Other entities represented in this entry:
Cytogenetic location: 1p36 Genomic coordinates (GRCh38) : 1:1-27,600,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36 | {Basal cell carcinoma, susceptibility to, 1} | 605462 | 2 |
Cutaneous basal cell carcinoma (BCC) is the most common cancer among people of European ancestry (Stacey et al., 2009). The primary environmental risk factor for BCC is sun exposure, but genetics also has a substantial role. Some of the sequence variants that confer susceptibility seem to operate through their association with fair-pigmentation traits common among Europeans, resulting in reduced protection from the damaging effects of ultraviolet (UV) radiation. Other sequence variants have no obvious role in pigmentation or UV susceptibility but instead seem to operate in the contexts of growth and differentiation of the basal layers of the skin (Stacey et al., 2008; Epstein, 2008; Gudbjartsson et al., 2008; Rafnar et al., 2009). See ASIP (600201), TYR (606933), and SHEP5 (227240) for examples of basal cell carcinoma associated with fair skin or sensitivity to sun.
Basal cell carcinoma occurs as a feature of multiple syndromes, including basal cell nevus syndrome (BCNS; 109400), Bazex syndrome (301845), Rombo syndrome (180730), Brooke-Spiegler syndrome (605041), Muir-Torre syndrome (158320), and xeroderma pigmentosum (see 278700).
Abnormalities in the Hedgehog signaling pathway are found in basal cell carcinomas; see SHH (600725) and SMOH (601500).
Genetic Heterogeneity of Susceptibility to Basal Cell Carcinoma
Susceptibility to basal cell carcinoma is a genetically heterogeneous trait. The BCC1 locus maps to chromosome 1p36. Also see BCC2 (613058) on 1q42; BCC3 (613059) on 5p15; BCC4 (613061) on 12q13; BCC5 (613062) on 9p21; and BCC6 (613063) on 7q32. Variation in the 3-prime untranslated region of TP53 (191170) increases susceptibility to basal cell carcinoma (BCC7; 614740).
Somatic mutation contributing to the formation of basal cell carcinoma has been identified in the RASA1 (139150), PTCH1 (601309), and PTCH2 (603673) genes.
Basal cell carcinomas are usually managed surgically. Von Hoff et al. (2009) reported the results of a phase I clinical trial using GDC-0449, a small molecule inhibitor of SMO (601500), on metastatic or locally advanced basal cell carcinoma. Of 33 patients followed over a median period of 9.8 months, 18 had an objective response to GDC-0449, 2 with complete resolution and 16 with a partial response. Among the other 15 patients, disease was either stable (11 patients) or progressive (4 patients). Among 6 patients, there were 8 grade 3 adverse events that were deemed to be possibly related to the study drug, including fatigue, hyponatremia, muscle spasm, and atrial fibrillation. One patient withdrew from the study because of adverse events.
In a Ptch1-Trp53 mouse model of BCC, Biehs et al. (2018) found that mice treated with the SMOH inhibitor vismodegib harbored quiescent residual tumors that regrew upon cessation of treatment. Profiling experiments revealed that residual BCCs initiate a transcriptional program that closely resembles that of stem cells of the interfollicular epidermis and isthmus, whereas untreated BCCs are more similar to the hair follicle bulge. This cell identity switch was enabled by a mostly permissive chromatin state accompanied by rapid Wnt (see 604663) pathway activation and reprogramming of superenhancers to drive activation of key transcription factors involved in cellular identity. Accordingly, treatment of BCC with both vismodegib and a Wnt pathway inhibitor reduced the residual tumor burden and enhanced differentiation. Biehs et al. (2018) concluded that their study identified a resistance mechanism in which tumor cells evade treatment by adopting an alternative identity that does not rely on the original oncogenic driver for survival.
Sanchez-Danes et al. (2018) used 2 genetically engineered mouse models of BCC to investigate the mechanisms by which inhibition of SMOH mediates tumor regression, and found that vismodegib mediates BCC regression by inhibiting a hair follicle-like fate and promoting the differentiation of tumor cells. However, a small population of tumor cells persists and is responsible for tumor relapse following treatment discontinuation, mimicking the situation found in humans. In both mouse and human BCC, this persisting, slow-cycling tumor population expresses LGR5 (606667) and is characterized by active Wnt signaling. Combining Lgr5 lineage ablation or inhibition of Wnt signaling with vismodegib treatment leads to eradication of BCC. Sanchez-Danes et al. (2018) concluded that vismodegib induces tumor regression by promoting tumor differentiation, and demonstrated that the synergy between Wnt and Smoothened inhibitors is a clinically relevant strategy for overcoming tumor relapse in BCC.
Happle (2000) postulated that there is an autosomal dominant phenotype characterized by multiple superficial BCC without associated anomalies that is distinct from nevoid basal cell carcinoma syndrome (109400). The author cited 2 lines of evidence in favor of this hypothesis. First, there are several reports of multiple cases of BCC occurring in 2 generations of a family, including male-to-male transmission. Second, there are 3 reports of strictly unilateral manifestation of multiple superficial BCC, suggesting somatic mosaicism. This occurrence is difficult to explain without the assumption that nonsyndromic multiple superficial BCC may occur as a distinct mendelian trait.
Ramachandran et al. (2001) presented evidence suggesting that different mechanisms underlie the development of truncal and nontruncal BCC. They studied 100 patients who, at the time of initial presentation, had truncal BCC lesions and 493 patients who had lesions on the head and neck. The 493 patients with head and neck lesions included 36 patients who subsequently developed truncal BCCs and 457 patients who did not. The mean truncal tumor accrual after initial presentation in patients who presented with initial truncal BCC lesions was 0.13 BCC lesions per year compared with 0.03 BCC lesions per year in patients who presented with initial head and neck lesions (P less than 0.001). Patients with truncal lesions were significantly younger at the time of initial presentation and developed more clusters of BCC lesions (2 to 10 new tumors at any presentation) compared with patients who did not develop tumors on the trunk.
Constitutive Hedgehog (see 600725) signaling underlies several human tumors, including BCC and basaloid follicular hamartoma in skin. Intriguingly, superficial BCCs arise as de novo epithelial buds resembling embryonic hair germs, collections of epidermal cells whose development is regulated by canonical Wnt (164820)/beta-catenin (116806) signaling. Yang et al. (2008) found that similar to embryonic hair germs, human BCC buds showed increased levels of cytoplasmic and nuclear beta-catenin and expressed early hair follicle lineage markers. Yang et al. (2008) also detected canonical Wnt/beta-catenin signaling in epithelial buds and hamartomas from mice expressing an oncogene, M2-SMO (601500.0001), leading to constitutive hedgehog signaling in skin. Conditional overexpression of the Wnt pathway antagonist Dkk1 (605189) in M2SMO-expressing mice potently inhibited epithelial bud and hamartoma development without affecting hedgehog signaling. Yang et al. (2008) concluded that their findings uncovered a hitherto unknown requirement for ligand-driven, canonical Wnt/beta-catenin signaling for hedgehog pathway-driven tumorigenesis, identified a new pharmacologic target for these neoplasms, and established the molecular basis for the well-known similarity between early superficial BCCs and embryonic hair germs.
In a genomewide SNP association study of 930 Icelanders with BCC and 33,117 controls, Stacey et al. (2008) observed signals from loci at chromosomes 1p36 and 1q42 (BCC2; 613058). These associations were replicated in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, p = 4.4 x 10(-12)) and rs801114 on 1q42 (OR = 1.28, p = 5.9 x 10(-12)). Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Stacey et al. (2008) estimated that approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers. The 1p36 SNP rs7538876 is in intron 13 of the peptidylarginine deiminase-6 gene (PADI6; 610363). The A allele of rs7538876 was associated with a younger age at diagnosis of BCC in both Icelandic and Eastern European samples (P = 6.0 x 10(-4)).
Friedman et al. (1993) analyzed 188 human tumor samples for mutations within the catalytic domain of the GAP gene and for mutations within its C-terminal SH2 region. Although no mutations could be demonstrated in the catalytic domain, 3 different nonsense mutations in the SH2 region were observed in basal cell carcinomas (e.g., 139150.0001). The region in which the mutations were clustered is A/T rich, raising the possibility that UV radiation is a contributing factor.
Using single-strand conformation polymorphism (SSCP), Gailani et al. (1996) screened 37 sporadic BCCs for mutations in the PTCH1 gene and found mutations in 16 (e.g., 601309.0009). Variants in 4 of these 16 were also found in constitutional DNA, and each had been found in at least 12% of normal controls. Nine of the 12 tumor-specific alterations were in the remaining allele of tumors with loss of heterozygosity (LOH) for 9q22, and in 3 tumors without LOH a single variant was found.
Of 26 sporadic BCC screened by Aszterbaum et al. (1998) for mutations in PTCH1, 3 had PTCH1 mutations (e.g., 601309.0010), each in a different exon of the gene. Each of these 3 had sustained deletion of the second allele. Aszterbaum et al. (1998) concluded that PTCH1 acts as a classic tumor suppressor gene, requiring 2 'hits' for tumorigenesis in at least some BCC.
Using SSCP and heteroduplex analysis, Smyth et al. (1999) identified a nucleotide substitution in the splice donor site of exon 20 of the PTCH2 gene (603673.0002) in a basal cell carcinoma.
Aszterbaum, M., Rothman, A., Johnson, R. L., Fisher, M., Xie, J., Bonifas, J. M., Zhang, X., Scott, M. P., Epstein, E. H., Jr. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J. Invest. Derm. 110: 885-888, 1998. [PubMed: 9620294] [Full Text: https://doi.org/10.1046/j.1523-1747.1998.00222.x]
Biehs, B., Dijkgraaf, G. J. P., Piskol, R., Alicke, B., Boumahdi, S., Peale, F., Gould, S. E., de Sauvage, F. J. A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition. Nature 562: 429-433, 2018. [PubMed: 30297801] [Full Text: https://doi.org/10.1038/s41586-018-0596-y]
Epstein, E. H. Basal cell carcinomas: attack of the hedgehog. Nature Rev. Cancer 8: 743-754, 2008. [PubMed: 18813320] [Full Text: https://doi.org/10.1038/nrc2503]
Friedman, E., Gejman, P. V., Martin, G. A., McCormick, F. Nonsense mutations in the C-terminal SH2 region of the GTPase activating protein (GAP) gene in human tumours. Nature Genet. 5: 242-247, 1993. [PubMed: 8275088] [Full Text: https://doi.org/10.1038/ng1193-242]
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Gudbjartsson, D. F., Sulem, P., Stacey, S. N., Goldstein, A. M., Rafner, T., Sigurgeirsson, B., Benediktsdottir, K. R., Thorisdottir, K., Ragnarsson, R., Sveinsdottir, S. G., Magnusson, V., Lindblom, A., and 26 others. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nature Genet. 40: 886-891, 2008. Note: Erratum: Nature Genet. 40: 1029 only, 2008. [PubMed: 18488027] [Full Text: https://doi.org/10.1038/ng.161]
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Ramachandran, S., Fryer, A. A., Smith, A., Lear, J., Bowers, B., Jones, P. W., Strange, R. C. Cutaneous basal cell carcinomas: distinct host factors are associated with the development of tumors on the trunk and on the head and neck. Cancer 92: 354-358, 2001. [PubMed: 11466690] [Full Text: https://doi.org/10.1002/1097-0142(20010715)92:2<354::aid-cncr1330>3.0.co;2-f]
Sanchez-Danes, A., Larsimont, J.-C., Liagre, M., Munoz-Couselo, E., Lapouge, G., Brisebarre, A., Dubois, C., Suppa, M., Sukumaran, V., del Marmol, V., Tabernero, J., Blanpain, C. A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy. Nature 562: 434-438, 2018. [PubMed: 30297799] [Full Text: https://doi.org/10.1038/s41586-018-0603-3]
Smyth, I., Narang, M. A., Evans, T., Heimann, C., Nakamura, Y., Chenevix-Trench, G., Pietsch, T., Wicking, C., Wainwright, B. J. Isolation and characterization of human Patched 2 (PTCH2), a putative tumour suppressor gene in basal cell carcinoma and medulloblastoma on chromosome 1p32. Hum. Molec. Genet. 8: 291-297, 1999. [PubMed: 9931336] [Full Text: https://doi.org/10.1093/hmg/8.2.291]
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Von Hoff, D. D., LoRusso, P. M., Rudin, C. M., Reddy, J. C., Yauch, R. L., Tibes, R., Weiss, G. J., Borad, M. J., Hann, C. L., Brahmer, J. R., Mackey, H. M., Lum, B. L., Darbonne, W. C., Marsters, J. C., Jr., de Sauvage, F. J., Low, J. A. Inhibition of the hedgehog pathway in advance basal-cell carcinoma. New Eng. J. Med. 361: 1164-1172, 2009. [PubMed: 19726763] [Full Text: https://doi.org/10.1056/NEJMoa0905360]
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