancer risks in this syndrome with respect to the type and location of PTEN mutations.
Methods 154 PHTS individuals with a deleterious germline PTEN mutation were recruited from the activity of the Institut Bergonié genetic laboratory. Detailed phenotypic information was obtained for 146 of them. Age and sex adjusted standardised incidence ratio (SIR) calculations, cumulative cancer risk estimations, and genotype–phenotype analyses were performed.
Results Elevated SIRs were found mainly for female breast cancer (39.1, 95% CI 24.8 to 58.6), thyroid cancer in women (43.2, 95% CI 19.7 to 82.1) and in men (199.5, 95% CI 106.39 to 342.03), melanoma in women (28.3, 95% CI 7.6 to 35.4) and in men (39.4, 95% CI 10.6 to 100.9), and endometrial cancer (48.7, 95% CI 9.8 to 142.3). Cumulative cancer risks at age 70 were 85% (95% CI 70% to 95%) for any cancer, 77% (95% CI 59% to 91%) for female breast cancer, and 38% (95% CI 25% to 56%) for thyroid cancer. The risk of cancer was two times greater in women with PHTS than in men with PHTS (p<0.05).
Conclusions This study shows a considerably high cumulative risk of cancer for patients with PHTS, mainly in women without clear genotype–phenotype correlation for this cancer risk. New recommendations for the management of PHTS patients are proposed.
Cowden syndrome (CS) is an autosomal dominant inherited disorder characterised by macrocephaly, benign lesions that can develop in many organs, and an increased risk of breast, thyroid and possibly other cancers. It is allelic to other seemingly unrelated clinical syndromes including the paediatric form Bannayan–Riley–Ruvalcaba syndrome (BRRS), Lhermitte–Duclos disease (LDD), SOLAMEN (segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus) syndrome, macrocephaly/autism syndrome, and juvenile polyposis syndrome, which are collectively referred to as PTEN hamartoma tumour syndrome (PHTS).
The PTEN gene, located on chromosome 10q23.3, encodes a dual specificity phosphatase that plays a tumour suppression role by negatively regulating the PI3K/Akt/mTOR cell survival signalling pathway. The PTEN structure reveals two main domains: the phosphatase domain (aa 7–185) which contains the PTEN active site in exon 5; and the C2 domain (aa 186–351) which binds phospholipids and positions the catalytic domain on the membrane.
Although it is generally accepted that CS patients show an elevated risk for breast and thyroid cancers, with risks generally being reported around 25–50% for breast cancer and 3–10% for thyroid cancer, more recent studies have revealed a higher risk for breast and thyroid cancers and have extended this elevated risk to other cancer sites including endometrial, kidney, colorectal cancers, and melanoma.
Because CS is rare and diagnosis difficult due to highly variable expressivity, data regarding genotype–phenotype correlations are limited and mostly based on a collection of case series, each generally comprising a small number of patients. To date, most studies have failed to demonstrate a consistent genotype–phenotype correlation in CS. This study aims to clarify these issues by: (1) collecting phenotypic and molecular data in a large series of PHTS patients sharing a deleterious germline PTEN mutation; (2) assessing cancer risks in these patients; and (3) investigating if a correlation exists between genotype and cancers, but also between genotype and non-malignant findings of the PHTS. The information generated by our data will also allow us to clarify and adapt surveillance recommendations.
Abstract and Introduction
Abstract
BackgroundPTEN hamartoma tumour syndrome (PHTS) encompasses several clinical syndromes with germline mutations in the PTEN tumour suppressor gene, including Cowden syndrome which is characterised by an increased risk of breast and thyroid cancers. Because PHTS is rare, data regarding cancer risks and genotype–phenotype correlations are limited. The objective of this study was to better define cancer risks in this syndrome with respect to the type and location of PTEN mutations.
Methods 154 PHTS individuals with a deleterious germline PTEN mutation were recruited from the activity of the Institut Bergonié genetic laboratory. Detailed phenotypic information was obtained for 146 of them. Age and sex adjusted standardised incidence ratio (SIR) calculations, cumulative cancer risk estimations, and genotype–phenotype analyses were performed.
Results Elevated SIRs were found mainly for female breast cancer (39.1, 95% CI 24.8 to 58.6), thyroid cancer in women (43.2, 95% CI 19.7 to 82.1) and in men (199.5, 95% CI 106.39 to 342.03), melanoma in women (28.3, 95% CI 7.6 to 35.4) and in men (39.4, 95% CI 10.6 to 100.9), and endometrial cancer (48.7, 95% CI 9.8 to 142.3). Cumulative cancer risks at age 70 were 85% (95% CI 70% to 95%) for any cancer, 77% (95% CI 59% to 91%) for female breast cancer, and 38% (95% CI 25% to 56%) for thyroid cancer. The risk of cancer was two times greater in women with PHTS than in men with PHTS (p<0.05).
Conclusions This study shows a considerably high cumulative risk of cancer for patients with PHTS, mainly in women without clear genotype–phenotype correlation for this cancer risk. New recommendations for the management of PHTS patients are proposed.
Introduction
Cowden syndrome (CS) is an autosomal dominant inherited disorder characterised by macrocephaly, benign lesions that can develop in many organs, and an increased risk of breast, thyroid and possibly other cancers. It is allelic to other seemingly unrelated clinical syndromes including the paediatric form Bannayan–Riley–Ruvalcaba syndrome (BRRS), Lhermitte–Duclos disease (LDD), SOLAMEN (segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus) syndrome, macrocephaly/autism syndrome, and juvenile polyposis syndrome, which are collectively referred to as PTEN hamartoma tumour syndrome (PHTS).
The PTEN gene, located on chromosome 10q23.3, encodes a dual specificity phosphatase that plays a tumour suppression role by negatively regulating the PI3K/Akt/mTOR cell survival signalling pathway. The PTEN structure reveals two main domains: the phosphatase domain (aa 7–185) which contains the PTEN active site in exon 5; and the C2 domain (aa 186–351) which binds phospholipids and positions the catalytic domain on the membrane.
Although it is generally accepted that CS patients show an elevated risk for breast and thyroid cancers, with risks generally being reported around 25–50% for breast cancer and 3–10% for thyroid cancer, more recent studies have revealed a higher risk for breast and thyroid cancers and have extended this elevated risk to other cancer sites including endometrial, kidney, colorectal cancers, and melanoma.
Because CS is rare and diagnosis difficult due to highly variable expressivity, data regarding genotype–phenotype correlations are limited and mostly based on a collection of case series, each generally comprising a small number of patients. To date, most studies have failed to demonstrate a consistent genotype–phenotype correlation in CS. This study aims to clarify these issues by: (1) collecting phenotypic and molecular data in a large series of PHTS patients sharing a deleterious germline PTEN mutation; (2) assessing cancer risks in these patients; and (3) investigating if a correlation exists between genotype and cancers, but also between genotype and non-malignant findings of the PHTS. The information generated by our data will also allow us to clarify and adapt surveillance recommendations.
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